Congenital and Partial Genetic Lipodystrophies

Congenital generalised lipodystrophy (Berardinelli–Seip syndrome; AGPAT2, BSCL2, CAV1, CAVIN1, biallelic PPARG and PCYT1A), familial partial lipodystrophies (LMNA-related Dunnigan type; PPARG, PLIN1, CIDEC, LIPE, AKT2, MFN2, CAV1 and forms without an identified monogenic cause) and lipodystrophies with neurological involvement (seipinopathies, CAV1, proteasome-associated autoinflammatory syndromes and progeroid forms). Cardiomyopathy and arrhythmias in laminopathies (dilated cardiomyopathy, progressive cardiac conduction disease, left ventricular noncompaction and Emery–Dreifuss muscular dystrophy) and Hutchinson–Gilford progeria appear as related entities.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From the earliest descriptions to adipose failure

The earliest descriptions of pathological adipose tissue loss, in the 19th century, concerned acquired forms, including progressive subcutaneous fat loss beginning in the face and upper half of the body, later named Barraquer–Simons. In 1946, Lawrence described a woman with severe adipose deficiency, insulin-resistant diabetes, hypertriglyceridaemia and hepatic steatosis and proposed that adipose tissue's inability to store energy was central to the disease, an interpretation revisited by the 2026 European consensus in defining lipodystrophy as expression of obesity complications (type 2 diabetes, MASLD, accelerated atherosclerosis and subfertility) in people without obesity [5]. Lawrence's name became associated with acquired generalised lipodystrophy (AGL, acquired generalized lipodystrophy), outside this article's genetic scope but included in the differential diagnosis [1, 69].

Congenital generalised disease was described by Berardinelli from two Brazilian patients published in 1954 under the title “An undiagnosed endocrinometabolic syndrome” [1, 70]. In 1959, Martin Seip described Norwegian patients from Rogaland county, hypothesising a diencephalic syndrome with lipodystrophy and gigantism, and in 1963 published a generalised lipodystrophy series with Trygstad [1, 71, 72]. The two Norwegian dates correspond to distinct publications, Seip's first description in 1959 and the 1963 article, explaining differing dates in GeneReviews and some dysmorphology textbooks [1, 4]. Senior and Gellis brought together total and partial lipodystrophy syndromes in 1964 [4]. Brunzell syndrome, combining bone cysts and lipoatrophic diabetes in five African-American siblings, is now considered a rare CGL complication after Fu and colleagues found biallelic AGPAT2 variants in three of those siblings [1, 73].

The dominant partial form was described in 1974 by Dunnigan, Cochrane, Kelly and Scott under the title “Familial lipoatrophic diabetes with dominant transmission. A new syndrome” [74]. Köbberling became associated with a partial form in which lipoatrophy is restricted to limbs and gluteal regions, with preserved or increased facial and truncal fat and no identified monogenic cause [11, 45].

1.2. Milestones in molecular discovery

The turn of the 21st century brought together two types of evidence. On the one hand, mice with almost total ablation of white adipose tissue reproduced severe insulin resistance, steatosis and premature death; on the other, positional cloning identified the first human genes [5]. In 2000, Shackleton and colleagues localised the partial lipodystrophy locus to chromosome 1q and found five different missense variants in LMNA in ten families and three individuals, in a gene already associated with autosomal dominant Emery–Dreifuss muscular dystrophy and dilated cardiomyopathy 1A, which revealed distinct functional domains of lamin A/C [75]. The same year, Hegele and colleagues showed, in Canadian families sharing a common ancestor, that the variant p.Arg482Gln (NM_170707.4:c.1445G>A) segregated with partial lipodystrophy, hyperinsulinaemia, dyslipidaemia, hypertension and diabetes, and that lipid abnormalities preceded glycaemic changes [76]. In 1999, Barroso and colleagues had described the first germline loss-of-function variants in PPARG, with a dominant-negative effect, in three individuals with severe insulin resistance, type 2 diabetes and early-onset hypertension [77].

In CGL, Magré and colleagues identified the BSCL2 locus at 11q13 in 2001 from Lebanese and Norwegian families and a gene homologous to murine Gng3lg, naming its protein seipin; in that series, 11 of 20 additional families were linked to 11q13 and the remainder to 9q34 [78]. In 2002, Agarwal and colleagues found AGPAT2 variants in 20 affected individuals from 11 families linked to 9q34 [79]. “Gng3lg”, still present in gene tables in recent textbooks, is historical nomenclature for the BSCL2 locus and should not be presented as a current gene [73, 80]. These were followed by CAV1 in 2008, a homozygous nonsense variant in a patient born to a consanguineous union [81], and CAVIN1 (then PTRF) in 2009, in five Japanese patients with generalised lipodystrophy and muscular dystrophy [82], with fatal arrhythmia and long QT in CGL4 described in 2010 [83]. Partial forms brought AKT2 in 2004 [84], CIDEC in 2009 [85], PLIN1 in 2011 [86], LIPE in 2014 with the Amish founder variant [87, 88], PCYT1A in 2014 [89] and MFN2 in 2017 [90].

Leptin replacement therapy had its first study in 2002, when Oral and colleagues treated nine women with lipodystrophy and leptin below 4 ng/mL, obtaining reductions of 1.9 points in glycated haemoglobin (HbA1c) and 60 % in triglycerides (TG) after four months [91]. Metreleptin was approved in Japan in 2013, the United States in February 2014 and the European Union in July 2018 [64, 65, 92].

1.3. Nomenclature, reclassifications and guidelines

The 2016 multi-society guideline, developed by 17 participants nominated by endocrine societies and graded according to the American Heart Association system (classes I, IIa, IIb and III; levels A, B and C), remains the latest multi-society diagnostic and treatment guideline; it divides lipodystrophies into four main categories, CGL, FPLD, AGL and acquired partial lipodystrophy (APL), with progeroid and autoinflammatory subtypes, and excludes human immunodeficiency virus (HIV)-associated forms and localised injectable drug-related forms [60]. The European Consortium of Lipodystrophies (ECLip), founded in 2014, published a consensus definition and candidate-gene evidence classification scheme in September 2026, which does not replace the therapeutic guideline [5]. Other documents are the 2025 Brazilian FPLD consensus, the 2021 Japan Endocrine Society guideline and a position endorsed by the Hellenic Endocrine Society published in February 2026 [11, 65, 93].

The GeneReviews chapter on Berardinelli–Seip syndrome, last comprehensively updated in December 2016, was retired on 11 June 2026 owing to outdated content; data used from it here are presented as historical and compared with later sources [1]. Some reference works contain errors that should not be reproduced: a dysmorphology text assigns types 1 and 2 to AGPAT2, whereas type 1 corresponds to AGPAT2 and type 2 to BSCL2 [1, 4], and a gene table places AGPAT2 at 9q31, whereas the cytoband is 9q34.3 [6, 80].

1.4. Definition of the entities

ECLip defines lipodystrophy as deficient development and/or inadequate maintenance of adipose tissue not attributable to nutritional deprivation or a systemic catabolic state; loss may be generalised or regional, coexist with expansion of other depots (the person may even meet obesity criteria) and is, as far as is known, irreversible. Total adipose mass is insufficient for diagnosis, particularly in partial forms, and adipose failure (insulin resistance and/or diabetes, hypertriglyceridaemia, low HDL cholesterol and MASLD) is the hallmark of most clinically significant forms; in lean individuals, diagnosis requires evidence of metabolic dysfunction and/or adipose histology [5].

CGL is the autosomal recessive form in which generalised lipoatrophy is associated with acromegaloid features, muscular hypertrophy, insulin resistance, hypertriglyceridaemia and hepatic steatosis, with antenatal, neonatal or early-childhood onset [2]. FPLD is a group of genetic lipodystrophies in which fat is lost from limbs and gluteal regions from childhood or early adulthood in most cases, frequently with acanthosis nigricans, insulin resistance, diabetes, hypertriglyceridaemia and hepatic steatosis [12]. Dunnigan-type FPLD is characterised by subcutaneous fat loss from trunk, buttocks and limbs, accumulation in neck, face, axillae and pelvic region, muscular hypertrophy and metabolic complications [3].

2. Molecular Genetics and Pathophysiology

2.1. The lipid droplet and triglyceride synthesis pathway

The adipocyte stores energy as triglycerides in a giant lipid droplet. Synthesis begins with glycerol-3-phosphate, converted by GPAT to lysophosphatidic acid; AGPAT acylates the latter to phosphatidic acid, which lipins (phosphatidic acid phosphatases) convert to diacylglycerol, and DGAT completes triglyceride synthesis [88]. Droplet formation requires structural proteins: seipin, a circular endoplasmic reticulum (ER) dodecamer interacting with AGPAT2, marks formation sites and enables droplet budding from the ER; CIDE family proteins, including CIDEC (FSP27), promote fusion into large droplets; and perilipins coat the droplet, perilipin 1 being most abundant in adipocytes. Lipolysis depends on adipose triglyceride lipase (ATGL, with coactivator CGI-58), releasing diacylglycerol, and hormone-sensitive lipase (HSL), converting it to monoacylglycerol; β-adrenergic stimulation and low insulin favour perilipin 1 and HSL phosphorylation by protein kinase A [88]. Seipin, CIDEC and perilipin 1 defects cause lipodystrophy, as do defects in AGPAT2, HSL and CTP:phosphocholine cytidylyltransferase alpha (CCTα, encoded by PCYT1A) [88].

Physiological consequences result from inability to store energy in adipose tissue. Lipids accumulate in liver, muscle and other organs, leptin and adiponectin secretion falls, hyperphagia increases energy intake and hepatic and peripheral insulin resistance develops, with hypertriglyceridaemia, diabetes and steatosis [6, 60]. In generalised disease, the measurable downstream deficiency is hypoleptinaemia, replaced by metreleptin [6, 63].

2.2. Genetic architecture and evidence level

In the GeneReviews series, 92 of 94 affected individuals with CGL had BSCL2 or AGPAT2 variants or linkage to these loci (Magré 2003) and 44 of 47 in a second series (Agarwal), supporting the approximately 95 % proportion stated in a dysmorphology textbook [1, 4]. A metabolic diseases text states that combined AGPAT2 and seipin deficiencies explain “approximately half” of severe CGL patients, citing Magré 2001 [88]. The divergence is explained by period and method: the 2001 work predates AGPAT2 identification and relied on linkage, whereas later series sequenced both genes; CAV1, CAVIN1, biallelic PPARG and PCYT1A were subsequently added, explaining a small fraction of cases [1, 60, 78, 79]. None of the sources consulted presents a recent unselected cohort re-estimating this proportion.

The 2016 guideline groups genes by inheritance: in autosomal recessive CGL, AGPAT2, BSCL2, CAV1, PTRF (CAVIN1), PCYT1A and PPARG; in autosomal dominant FPLD, LMNA, PPARG, AKT2 and PLIN1; in autosomal recessive FPLD, CIDEC, LIPE and PCYT1A; in progeroid syndromes, LMNA, ZMPSTE24, SPRTN, WRN, BANF1 (AR) and LMNA, FBN1, CAV1, POLD1, KCNJ6 (AD); in SHORT syndrome, PIK3R1; and in the autoinflammatory form, PSMB8 [60].

The 2026 ECLip consensus proposed a two-axis evidence scheme. On the human axis, H1 (confirmed) requires robust anatomical deficiency and robust adipose failure (insulin resistance with low HDL, high TG or MASLD) and/or histology, with more than three unrelated families or one family with more than four affected individuals and clear cosegregation; H2 (probable) requires at least suggestive anatomical and functional evidence with two to three cosegregating affected individuals; H3A corresponds to one affected individual or imperfect cosegregation; H3B to reduced adipose tissue with a plausible non-lipodystrophic explanation and without adipose failure; H4 to absent evidence and H5 to refutation. On the biological axis, B1 requires an animal model recapitulating the phenotype and/or a cellular model with impaired adipogenesis, lipogenesis or lipolysis, B2 altered gene function without specific abnormalities and B0 absent evidence; allele frequency and gnomAD constraint are weighed against prevalence. “Perfect” cosegregation allows non-manifestation during negative energy balance or in lean prepubertal individuals [5].

ECLip retains separate human, genetic and experimental evidence levels without competing with ClinGen's gene–disease validity classification, which assigns a single score [5]. In ClinGen, PPARG–FPLD3 is “Definitive” with semidominant inheritance, CIDEC–FPLD “Moderate” (July 2026), AKT2–FPLD “Limited” and MFN2–multiple symmetric lipomatosis “Definitive” autosomal recessive [14, 16, 18, 19].

2.3. AGPAT2 and congenital generalised lipodystrophy type 1

AGPAT2 (9q34.3; MANE Select reference transcript NM_006412.4) has six exons spanning less than 20 kb and encodes a 278-amino-acid protein, 1-acylglycerol-3-phosphate O-acyltransferase 2 (LPAAT-β), an ER enzyme acylating the sn-2 position of lysophosphatidic acid to form phosphatidic acid, the second step in de novo glycerophospholipid and triacylglycerol synthesis; it is the isoform on which adipose tissue depends and its messenger RNA is highly expressed there [1, 6, 79, 94]. Loss of function reduces adipocyte triacylglycerol synthesis and storage and may increase tissue lysophosphatidic acid, with adipocyte toxicity [1].

The spectrum includes frameshift, nonsense, splicing and missense variants and single-amino-acid deletions. The GeneReviews list, supplied by the author without independent classification verification by the editorial team, includes recurrent c.183-2A>G (historical designation IVS1-2A>G); c.182+1G>A; c.194G>A p.(Trp65Ter); c.202C>T p.(Arg68Ter); c.299G>A p.(Ser100Asn); c.335C>T p.(Pro112Leu); c.492+1G>A; recurrent c.493-1G>C; recurrent deletion of exons 3 and 4; c.514G>A p.(Glu172Lys); c.538del p.(Asp180ThrfsTer73); recurrent c.589-2A>G (IVS4-2A>G); c.646A>T p.(Lys216Ter); c.661+2T>G; c.676C>T p.(Gln226Ter); c.713C>G p.(Ala238Gly); and c.755_763del p.(Met252_Thr254del), described on NM_006412.3 [1]. In variants validated on the MANE transcript, c. numbering remains unchanged: c.589-2A>G corresponds to NC_000009.12:g.136674809T>C and c.202C>T p.(Arg68Ter) to g.136677537G>A [94]. Variant c.589-2A>G affects splicing and the 2016 guideline describes its protein consequence as p.(Val197GlufsTer32) [60, 94]. Almost all CGL patients of African origin carry c.589-2A>G [1]. There is no relationship between variant location or type and severity of lipodystrophy or metabolic complications [1]. The Turkish national study described four new AGPAT2 variants (c.144C>A, c.667_705delinsCTGCG, c.268del and c.316+1G>T), whose transcript is not stated in the abstract [95].

2.4. BSCL2, seipin and allelic diseases

BSCL2 (11q12.3) has 11 exons spanning at least 14 kb and produces 1.8, 2.0 and 2.4 kb transcripts; the 1.8 and 2.4 kb transcripts are ubiquitous and the 2.0 kb transcript selectively highly expressed in brain and testes, a pattern invoked to explain intellectual impairment, voracious appetite and macrogenitosomia in type 2 [1]. Seipin is a multipass ER protein that, with LDAF1, marks lipid droplet formation sites, directs triacylglycerol aggregation in the nascent core and budding; in early adipogenesis it restricts GPAT3 and GPAT4, preventing phosphatidic acid accumulation and blockage of PPARγ-directed differentiation, and is essential to adipocyte maturation [7]. A dual role has been proposed, inhibiting droplet formation in non-adipose cells and promoting adipogenesis, and interaction with neurotransmission as a possible basis of intellectual impairment; in mice, seipin reduction decreases AGPAT2 and DGAT2 expression [1].

Nomenclature requires care. Historical literature uses the short 398-amino-acid isoform (NM_032667, NP_116056.3), whose numbering GeneReviews retained to avoid inconsistencies, whereas MANE Select is the long isoform NM_001122955.4 (NP_001116427.1, 462 amino acids), differing by 192 nucleotides and 64 amino acids [1, 94]. The encephalopathy-associated exon 7 variant is designated c.793C>T p.(Arg265Ter) on NM_032667 and c.985C>T p.(Arg329Ter) on NM_001122955.4; these are the same variant (NC_000011.10:g.62691300G>A), described on different transcripts rather than two distinct variants [1, 20, 94].

The remaining variants in the GeneReviews list, on NM_032667.5, include c.142C>T p.(Leu48Phe), c.154_155dup p.(Tyr53SerfsTer40), c.193delinsGGA p.(Pro65ArgfsTer28), c.574-2A>G, c.672-3C>G, c.672-2A>C, c.672-2A>G, c.671+5G>A, c.634G>C p.(Ala212Pro), described in Norwegian patients and displacing adiposomes to the nuclear membrane–ER junction, c.782dup p.(Ile262HisfsTer12) and c.823C>T p.(Arg275Ter), producing malformed droplets; a large deletion and a large insertion-deletion have also been described [1]. Most CGL2 variants are frameshift or premature termination variants [1, 78]. With one exception, there is no correlation between variant location or type and phenotype, including intellectual impairment, and individuals with the same variant may be discordant for this feature [1]. The exception is the exon 7 variant: in five Spanish infants, homozygous or compound heterozygous, lipodystrophy was followed after a few months by neurological regression and death [1, 97]. Exon 7 skipping generates an aberrant isoform, lethal in homozygosity and compound heterozygosity with another CGL2 allele, causing early-onset progressive encephalopathy (OMIM 615924), also called Celia's encephalopathy, with rapid cortical and basal ganglia neurodegeneration, motor and cognitive regression in the early years, seizures, tremor, ataxic gait and death frequently in the first decade; the lipodystrophic appearance may be mild or typical [7, 20, 26, 88].

Heterozygous BSCL2 variants eliminating the N-glycosylation motif, p.Asn88Ser and p.Ser90Leu in historical numbering, cause misfolded protein, ER accumulation, ER stress and cell death, a toxic gain of function manifesting as autosomal dominant neurological seipinopathy: Silver syndrome, distal hereditary motor neuropathy type V, spastic paraplegia 17 (SPG17) and Charcot–Marie–Tooth type 2 (CMT2) variants [20, 98]. Through this mechanism, null variant heterozygotes, such as parents of a child with CGL2, do not have neurological disease, and CGL patients do not usually develop upper or lower motor neuron signs [20, 88]. Progressive myoclonic epilepsy may occur with or without lipodystrophy in CGL2 patients, and seipinopathy appears among complex lipid defects causing dystonia, spasticity and epilepsy [4, 99].

2.5. CAV1, CAVIN1 and caveolae

Caveolin-1, encoded by CAV1 (7q31.2; MANE NM_001753.5), is the main structural protein of caveolae, plasma membrane invaginations abundant in adipocytes, and is also present in lipid droplets [8, 94]. Cavin-1, encoded by CAVIN1 (17q21.2; MANE NM_012232.6; formerly PTRF), is essential for caveola formation and caveolin stabilisation; in CGL4 patients, biopsies show deficiency and mislocalisation of all three caveolins and reduced caveolae, and fibroblasts have less than 3 % of normal caveolae [1, 9, 82, 83]. These data confirm caveolin deficiency as a cause of the lipodystrophic process [1].

CAV1 has three distinct gene–disease relationships. Biallelic loss-of-function variants cause CGL3, with almost complete absence of adipose tissue from infancy; the first description was the homozygous nonsense variant NM_001753.5:c.112G>T p.(Glu38Ter), which affects the alpha and beta isoforms and abolishes expression in fibroblasts [8, 81]. Heterozygous loss-of-function variants cause heritable pulmonary arterial hypertension (PAH) with reduced penetrance, accounting for less than 1 % of heritable PAH (10 of 2572 PAH Biobank patients) [8]. Heterozygous de novo null variants cause a neonatal-onset progeroid generalised lipodystrophy, with thin mottled skin from birth, congenital or early cataracts and PAH, a phenotype that OMIM groups, together with that of a family with an inherited variant, partial lipodystrophy, congenital cataracts and late-onset neurological disease, under the FPLD7 entry (OMIM 606721; alternative title “partial lipodystrophy, congenital cataracts, with or without neurodegeneration syndrome”); cataracts are the feature common to both presentations (section 3.10) [8, 11, 32, 100].

2.6. Biallelic PPARG and PCYT1A

Nuclear receptor PPARγ, encoded by PPARG (3p25.2), is the master regulator of adipocyte differentiation and the pharmacological target of thiazolidinediones [14]. Biallelic variants cause an autosomal recessive CGL form with neonatal or childhood onset (ORPHA:696242), described only in classification by the sources consulted [60, 101].

PCYT1A encodes CCTα, the enzyme catalysing the rate-limiting step in the Kennedy pathway of phosphatidylcholine synthesis, the principal membrane phospholipid [10, 88]. The gene has three presentations without obvious clinical overlap: spondylometaphyseal dysplasia with cone–rod dystrophy (the main phenotype), isolated retinal dystrophy and lipodystrophy with extreme insulin resistance, hypertriglyceridaemia, steatosis, diabetes, short stature and low HDL, without retinal or skeletal involvement [10, 89]. Classification of this form differs between sources. The original article describes congenital lipodystrophy and a metabolic diseases text describes two unrelated women with partial lipodystrophy, without skeletal or visual abnormalities, placing CCTα deficiency among partial forms [88, 89]. A curated gene database calls it congenital generalised lipodystrophy type 5 (OMIM 620680), the 2016 guideline places PCYT1A among both CGL and autosomal recessive FPLD genes, and ECLip classifies the association as probable (H2B1), illustrating it with a boy diagnosed at 10 years [5, 10, 60]. The more cautious designation is “PCYT1A-related lipodystrophy”, with distribution documented individually.

2.7. LMNA and familial partial lipodystrophy type 2 (Dunnigan)

LMNA (1q22; MANE NM_170707.4, lamin A) encodes lamins A and C, intermediate filaments of the nuclear lamina, through alternative splicing [13, 94, 102]. FPLD2 is autosomal dominant and caused by missense variants; most involve arginine 482, a basic residue in the globular tail domain replaced by a neutral residue [11, 13, 103]. On MANE, codon 482 variants are c.1444C>T p.(Arg482Trp) (NC_000001.11:g.156136984C>T), c.1445G>A p.(Arg482Gln) (g.156136985G>A) and c.1445G>T p.(Arg482Leu) (g.156136985G>T) [94]. Variant c.575A>T p.(Asp192Val), outside codon 482, illustrates Dunnigan-type FPLD in the 2016 guideline [60, 94]. LMNA accounts for approximately 80 % of FPLD with a known genetic cause in clinical series [11]. In the pathophysiological model described, adipocytes degenerate at puberty, followed by abnormal fat deposition [13].

The variant p.Arg482Gln has a founder effect in Canadian families and, in the rural Pennsylvania DiscovEHR cohort, accounted for 16 of 30 genetic cases [57, 76]. Variant location modulates the cardiac phenotype: in a cohort of 122 patients with FPLD, LMNA variants outside codon 482 were associated with more arrhythmias, atrial fibrillation or flutter and conduction disease than those at codon 482 [61]. The variant NM_170707.4:c.1045C>T p.(Arg349Trp) causes a phenotype with lipodystrophy, nephrotic-range proteinuria and focal segmental glomerulosclerosis (FSGS), with loss of interaction between lamin A/C and nucleoporin 155, whereas carriers of missense variants at Arg482 have a very low risk of progressive chronic kidney disease [94, 104]. The variants NP_733821.1 (NM_170707.4) p.(Thr528Arg), p.(Arg527Pro), p.(Arg541Pro) and p.(Arg453Trp), published designation at protein level, were described in five families with overlapping FPLD2 and Emery–Dreifuss muscular dystrophy [105]. Severe semidominant lipodystrophic laminopathy (ORPHA:280365, seven cases) combines severe partial lipoatrophy of the limbs, trunk and abdomen with faciocervical accumulation, diabetes, acanthosis, steatosis, hypertriglyceridaemia, low leptin and adiponectin and severe rhythm and conduction disorders [51].

LMNA has allelic diseases beyond the scope of this article: dilated cardiomyopathy with conduction disease, in which sudden death may occur with minimal systolic dysfunction; Emery–Dreifuss muscular dystrophy; limb-girdle muscular dystrophy 1B; CMT2B1, autosomal recessive; mandibuloacral dysplasia type A, autosomal recessive; Hutchinson–Gilford progeria, due to the synonymous variant NM_170707.4:c.1824C>T p.(Gly608=), which generates progerin through a different toxic gain-of-function mechanism; restrictive dermopathy; Malouf syndrome; and Slovenian heart–hand syndrome [13, 102, 106]. The combination of contractures, conduction disease and lipodystrophy should suggest a laminopathy [106].

2.8. PPARG and familial partial lipodystrophy type 3

On MANE (NM_138711.6, NP_619725.3), PPARG encodes isoform PPARγ1, but FPLD3 literature frequently uses PPARγ2 numbering (NM_015869), differing by 90 nucleotides and 30 amino acids [94]. Thus, variant c.581G>A p.(Arg194Gln), described in a patient in the Portuguese series on NM_015869.5, corresponds to c.491G>A p.(Arg164Gln) on MANE (NC_000003.12:g.12392714G>A); a report omitting the transcript may mislead database searches [94, 96]. The mechanism is loss of function or dominant-negative, with low leptin; FPLD3 is fat redistribution rather than absence [14, 77]. Inheritance is autosomal dominant for OMIM and most GenCC submitters and semidominant for ClinGen, which considers biallelic cases more severe [14]. Common variant Pro12Ala (rs1801282) is a susceptibility polymorphism and should not be reported as a monogenic cause of obesity or type 2 diabetes [14]. In UK Biobank, 22 of 31 carriers of pathogenic lipodystrophy gene variants had PPARG variants (17 truncating and 5 rare missense), the reverse of clinical series dominated by LMNA [57].

2.9. PLIN1 and familial partial lipodystrophy type 4

PLIN1 (15q26.1; MANE NM_002666.5) encodes perilipin 1 [15, 94]. Gandotra and colleagues described two heterozygous frameshift variants in three families in 2011, with small adipocytes, macrophage infiltration and subcutaneous tissue fibrosis, defining FPLD4 as a primary lipid droplet defect [86]. Disease results from C-terminal frameshifts extending the protein rather than haploinsufficiency: early truncating variants found in population databases are not associated with lipodystrophy, requiring cautious interpretation of a PLIN1 loss-of-function variant [15, 107]. Six families had been published by 2019, with four added by a French report [15, 108].

2.10. CIDEC and familial partial lipodystrophy type 5

CIDEC (3p25.3; MANE NM_001321142.2) encodes FSP27, which promotes lipid droplet fusion and formation of the unilocular droplet [16, 94]. FPLD5 is autosomal recessive and has two probands: a 19-year-old woman homozygous for the truncating variant p.Glu186Ter, with multilocular white adipocytes [85], and an 18-year-old Hispanic woman homozygous for NM_001199623.2:c.224G>T p.(Ser75Ile), who also had a homozygous WRN variant (NM_000553.6:c.1856T>G p.(Leu619Arg)) and invasive papillary thyroid carcinoma at 17 years, attributed to WRN [16, 109]. The CIDEA gene, sometimes confused with CIDEC, has no human lipodystrophy disorder described in the sources consulted; FPLD5 corresponds to CIDEC [5, 85, 109].

2.11. LIPE and familial partial lipodystrophy type 6

LIPE (19q13.2; MANE NM_005357.4) encodes hormone-sensitive lipase [17, 94]. FPLD6 is autosomal recessive and results from loss of function; adipose biopsy shows small adipocytes, impaired lipolysis, diacylglycerol accumulation and inflammation [88]. The founder variant is a 19-base-pair deletion causing a frameshift, identified in the Old Order Amish among 2738 genotyped individuals, a frequency that cannot be generalised [17, 87]. An Israeli-Arab sibship homozygous for NM_005357.4:c.3103G>T p.(Glu1035Ter), a Canadian sibship and three French patients have also been described [17, 110, 111].

2.12. AKT2, MFN2, ADRA2A and FPLD1

AKT2 (19q13.2; MANE NM_001626.6) has two opposite phenotypes. Activating variant p.Glu17Lys, de novo, constitutional or mosaic, causes hypoinsulinaemic hypoglycaemia with hemihypertrophy; loss-of-function p.Arg274His (NM_001626.6:c.821G>A, NC_000019.10:g.40237979C>T), described in a single family with dominantly transmitted severe insulin resistance and diabetes, inhibits coexpressed normal AKT (dominant-negative effect) [18, 84, 94]. With only one family, ClinGen classifies the FPLD association as “Limited” [18].

Biallelic MFN2 variants (1p36.22; MANE NM_014874.4) with at least one p.Arg707Trp allele cause multiple symmetric lipomatosis with partial lipodystrophy: massive upper-half adipose overgrowth with suppressed leptin expression, UCP1-negative unilocular adipocytes with mitochondrial fragmentation and frequently distal axonal neuropathy [19, 90]. The usual MFN2 allelic disease is CMT2A, approximately 90 % autosomal dominant [19].

The Brazilian consensus also includes autosomal dominant ADRA2A-related FPLD with fat loss from trunk and extremities and increased face and neck fat, and defines “FPLD type X” as the clinical phenotype without a determined cause and a Köb index below 3.477 [11]. FPLD1 (Köbberling) is considered polygenic or oligogenic; ECLip excluded it from the monogenic scheme and its authors estimate it may affect 10 % or more of adults, bridging to common obesity with an arbitrary demarcation [5, 11].

2.13. Reference transcripts and modifiers

Source of transcripts and conversions: VariantValidator, GRCh38, accessed on 10 October 2026 [94]. Some variants in the literature cannot be normalised safely: the BSCL2 variant “Chr11:62.694.680 G>T” in a Brazilian case is given only as a genomic coordinate, without a genome build [112]; the BSCL2 variant “c.766-49T>C” in the Portuguese series is invalid on NM_032667.6 and corresponds, on NM_001122955.4, to a deep intronic variant of unestablished significance [94, 96]; and the Turkish BSCL2 and CAVIN1 variants were published without a transcript in the abstract [95].

Known phenotypic modifiers are mainly non-genetic. Within the same family with LMNA p.(Arg482Trp), sex, age and hormonal status modulate expressivity [113]; disease is more severe and earlier in women in almost all clinical series, although part of this difference results from ascertainment bias [11, 57]. In CGL, phenotypic variability among carriers of the same AGPAT2 and BSCL2 variants led Fu and colleagues to suggest the existence of modifiers [73]. Amish heterozygotes for the LIPE null variant show a tendency towards insulin resistance and higher TG (1.24 ± 0.80 mmol/L versus 0.96 ± 0.67 mmol/L in controls), with normal fat mass and blood pressure [87, 88].

3. Clinical Spectrum and Manifestations by System

3.1. Congenital generalised lipodystrophy: natural history by age

CGL is usually diagnosed at birth or shortly afterwards, and all children with neonatal or infantile presentation have lipoatrophy in the first year of life; the face may be normal at birth and become atrophic in the first few months [1, 80]. Severe forms may begin prenatally, with intrauterine growth restriction (IUGR), but prenatal growth is normal in most cases [1, 4]. Muscular hypertrophy and lipoatrophy are generally evident at birth and confer an athletic appearance even in young children [4]. The first few months bring growth retardation or, conversely, accelerated growth with advanced bone age, hepatomegaly, facial dysmorphism, macroglossia and developmental delay; appetite is voracious and metabolism is increased in childhood, and final height is normal or slightly above average [1, 4]. Hyperphagia may manifest in infants and children as irritability or aggression [60]. Hyperinsulinaemia and elevated TG are present from infancy and may cause chylomicronaemia, eruptive xanthomas and acute pancreatitis; HDL cholesterol is low [4].

The absence of metabolically active adipose tissue (subcutaneous, intermuscular, intra-abdominal, intrathoracic and bone marrow) is the rule, with relative preservation, in some patients, of mechanical adipose tissue in the orbits, palms, soles, scalp, buccal region, tongue, breasts, perineum, periarticular region and epidural space [4, 88]. Craniofacial appearance includes prominent supraorbital ridges, prognathism, macroglossia and an acromegaloid appearance, with progressive facial lipoatrophy, prominent malar bones and a thin nose; the hands and feet are slightly enlarged, the external genitalia enlarged (phallic enlargement or clitoromegaly), bone density increased and superficial limb veins large (phlebomegaly) [1, 4]. The skin is thick, with predominantly axillary hyperpigmentation and acanthosis nigricans in the groins, neck and axillae, sometimes verrucous; there is hypertrichosis with curly hair and low anterior and posterior hairlines, independent of hormonal stimulation, and an umbilical hernia or umbilical prominence [1, 4, 60]. Acromegaloid features do not represent acromegaly: insulin-like growth factor 1 (IGF-1) is low to normal and growth hormone is suppressible by glucose [62]. Occasional manifestations include corneal opacities, percussion myxoedema, hyperhidrosis, amenorrhoea, polycystic ovaries and female precocious puberty [4].

Insulin resistance is present in all patients, with elevated insulin and C-peptide from the early years [1]. According to GeneReviews, approximately 25 % to 35 % develop diabetes, mainly between 15 and 20 years, which is difficult to control and frequently has weight loss, polydipsia, polyuria or asthenia as the initial finding in the second decade; the summary of the same chapter reports a mean age at onset of 12 years and cases in infancy, an internal discrepancy reflecting different series [1]. In the prospective LD-Lync registry (266 patients), median age at diabetes diagnosis was 16 years in generalised forms and 35 in partial forms, and that at hypertriglyceridaemia diagnosis was 20 and 30 years, respectively [114]. In CGL2, diabetes develops earlier than in CGL1 [4]. Hepatomegaly due to steatosis is present in virtually all patients and progresses to cirrhosis, with oesophageal varices as a potentially fatal complication; CGL2 carries a high risk of early cirrhosis [1, 4, 60]. Hypertrophic cardiomyopathy (HCM) occurs in 20 % to 25 % and causes heart failure and early mortality, at around 30 years; children with heart failure due to HCM in the first year of life and death from cardiomyopathy at 19 months have been described [1, 115]. Adults develop premature atherosclerosis, diabetic nephropathy and retinopathy, and epiphyseal and metaphyseal cysts of the long bones (8 % to 20 %), usually diagnosed in the second decade, predominate in patients with biallelic AGPAT2 variants [1, 4, 116]. In a series of 75 patients, three girls had precocious puberty before 7 years [1, 117]. Women may have oligomenorrhoea, amenorrhoea or polycystic ovary syndrome (PCOS) [1]. Respiratory infections and sepsis may be related to poor glycaemic control, but also occur in infants without diabetes; hypoleptinaemia may impair the function of macrophages, which are rich in leptin receptors, through a mechanism that remains unclear [4]. Some adults reach diagnosis through plastic surgery (facial lipoatrophy), cardiology (HCM) or gastroenterology (hepatomegaly) [1].

The French PNDS (French National Diagnosis and Care Protocol) for CGL adds details of the course by age. Glycaemic abnormalities may be present in the neonatal period, generally attenuate in early childhood and reappear in adolescence or adulthood, when they progress to diabetes; hyperinsulinaemia and hypertriglyceridaemia are present from birth, and fasting insulin is often 15 mU/L or higher and may exceed 200 mU/L during the OGTT [58]. Outside the neonatal period, in which steatotic hepatomegaly may reveal the disease, steatosis is diagnosed at a median age of 12 years, earlier and more severely in CGL2, and is present in more than 90 % of adults [58]. Hyperinsulinaemia accelerates linear growth and bone maturation; adrenarche and puberty may be early, and in adolescent girls the hypertrophied ovarian stroma produces excess androgens, with hirsutism, clitoral hypertrophy and early menstrual irregularity [58]. Dysovulation also has a hypothalamic component, with hypo-oestrogenism and a reduced luteinising hormone (LH) response to gonadotrophin-releasing hormone (GnRH) described in young patients, attributed to profound hypoleptinaemia; the absence of PCOS does not rule out the diagnosis [58]. HCM, more frequent with BSCL2, affects the left ventricle and sometimes the right, begins with non-specific diastolic dysfunction without a restrictive pattern, is usually concentric and symmetrical, sometimes asymmetric septal, and only in advanced forms progresses to systolic dysfunction, a picture close to diabetic cardiomyopathy; the proposed mechanisms are infiltration by ectopic lipids and fibrosis, hyperinsulinaemia and loss of metabolic flexibility [58]. Atherosclerotic complications (coronary disease, stroke, peripheral arterial disease) have been described in very few patients [58].

3.2. Differences between CGL1 and CGL2

The whole-body magnetic resonance imaging (MRI) study by Simha and Garg, in ten patients (seven with AGPAT2 and three with BSCL2), showed absence of metabolically active fat in both and loss of mechanical fat only in CGL2 [6, 118]. In the Turkish nationwide study (33 patients from 22 families), CGL1 preserved fat in the palms, soles, scalp and orbits and had lower adiponectin than CGL2, liver involvement was more severe in CGL2 and organ complications developed at young ages [95]. In women with CGL1, the metabolic phenotype is earlier and more pronounced than in men [116]. Many patients with CGL2 do not reproduce, whereas pregnancies have been described in women with CGL1 [1].

According to the French PNDS, CGL1 and CGL2 account for around 90 % of CGL and share most of the metabolic, cardiac, hepatic, gonadotrophic and bone features [58]. More than half of patients with CGL1 are of African origin, whereas CGL2 occurs mainly in families of European or Middle Eastern origin; lipoatrophy is complete in CGL2 and may spare the extremities, the retro-orbital regions and periarticular fat in CGL1, and intellectual disability, generally mild to moderate, points towards CGL2 [58]. Some studies, but not all, have described a higher risk of premature death in CGL2, mainly infectious, hepatic or cardiovascular, which the PNDS authors relate at least in part to the unfavourable socioeconomic and healthcare context of the populations studied [58]. The BSCL2-related form with progressive encephalopathy (OMIM 615924) had been described in 23 patients worldwide by 2022 [58].

3.3. CGL3, CGL4 and other generalised forms

In CGL3, creatine kinase (CK) is elevated between 2.5 and 10 times the upper limit of normal, in addition to the classical CGL features [1, 80]. The first patient, homozygous for p.Glu38Ter, had almost complete absence of subcutaneous and visceral fat on MRI, with dorsal remnants, severe insulin resistance, dyslipidaemia and mild hypocalcaemia attributed to probable vitamin D resistance [81]. Two Hispanic siblings with a homozygous missense variant had hypotonia, elevated CK, atlantoaxial instability and generalised lipodystrophy [1, 119]. In the largest family described, consanguineous and of Turkish origin, four individuals (8 months to 18 years) homozygous for the frameshift variant NM_001753.5:c.237_238del p.(His79GlnfsTer3), in exon 3 and absent from population databases, had generalised lipodystrophy from the first months of life, sparing the palms, soles, retro-orbital fat and bone marrow fat, with growth delay in infancy and a triangular face; three had muscular hypertrophy, the two oldest acanthosis nigricans, three elevated fasting insulin and TG, all four low HDL, three vitamin D deficiency and the two studied reduced bone mineral density [94, 120, 121]. Two developed dysphagia due to achalasia at 15 and 18 years, successfully treated by endoscopic myotomy, and one had atypical retinitis pigmentosa; none had PAH, and the nine heterozygotes, including the seven parents tested, were asymptomatic and without metabolic abnormalities [8, 120, 121]. Fibroblasts from the index patient of this family and from the 2008 patient completely lacked caveolae and expression of caveolin-1 and its partners caveolin-2 and cavin-1, with cellular insulin resistance, increased oxidative stress and premature senescence; the authors consider achalasia a specific manifestation of caveolin-1 loss that requires its own management [120].

CGL4 is distinguished by myopathy with elevated CK. The initial five Japanese patients had muscular hypertrophy, “muscle mounding”, distal myopathy, mild metabolic complications and normal intelligence [1, 82]. In the series from Oman and the United Kingdom (eight families), five members died suddenly in adolescence; the electrocardiogram (ECG) showed long QT, bradycardia and supraventricular and ventricular tachycardias, and there was myopathy with muscle “rippling”, smooth muscle hypertrophy with altered gastrointestinal motility and hypertrophic pyloric stenosis, osteopenia or osteoporosis and atlantoaxial instability [83]. In a recent teaching case, with the homozygous CAVIN1 variant NM_012232.6:c.160del p.(Val54CysfsTer2), CK was 2903 U/L, leptin undetectable, TG 257 mg/dL and HbA1c 4.5 %; the authors emphasise that arrhythmias may include exercise-induced catecholaminergic polymorphic ventricular tachycardia, that a normal resting ECG does not exclude them and that diabetes develops slightly later than in other CGL forms [116]. Muscular hypertrophy was documented in 21 of 21 patients with generalised lipodystrophy and in 25 of 34 with partial lipodystrophy in a multicentre study of neuromuscular manifestations [88, 122].

Lipodystrophy due to PCYT1A has been described with extreme insulin resistance, hypertriglyceridaemia, severe steatosis, diabetes, low HDL and short stature, with onset in childhood [10, 89]. Progressive encephalopathy associated with the BSCL2 exon 7 variant (section 2.4) may present as generalised lipodystrophy with frequent myoclonus; in one teaching case, myoclonic seizures reached 60 per day [20, 116].

The French PNDS summarises CGL3 in five patients from two families in 2022, with lipoatrophy that, according to the protocol, spares only retro-orbital and bone marrow fat (the 2021 Turkish family also spared the palms and soles), without bone cysts and with achalasia and severe dysphagia from adolescence [58, 120]. In CGL4, lipoatrophy spares mechanical periarticular fat and the metabolic abnormalities may be less severe; the severe arrhythmias (catecholaminergic polymorphic ventricular tachycardia, long QT) result from functional abnormalities of cardiac ion channels (HCN4, SCN5A, CACNA1C), in a channelopathy picture, and the muscular dystrophy, with non-specific myopathic histology and elevated CK, causes weakness, spinal rigidity, atlantoaxial instability, scoliosis, Achilles tendon retraction and foot deformities, with pyloric stenosis and/or achalasia described [58]. The same protocol includes among the very rare causes of generalised lipodystrophy biallelic LMNA and PPARG variants, two de novo variants of EPHX1 (epoxide hydrolase 1) in a complex multisystem form that requires hepatic and neurological follow-up, and biallelic TYMP (thymidine phosphorylase) variants in an autosomal recessive syndrome that presents as CGL and is later completed by manifestations of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), which requires a search for gastrointestinal, ophthalmological and neurological involvement [58].

3.4. Familial partial lipodystrophy: common features

In FPLD, fat distribution is normal in early childhood and fat loss from the limbs, buttocks and hips develops around puberty, with regional accumulation producing a cushingoid appearance; muscular hypertrophy is common and metabolic complications become frequent in adulthood, with an increased risk of coronary disease and, occasionally, early cardiomyopathy [60]. Hypertriglyceridaemia is among the earliest manifestations and precedes hyperglycaemia [11, 76]. Most identified patients are female, PCOS is common and many patients may have been diagnosed only with metabolic syndrome [88]. The presence of lipomas and adipose hypertrophy at the nape, face and trunk increases suspicion [88, 123]. Recognition is more difficult in men [5, 60].

3.5. FPLD2 (Dunnigan)

In FPLD2, subcutaneous fat loss affects the limbs, buttocks and trunk, and fat accumulates in the face, neck (double chin), submandibular region, supraclavicular fossa and mons pubis and genitalia (“Dunnigan sign”); the musculature and veins of all four limbs are prominent regardless of exercise [11, 13]. In women, the Brazilian consensus describes broad shoulders relative to the hips, a height-to-leg-length ratio greater than 2 and small, broad hands with infiltrated tapering fingers, and, less frequently, Achilles tendon contracture and limb-girdle weakness [11]. Onset is in childhood or puberty in girls and young adulthood in men, who have a less aggressive metabolic profile and later diagnosis [11]. Diabetes usually develops after 20 years [13].

In a systematic review of 494 individuals with LMNA-related FPLD, 83 % had dyslipidaemia and 61 % diabetes, and 7.8 % had at least one episode of acute pancreatitis, with a 3.2-fold greater risk in the presence of diabetes and a 12-fold greater risk with hypertriglyceridaemia [11]. Among 102 adults with FPLD2 (mean age 39 years), 41 % had diabetes and 24 % prediabetes, 86 % of the latter having impaired glucose tolerance at 2 hours with normal fasting glucose [11]. In a series of 258 patients (195 women), hypertriglyceridaemia and diabetes were more prevalent in women, but cardiovascular event rates were similar in men and premenopausal women [11]. Myalgia, weakness or muscular dystrophy are associated mainly with the variant p.(Arg482Trp) (c.1444C>T) [11].

The French PNDS for FPLD2 describes the most common presentation: a young woman consulting because of her body appearance, menstrual disturbances, hirsutism or pain (myalgia, hand pain), or a patient with atypical diabetes, autoantibody-negative, young, not overweight, with signs of insulin resistance and a family history; in complex laminopathy forms, the disease may be revealed by cardiac or myopathic signs [59]. The face may become cushingoid, with a double chin, filling of the supraclavicular fossae and sometimes a buffalo hump; with the arms outstretched in a cross, periumeral lipoatrophy gives the bicipital contours an “axe-cut” appearance; the body habitus is pseudo-athletic, with hypertrophied calves, marked muscular gluteal contour, poorly developed breasts and a flat abdomen, which may become protuberant because of wall amyotrophy, visceral fat and hepatomegaly, and there may be small subcutaneous lipomas on the abdomen and limbs [59]. In women, the shoulders are often broader than the pelvis, the lower limbs short relative to the trunk and the hands small and broad, with short, infiltrated fingers; acanthosis affects the axillae and friction areas (waist, nape of the neck), with acrochordons [59]. Nerve compression syndromes, sometimes multifocal (carpal tunnel, ulnar nerve at the elbow, tarsal tunnel, meralgia paraesthetica), are frequent, alongside diabetic polyneuropathy [59]. Women generally have more severe forms, of both the lipodystrophy and the metabolic complications, and some individuals, especially men, remain asymptomatic or paucisymptomatic for a long time, which matters for family screening [59]. Hypertriglyceridaemia may begin before puberty, especially in girls, and steatosis affects more than 80 % of patients [59]. Penetrance is almost complete, and anticipation has been described, with earlier and more severe metabolic complications over the generations, perhaps partly due to environmental factors [59].

The same protocol distinguishes two cardiovascular profiles. Patients with the classical phenotype associated with codon 482 variants are mainly at risk of early atherosclerosis, which may arise even without diabetes and sometimes before 45 years of age; patients with complex phenotypes, combining lipodystrophy and skeletal and/or cardiac muscle laminopathy, usually due to other LMNA variants, are at risk of dilated cardiomyopathy, heart failure, conduction disease, supraventricular and ventricular arrhythmias and sudden death [59]. The predictors of malignant arrhythmia and sudden death identified are male sex, a non-missense LMNA variant, atrioventricular block (first-degree or advanced), non-sustained ventricular tachycardia and left ventricular dysfunction [59]. Partial lipodystrophy is also a risk factor for obstructive sleep apnoea syndrome [59]. In forms with muscular dystrophy, especially limb-girdle, there are Achilles tendon or elbow contractures, difficulty standing on the heels, toe walking, winged scapulae, waddling gait and difficulty rising or climbing stairs; advanced disease may compromise the respiratory muscles, and muscle MRI shows fatty degeneration of thigh muscle groups with hypertrophied calves [59]. In long-standing, poorly controlled diabetes, signs of dysautonomia may appear (orthostatic hypotension, absence of heart rate variation with exercise, delayed gastric emptying, bowel transit disturbances, neurogenic bladder, erectile dysfunction) [59]. In the reproductive sphere, women with FPLD have more ovarian cysts than the general population, even without the other PCOS criteria, and male fertility has not been studied [59].

Cardiac involvement in FPLD2 was underestimated in reference works from 2017, which stated that there was no strong evidence of cardiac involvement in the partial lipodystrophy phenotypes of laminopathies [106]. In the retrospective cohort of 122 patients with FPLD (13 to 77 years; 101 women; Michigan and Turkey), LMNA variants were associated with arrhythmia (odds ratio, OR, 3.77, with a 95 % confidence interval, CI, of 1.45–9.83), atrial fibrillation or flutter (OR 5.78; 95 % CI 1.04–32.16) and shorter time to first arrhythmia (hazard ratio, HR, 3.52; 95 % CI 1.34–9.27); variants outside codon 482, compared with those at codon 482, were associated with arrhythmia (OR 4.74; 95 % CI 1.41–15.98), atrial fibrillation or flutter (OR 17.67; 95 % CI 2.45–127.68) and conduction disease (OR 5.71; 95 % CI 1.37–23.76) [61]. The wide confidence intervals reflect the small number of events. The 2016 guideline already mentioned ischaemic disease, cardiomyopathy, arrhythmias and sudden death in LMNA-related FPLD2 [60]. In five families with overlapping FPLD2 and Emery–Dreifuss (8 women aged 18 to 57 years and 3 men aged 25 to 41 years), seven patients had contractures and proximal weakness, five received an implantable cardioverter-defibrillator or pacemaker, all the women and only two men had limb fat loss, and four women had diabetes and hypertriglyceridaemia [105]. Epicardial fat is increased and inversely proportional to leptin [11]. Arrhythmic risk stratification and the indication for an implantable cardioverter-defibrillator in laminopathies include the Wahbi score (839 adults with LMNA variants) [13, 124].

The 2022 French PNDS for laminopathies with cardiac presentation places FPLD2 within the spectrum of LMNA disorders. In forms with lipodystrophy and in progeroid forms, cardiovascular disease may take the form of early and severe atherosclerosis, valvular and arterial calcification or dilated cardiomyopathy; it is rarely the first manifestation, but some FPLD2 cases and some complex phenotypes are revealed by the heart [125]. The protocol stresses that no study has shown that any clinical form (FPLD2, Emery–Dreifuss dystrophy, limb-girdle dystrophy 1B or Charcot–Marie–Tooth type 2) has, in itself, a lower or higher risk of cardiomyopathy than the others, so all carriers warrant specific cardiological follow-up [125]. The natural history data it gathers come mainly from families with cardiac or neuromuscular presentation, not from FPLD2 cohorts with codon 482 variants, and therefore cannot be transposed directly: rhythm and conduction disturbances precede cardiomyopathy by around ten years on average; in a meta-analysis of 299 carriers, arrhythmias or conduction disease affected 74 % of carriers between 20 and 30 years and 92 % after 30, pacemaker implantation rose from 3 % between 10 and 20 years to 44 % after 30, and heart failure from 10 % before 30 years to 64 % after 50; in the largest laminopathy cohort (444 derivation and 145 validation patients, followed for 3.6 and 5.1 years), severe ventricular arrhythmia occurred in 19.3 % and 23.4 %, around 3.9 % per year, a value close to the approximately 4 % per year of the French national registry [124, 125]. LMNA carriers also had more arterial and venous thromboses than patients with idiopathic dilated cardiomyopathy, with a risk ratio close to 5 [125].

3.6. FPLD3 (PPARG)

FPLD3 combines distal lipoatrophy, with gluteofemoral loss, with increased, decreased or normal facial fat and increased truncal and visceral fat; insulin resistance is frequently severe and disproportionate to body mass index (BMI), with diabetes, marked hypertriglyceridaemia and risk of acute pancreatitis, steatosis, hypertension, xanthelasmas, axillary and cervical acanthosis, hirsutism and lower-limb muscular hypertrophy, and is easily mistaken for type 2 diabetes with dyslipidaemia [14, 46]. In a series of 91 patients with 41 PPARG variants, 75.8 % were women, mean age at onset was 20 years and prevalences were 91 % for hypertriglyceridaemia, 87.5 % for MASLD, 77 % for diabetes, 59.5 % for hypertension and 58.7 % for PCOS [11]. In the comparison between 256 patients with FPLD2 and 32 with FPLD3, hypertriglyceridaemia (66 % versus 84 %) and diabetes (44 % versus 72 %) were more frequent in FPLD3, which had greater skinfold thickness and regional fat: lipoatrophy is less marked and metabolic disease more severe [11]. Hypertension may be very severe in PPARG-related FPLD [62].

3.7. FPLD4, FPLD5, FPLD6 and rare forms

In FPLD4, subcutaneous fat loss mainly affects the lower limbs and gluteal region, typically after puberty and with variable severity; it is associated with severe hypertriglyceridaemia, insulin-resistant diabetes, steatosis and hypertension, and in the largest series muscular hypertrophy, acromegaloid features and PCOS with hirsutism were stereotypical signs [15, 47]. BMI may be normal because muscular hypertrophy compensates for fat loss; most patients do not have the marked facial and nuchal accumulation of FPLD2, although facial and cervical accumulation may occur [88, 108].

In FPLD5, fat is lost from the limbs, femorogluteal region and subcutaneous abdominal wall, with visceral, cervical and axillary preservation; probands presented in adolescence or early adulthood with acanthosis, hirsutism, insulin-resistant diabetes, hypertriglyceridaemia, hepatomegaly with steatosis and, in the first case, pancreatitis [16, 48, 88].

FPLD6 begins in adulthood with lower-limb fat loss and accumulation in the face, neck, shoulders, axillae, trunk and pubis, with symmetrical pseudolipomatous masses indistinguishable from multiple symmetrical lipomatosis and increased visceral fat [17, 49]. Among nine patients homozygous for frameshifts, four had muscle symptoms, five hyperCKaemia (438 to 771 IU/L) and four myopathy on biopsy; seven of nine (78 %) had diabetes, five of seven (71 %) steatosis, and TG ranged from 1.7 to 6.0 mmol/L [88]. In the Israeli-Arab sibship, progressive symmetrical distal myopathy accompanied hypertriglyceridaemia and low HDL, and in the French series all three patients had neuromuscular manifestations and retinal deposits resembling autofluorescent drusen [17, 110, 111]. FPLD6 is also associated with vitiligo and hypertension [17, 49].

In the family with AKT2 p.Arg274His, distal lipoatrophy accompanied severe hepatic and peripheral insulin resistance, hyperinsulinaemia and diabetes, with acanthosis and hypertension described [50, 84]. Multiple symmetrical lipomatosis due to MFN2 manifests from childhood to young adulthood with disfiguring, non-encapsulated cervical and thoracic masses that may compress the airway and oesophagus, lipoatrophy elsewhere, distal axonal neuropathy and very low leptin [19, 62, 90]. FPLD7 due to de novo CAV1 variants manifests in the neonatal period with a progeroid appearance, thin mottled skin and cataracts [8]. FPLD1 restricts fat loss to the gluteal region and limbs, with truncal excess and a normal face and genitalia, a “step” between normal and lipodystrophic areas, leptin proportional to BMI and, apparently, more hypertriglyceridaemia, pancreatitis and coronary disease than FPLD2 [11, 45].

3.8. Manifestations by system

The liver is the most consistently affected organ. The 2016 guideline describes progression from steatosis to fibrosis and cirrhosis in CGL, AGL and FPLD, and inconsistently in APL, and lists liver failure, gastrointestinal haemorrhage and hepatocellular carcinoma among causes of death [60]. In a series of 23 patients with partial lipodystrophy (7 with FPLD2) investigated by MRI and biopsy, 22 had metabolic dysfunction-associated steatohepatitis (MASH), with a mean activity score of 6 ± 2, and 18 (78.3 %) had fibrosis; liver fat correlated with HbA1c and log TG [11]. In women with FPLD2, pancreatic fat measured by MRI was higher than in controls (5.26 ± 1.5 versus 4.08 ± 0.64; p = 0.034) and inversely related to the disposition index [11].

The kidney may be damaged by diabetic nephropathy, FSGS (particularly in CGL) or membranoproliferative glomerulonephritis (particularly in APL) [60]. In FPLD, renal biopsy shows glomerular hypertrophy, mesangial expansion, podocyte injury, diabetic nephropathy, FSGS or membranoproliferative glomerulonephritis, most often secondary to poorly controlled hypertension and diabetes [11]. The LMNA p.(Arg349Trp) variant causes nephrotic-range proteinuria and renal failure at a median age of 43 years [104].

Reproductive dysfunction has distinct mechanisms in the two forms: in generalised lipodystrophy, profound leptin deficiency suppresses gonadotrophin-releasing hormone and causes hypothalamic amenorrhoea; in partial forms, hyperinsulinaemia and androgen excess predominate, with anovulation and infertility [126]. Among 14 women with FPLD2, more than half had PCOS and approximately 30 % infertility; in a PCOS clinic with 1200 patients, 18 partial lipodystrophy phenotypes were found, 12 of them familial forms (1 %): nine LMNA, one PPARG and two PLIN1 [11]. The 2016 guideline lists pre-eclampsia, miscarriage and macrosomia among reproductive complications [60].

The skin shows hirsutism, acanthosis in the axillae, neck and groins, thick, seborrhoeic or acneiform skin, skin tags, eruptive xanthomas on extensor surfaces, leukomelanoderma and sometimes a scleroderma-like presentation with telangiectasias; lipomas are common with LMNA, MFN2 and LIPE [11]. Eruptive xanthomas and lipaemia retinalis indicate severe hypertriglyceridaemia [62]. Psychological consequences include anxiety, depression, stigma and discrimination; in a partial lipodystrophy cohort, 78.3 % had chronic pain (arthritis, low back pain, fibromyalgia, myopathy), attributed to loss of mechanical cushioning, systemic inflammation and central sensitisation [11, 62]. In generalised lipodystrophy, loss of adipose tissue from the sole causes plantar calluses, reduced energy reserves decrease physical endurance and thermoregulation in the cold is impaired [65].

According to the French PNDS, bone in CGL1 and CGL2 shows three radiographic patterns: diffuse osteosclerosis, axial and peripheral, of cancellous and cortical bone, which explains the increased mineral density; well-defined epiphyseal, metaphyseal and/or diaphyseal lytic lesions with a “punched-out” appearance, sometimes extensive and multicystic with a “honeycomb” pattern, mainly in the femur, tibia and humerus and sometimes in the metacarpals, painless; and pseudo-osteopoikilosis, with multiple islands of homogeneous osteosclerosis [58]. The lesions develop from adolescence, have not been observed in CGL3 or CGL4, and only rarely are complicated by fracture, usually after direct trauma to a lytic lesion [58]. Mineral density is increased mainly in the trabecular bone of the spine and in CGL2, perhaps because of hyperinsulinaemia and hypoleptinaemia, and microarchitecture measured by the trabecular bone score appears preserved [58]. Dysplasias (coxa valga) and anatomical variants (butterfly vertebra) have also been described in CGL1 and CGL2, scoliosis in CGL1, CGL2 and CGL4 and atlantoaxial instability in CGL4, and the almost constant muscular hypertrophy is often accompanied by musculotendinous pain, sometimes disabling [58]. Inflammatory arthralgia is not part of the usual CGL picture and points towards acquired generalised lipodystrophy with autoimmune disease [58].

3.9. Cohorts, natural history and treated disease

Natural history sources mix treated and untreated patients, and each figure should be read in the context of its population. In the European ECLip registry (19 centres in 13 countries; 631 patients between 2017 and 2023, with prospective data in 467), 82.7 % were women and 86.5 % adults, median age was 44 years and FPLD accounted for 57.4 % of cases (FPLD2 37.9 %); in men, CGL was almost as frequent as FPLD (33.3 % versus 35.8 %). More than 70 % had metabolic complications (dyslipidaemia 59.0 %, diabetes 48.4 %), 11.6 % used metreleptin and there were 34 deaths, mainly cardiovascular and from cancer, with median age at death of 27 years in generalised forms and 72 years in partial forms [127]. In the prospective LD-Lync registry (266 patients; median age 39 years, 6 to 76; 216 women), 75.9 % had hypertriglyceridaemia, 72.0 % diabetes, 68.4 % steatosis, 48.8 % hypertension, 21.8 % pancreatitis and 7.1 % cirrhosis [114]. Among 112 patients treated with metreleptin at the National Institutes of Health (NIH), 94 % had liver disease, 79 % hyperphagia, 77 % altered physical appearance, 63 % a renal abnormality, 39 % pancreatitis and 80 % of women of reproductive age reproductive dysfunction [128].

The UK Biobank population genetic study allows observation of FPLD without clinical ascertainment bias. Among 490,414 participants with sequenced genomes (40 to 70 years at recruitment, predominantly European and healthier than the general population), the 31 carriers of pathogenic variants had similar BMI (26.5 versus 27.4 kg/m²; p = 0.22), lower body fat percentage (24.7 % versus 31.4 %), higher BMI-adjusted waist-to-hip ratio, lower HDL (0.99 versus 1.45 mmol/L) and higher TG (2.9 versus 1.7 mmol/L) than non-carriers. Over a mean follow-up of 13.6 years, adjusted HRs were 4.41 (95 % CI 2.5–7.76) for diabetes, 2.97 (1.42–6.24) for coronary disease, 5.28 (2.52–11.07) for heart failure and 4.02 (2.16–7.48) for all-cause mortality; cumulative mortality by 80 years was 68.3 % (95 % CI 25.0–86.6) versus 17.7 %. None of the 31 carriers had a diagnosis of lipodystrophy in their clinical record [57]. Metabolic differences were smaller in men, and waist-to-hip ratio was increased only in women [57]. Compared with 58 clinically identified NIH cases, UK Biobank carriers were older (57.6 versus 38 years), less frequently women (45.2 % versus 93.1 %) and diabetic (38.7 % versus 65.5 %), and diabetes by 50 years affected 9.7 % versus 78.2 % of clinical cases; the authors attribute the female predominance in clinical series to ascertainment bias [57]. These are associations, with possible survival bias, and do not constitute causal evidence [57].

In untreated CGL or CGL treated before metreleptin, life expectancy is reduced by 30 years or more [4, 129]. In Rio Grande do Norte, 20 patients with CGL died between 1997 and 2017 at a mean age of 27.1 ± 12.4 years, compared with a life expectancy in the reference population of 62.9 ± 4.8 years; causes were infections (35 %), liver disease (35 %), renal failure (3 patients), sudden death or infarction (2) and acute pancreatitis (1) [129]. In Turkey, 11 of 72 patients with generalised lipodystrophy died at a mean age of 35 years, from sepsis and renal, cardiovascular and liver disease [66]. Metreleptin alters the metabolic trajectory (section 7), and an analysis of 103 treated and untreated patients estimated a 65 % reduction in mortality risk, in an observational study in which treated patients had more severe disease [11, 62].

3.10. Lipodystrophies with neurological involvement

The association between lipodystrophy and neurological disease does not define a single entity, but a group of monogenic disorders in which the gene product acts simultaneously on the adipocyte and on the neuron, the peripheral nerve or muscle. The mechanisms fall into four families: seipin, an endoplasmic reticulum protein in which loss of function, toxic gain of function and an aberrant isoform produce distinct diseases; caveolin-1, whose de novo haploinsufficiency causes a neonatal progeroid lipodystrophy and whose inherited variant has been associated with spastic-ataxic disease; the proteasome, whose dysfunction causes the autoinflammatory syndromes with panniculitis and secondary lipodystrophy (CANDLE/PRAAS), with basal ganglia calcification and cognitive impairment; and the progeroid syndromes, in which fat loss accompanies deafness, cerebrovascular disease or leukodystrophy [20, 22, 23, 100]. The ECLip diagnostic algorithm treats autoinflammatory signs (recurrent fever, erythematous-oedematous plaques, nodular panniculitis, arthralgia, microcytic anaemia, raised acute-phase reactants) as a separate clue, distinct from lipodystrophies with primary adipose failure [5].

Seipinopathies: one gene, three mechanisms

Biallelic null BSCL2 variants cause CGL2, with intellectual disability in around 80 % of patients, compared with around 10 % in CGL1 (section 3.2); patients with CGL do not usually develop upper or lower motor neuron signs, and heterozygous parents of null variants do not have neurological disease [1, 20]. Progressive myoclonic epilepsy may occur in CGL2 with or without the lipodystrophic appearance, which partly overlaps classical CGL2 and the exon 7-associated encephalopathy [4, 21].

Progressive encephalopathy with or without lipodystrophy (PELD, OMIM 615924), described in Spanish infants with the variant c.985C>T p.(Arg329Ter) in NM_001122955.4 (c.793C>T in historical numbering), results from exon 7 skipping and an increase in a transcript encoding a truncated seipin, which aggregates, induces endoplasmic reticulum stress and leads to neuronal apoptosis [20, 21, 97]. In the original series, six children from four families in the Murcia region, all with c.985C>T on at least one allele (consistent with a founder effect), developed symptoms between 2 and 3 years of age, with psychomotor regression, loss of language, spasticity, ataxia, tremor, myoclonus, dystonia and seizures; five died between 6 and 8 years, mainly from respiratory failure or infection, and five had a mild lipodystrophic appearance, which regressed in at least one [33, 97]. A review of 24 patients published in 2025 showed that most had neurological symptoms before 3 years and regression before 6, with no difference between the sexes; developmental delay and regression were the most frequent symptoms, epilepsy affected 20 of the 24 patients, mainly with myoclonic seizures, MRI showed cerebral atrophy predominantly in the caudate and the electroencephalogram had slow background activity with multifocal or generalised discharges; status epilepticus was the cause of death in at least four patients [21]. The variant c.974dup p.(Ile326HisfsTer12) in NM_001122955.4 (NC_000011.10:g.62691317dup), also in exon 7, was associated with later regression (up to 15 years) and survival to 28 years, which the authors relate to lower expression of the aberrant transcript; the index case of that review, homozygous, had regression at 9 years and died two years later in status epilepticus [21, 94]. All patients with c.974dup, c.1048C>T or c.1076dup had a lipodystrophic appearance, whereas the two carriers of isolated heterozygous variants (c.445C>G and c.566T>A) did not, and both homozygotes and compound heterozygotes could have lipodystrophy or not [21]. The authors propose including PELD among the progressive myoclonic epilepsies and BSCL2 in progressive myoclonic epilepsy panels; isolated reports have described delayed regression or better seizure control under metreleptin, a case-series finding without controlled comparison [21].

Heterozygous variants that destroy the seipin N-glycosylation motif, all in exon 3, cause autosomal dominant neurological seipinopathy through toxic gain of function, with accumulation of misfolded protein in the endoplasmic reticulum, without lipodystrophy [20, 98]. In NM_001122955.4 (MANE), p.Asn88Ser corresponds to c.455A>G p.(Asn152Ser), p.Ser90Leu to c.461C>T p.(Ser154Leu), p.Ser90Trp to c.461C>G p.(Ser154Trp) and the variant of uncertain significance p.Arg96His, described in a Taiwanese patient with sporadic distal motor neuropathy, to c.479G>A p.(Arg160His) [20, 94]. Onset ranges from 6 to 66 years (mean 19), progression is slow and life expectancy normal; upper motor neuron involvement (spasticity, hyperreflexia, variable Babinski sign) combines with lower motor neuron involvement (amyotrophy of the peroneal muscles and small hand muscles, especially thenar and first dorsal interosseous, often unilateral), with pes cavus and, as a rule, without paraesthesia, sensory deficit or sphincter disturbances [20]. In a study of 90 p.Asn88Ser carriers from a large Austrian family and two German families, the six subtypes sometimes coexisted within the same family: asymptomatic non-penetrance in 4.4 %, subclinical involvement in 20 %, distal spinal muscular atrophy predominantly affecting the hands in 31.1 %, Silver syndrome in 14.5 %, a CMT-like phenotype with sensory deficit in 20 % and spastic paraparesis without hand involvement in 10 % (24.4 % asymptomatic or subclinical in total); the Austrian family's genealogy goes back to a couple born in 1682 [20, 34]. The heterogeneity prompted a search for modifiers, with a candidate locus at 16p13 in a Dutch family [34]. p.Ser90Leu is associated with more severe phenotypes (Silver syndrome and spastic paraplegia), with some patients in a wheelchair in the second decade, and p.Ser90Trp, described in a Korean family with CMT2, is accompanied by sensory loss in 73 % of those affected [20]. Electrophysiology shows reduced compound motor action potentials in the lower limbs, with conduction velocities sometimes below 37 m/s and partial blocks, and reduced sensory potentials in advanced disease [20]. Around 30 families with p.Asn88Ser or p.Ser90Leu have been described, and BSCL2 explained 7 % of a cohort of 112 patients with distal hereditary motor neuronopathy [20]. As all known pathogenic variants lie in exon 3, targeted sequencing of that exon may precede the panel when the phenotype is typical [20]. Treatment is symptomatic (physiotherapy, orthopaedic footwear, orthoses, surgical correction of foot deformities), with annual neurological assessment of gait, strength, atrophy and reflexes; the differential diagnosis includes GARS1 neuropathy, ALS4 (SETX), SPG3A (ATL1), HSPB8-related distal motor neuronopathy, amyotrophic lateral sclerosis, multifocal motor neuropathy and upper-limb entrapment syndromes [20]. The neurological management of these forms follows that of hereditary spastic paraplegias and Charcot-Marie-Tooth disease.

Caveolin-1: neonatal lipodystrophy, cataracts and neurodegeneration (FPLD7)

In a trio exome sequencing study of 6 of 14 probands with neonatal-onset generalised lipodystrophy referred to a North American centre, two patients of European origin had heterozygous de novo null CAV1 variants: NM_001753.5:c.424C>T p.(Gln142Ter) in a Spanish boy and c.479_480del p.(Phe160Ter) in a girl [22, 94]. Both had, from birth, generalised loss of subcutaneous fat with preservation of the buttocks, palms and soles, thin mottled skin with visible vessels (cutis marmorata), a triangular face, sparse hair, normal linear growth with poor weight gain, normal cognitive development, normal glucose and TG and low HDL [22]. The boy required bilateral cataract surgery at 30 months; the girl had prenatal pleural effusion, bilateral neonatal pneumothorax, dysphagia with aspiration and gastrostomy, a pulmonary arteriovenous malformation and biopsy-confirmed PAH, with a pulmonary artery pressure of 40 to 50 mmHg at catheterisation [22]. CAV1 sequencing in eight other patients with neonatal lipodystrophy and progeroid features was negative, and the phenotype overlaps that of Wiedemann–Rautenstrauch syndrome [22]. A second group described, by genome sequencing, a 3-year-old girl with the de novo p.(Phe160Ter) variant, neonatal progeroid appearance, lipodystrophy, PAH, cutis marmorata, feeding disorder and growth delay, with reduced caveolin-1 in fibroblasts, and attributed the severity, as a hypothesis, to additional rare variants in AGPAT2 and LPIN1 [130]. A 2016 study clarified that this girl is the same patient as in the 2015 series, so these two publications describe two independent probands and not three [139]. The clinical data then published complete the phenotype: birth weight 2466 g and length 46 cm (below the 5th centile), head circumference at the 65th centile, triangular face, wide anterior fontanelle and generalised congenital cutis marmorata telangiectatica; weight below the 5th centile from 3 months, with height and head circumference at the 50th centile; TG 168 mg/dL at 27 months and normal at 30, normal total and LDL cholesterol, persistently low HDL, leptin 1.0 ng/mL at 30 months, low insulin (1.3 µU/mL) at 35 months and no steatosis on ultrasound; monthly episodes of abdominal pain and diarrhoea, with two hospital admissions for dehydration and a duodenal biopsy with a Marsh IIIA lesion and negative anti-transglutaminase antibody; and global cerebral atrophy on MRI at 7 months, with developmental milestones achieved on time and a normal neurological examination [139]. PAH was suspected on echocardiography at 15 months, lung biopsy at 18 months showed focal muscular thickening of the pre-acinar arterioles and catheterisation at 35 months confirmed it, with a mean pulmonary artery pressure of 33 mmHg, pulmonary capillary wedge pressure of 11 mmHg and pulmonary vascular resistance of 3.97 Wood units, which fell to 21 mmHg and 2.07 Wood units with nitric oxide at 80 ppm and 100 % oxygen [139]. In this patient's fibroblasts, hybrid caveolae form, which retain their mechanical protection function, but the truncated protein, lacking around 20 C-terminal amino acids, reduces the colocalisation of cavin-1 with caveolin-1, exposes the carboxyl terminus of the normal protein and destabilises the 8S and 70S oligomers required for caveola assembly, findings reproduced in Cav1-null murine embryonic fibroblasts [139].

In 2026, the case was published of a Chinese girl followed in Beijing with the de novo variant NM_001753.5:c.424C>T p.(Gln142Ter), absent in both parents and identical to that of the 2015 Spanish boy [94, 140]. She had normal weight and fat distribution at birth, generalised livedo reticularis from birth, diagnosed at 5 months as telangiectasia of the marmorata type, progressive loss of subcutaneous fat with preservation of the buttocks, an aged-looking face with a thin nose and lips, digital clubbing and, at 13 years, 146 cm and 32 kg (below the 3rd centile); she underwent bilateral phacoemulsification with intraocular lens implantation at 3 years for congenital cataracts, and metabolic screening of blood and urine was normal [140]. At 3 years and 11 months, after a respiratory infection, echocardiography showed an estimated pulmonary systolic pressure of 69 mmHg with dilatation of the right heart chambers, and pulmonary CT angiography showed mosaic perfusion; the parents declined catheterisation [140]. Treated successively with tadalafil, ambrisentan, selexipag and subcutaneous treprostinil, with a period without follow-up between 2017 and 2023, the estimated pulmonary systolic pressure rose to 95 to 105 mmHg, with syncope, long QT and complete right bundle branch block; atrial septostomy and heart–lung transplantation were proposed and declined, and the patient died at 13 years of a pulmonary hypertensive crisis and multiorgan failure after gastroenteritis [140]. In the three published probands with the neonatal form (two with p.(Gln142Ter) and one with p.(Phe160Ter)), PAH occurred in the two girls and not in the boy, and cataracts in the Spanish boy and the Chinese girl; the fatal course of the latter case, despite combination therapy, supports echocardiography at diagnosis and early referral to a paediatric PAH centre [22, 139, 140].

The neurological component belongs mainly to the family described by Berger in 2002 and studied by Cao in 2008, of northern European origin [22, 32]. The proband, with atypical lipodystrophy of the face and upper trunk from birth, fat accumulation in the buttocks, thighs, legs and visceral region, congenital cataracts, pigmentary retinopathy, type V hyperlipidaemia with pancreatitis and insulin resistance, developed at 18 years a spastic-ataxic gait with lower-limb paraesthesia, clonus, hyperreflexia and bilateral Babinski sign, with signal change in the cervical spinal cord on MRI; the father, with congenital cataracts, retinitis pigmentosa and diabetes, had minimal neurological manifestations, and a paternal aunt with the same fat distribution had weakness and ataxia from 18 to 20 years, became wheelchair-bound within two years and died at around 40 [22, 32]. Father and daughter were heterozygous for NM_001753.5:c.400del p.(Ile134LeufsTer5), identified in CAV1 screening of 60 patients with partial lipodystrophy; the difference in neurological severity between them suggests genetic or environmental modifiers [22, 32, 94]. A third carrier, with the variant c.-88delC in the 5' untranslated region (the authors' designation, at a position outside the current transcript NM_001753.5), had partial lipodystrophy, severe hypertriglyceridaemia with pancreatitis and diabetes, without ocular or neurological abnormalities [22, 32, 94]. OMIM now groups the familial form and the de novo neonatal form under entry 606721, designated familial partial lipodystrophy type 7 (FPLD7), with the alternative title “partial lipodystrophy, congenital cataracts, with or without neurodegeneration syndrome” (LCCNS), of autosomal dominant inheritance and highly variable phenotype, in which early-onset cataracts and late lower-limb spasticity occur only in some patients [32]. Cataracts are the feature shared by the familial and neonatal forms. In a newborn or infant with generalised fat loss, a progeroid appearance and cutis marmorata, ophthalmological examination and echocardiography identify the two complications described in these patients (cataracts and PAH) [8, 22, 130].

CANDLE/PRAAS: inflammatory lipodystrophy with central nervous system involvement

The proteasome-associated autoinflammatory syndromes (PRAAS) include chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), the syndrome of joint contractures, muscle atrophy, microcytic anaemia and panniculitis-induced lipodystrophy (JMP) and Nakajo–Nishimura syndrome, described independently and now recognised as a single entity when caused by biallelic variants of PSMB8, which encodes the β5i catalytic subunit of the immunoproteasome [27, 131]. Proteasome dysfunction leads to accumulation of ubiquitinated and oxidised proteins and maintains constitutive type I interferon production, so CANDLE/PRAAS is classified among the interferonopathies [23, 131]. The lipodystrophy does not result from a primary defect of adipocyte differentiation: it develops progressively on top of neutrophilic panniculitis, predominantly in the face and upper limbs [23, 131]. JMP syndrome was defined in a Portuguese man, the son of consanguineous parents, and in two Mexican siblings, the latter with seizures and none with intellectual disability, with the homozygous variant NM_148919.4:c.224C>T p.(Thr75Met), which reduces the chymotrypsin activity of the immunoproteasome [35]; this variant recurs in Portuguese, Mexican and other patients with CANDLE and behaved, in one series, as a mutational hotspot rather than a single founder haplotype [27, 94, 141]. Nakajo–Nishimura syndrome, concentrated in the Kansai region (Japan), derives from a single founder with the homozygous variant c.602G>T p.(Gly201Val), which prevents immunoproteasome maturation; a Japanese review writes it as c.602C>T, a notation incompatible with the glycine-to-valine substitution, and the validated form in NM_148919.4 is c.602G>T (NC_000006.12:g.32841671C>A) [94, 131].

The genetic architecture extends beyond PSMB8: there are digenic forms due to the combination of a heterozygous PSMB8 variant with another in PSMA3 or PSMB4 (included in PRAAS1), PRAAS3 (OMIM 617591), due to biallelic PSMB4 variants or digenic combination of PSMB4 with PSMB9, autosomal dominant forms due to loss of function of POMP, a proteasome assembly chaperone (PRAAS2, OMIM 618048), and recessive forms due to PSMG2 (PRAAS4, OMIM 619183) and PSMB10 (PRAAS5, OMIM 619175) [23, 28–30, 35, 37, 131]. Dominant forms with immunodeficiency have broadened the spectrum: the de novo PSMB9 variant NM_002800.5:c.467G>A p.(Gly156Asp), in two Japanese infants with neonatal autoinflammation, myositis, basal ganglia calcification, PAH and immunodeficiency (PRAAS6, OMIM 620796, autosomal dominant) [44], and monoallelic dominant-negative PSMB8 variants, described in seven patients from five families with neonatal immunodeficiency, B lymphopenia and hypogammaglobulinaemia requiring immunoglobulin, inflammatory lung disease (5 of 6), enteropathy (5 of 7), raised transaminases (4 of 7) and myositis (4 of 7), but generally without the lipodystrophy or joint changes of the recessive forms [29, 94, 133]. The de novo PSMB8 variant NP_683720.2:p.(Gly209Arg), also dominant negative, was associated with early systemic inflammation, panniculitis, cytopenias, infections and porto-sinusoidal vascular disease, with a partial response to Janus kinase (JAK) inhibition and interferon α/β receptor blockade [142]. Because of this heterogeneity, confirmation requires joint analysis of all proteasome genes and POMP, and digenic disease may require study of both parents [23, 27].

The disease begins in the first weeks of life: all patients with CANDLE in the North American expanded access programme had symptoms before 2.5 weeks, although onset at 14 years has been described [23, 143]. It combines recurrent or almost daily fever, acral chilblain-like lesions, erythematous-violaceous annular plaques and nodules, neutrophilic panniculitis, myositis with a patchy pattern on muscle MRI, contractures of the hands and feet, hepatosplenomegaly, microcytic anaemia, cytopenias, autoantibodies (antinuclear antibodies in up to 42 %), PAH and metabolic syndrome with hepatic steatosis in 40 to 80 % of patients, often in the first decade [23, 27]. Skin biopsy shows an infiltrate of immature myeloid cells with karyorrhexis that may be mistaken for leukaemia cutis, and the blood interferon signature, available only in specialised laboratories, supports the diagnosis without excluding it when negative [23, 27]. The Japanese criteria for Nakajo–Nishimura syndrome require five of eight features (autosomal recessive inheritance; pernio-like erythema of the hands and feet in winter from childhood; recurrent fever; infiltrated and migratory erythema nodosum, sometimes annular; progressive muscle and fat lipodystrophy, predominantly in the face and upper limbs; long clubbed fingers or contractures; hepatosplenomegaly; basal ganglia calcification), and PSMB8 homozygosity defines the diagnosis regardless of the number of criteria [131]. In the 28 Japanese patients compiled, lipodystrophy was present in 26 of 26 assessed, basal ganglia calcification in 14 of 16, intellectual disability in 8 of 22 and consanguinity in 19 of 27 [131].

Neurological involvement takes several forms. The 2021 joint recommendation of the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) mentions headache and aseptic meningitis, basal ganglia calcification that is less frequent, less severe and later than in Aicardi–Goutières syndrome, unusual leukoencephalopathy and mild developmental delay, and recommends brain MRI (or computed tomography, more sensitive for calcifications) when there are neurological symptoms [23]. In the systematic review of 46 patients with CANDLE or a similar picture treated with JAK inhibitors, neurological involvement was reported in 78.2 % of cases, including neurodevelopmental delay, cerebellar vermis hypoplasia, basal ganglia calcification and aseptic meningitis, in a sample of published reports rather than a systematic cohort [144]. In six adolescents and young adults with confirmed CANDLE, assessed with the Wechsler scales, all had an IQ below 85 at every assessment and four had values of 69 or lower [132]. In the same work, brain organoids derived from patient induced pluripotent stem cells showed deficient neuronal maturation associated with excess polyamines due to dysregulation of ornithine decarboxylase, also observed in the cerebrospinal fluid of three patients, and corrected in vitro by inhibition of this enzyme; this is preclinical evidence, without a trial in patients [132]. Treatment with JAK inhibitors, doses and monitoring are described in section 7.15.

Progeroid forms and other syndromic lipodystrophies with neurological involvement

In MDPL, sensorineural deafness is the main neurological component and appears at the end of the first or in the second decade, with cases of congenital onset and onset up to 32 years [24, 40, 145]. In a series of 14 new patients compared with the literature, carriers of the recurrent deletion p.(Ser605del) (n = 26) had, compared with carriers of missense variants (n = 15), more mandibular hypoplasia (100 % versus 57 %), small mouth (100 % versus 36 %), crowded teeth (91 % versus 44 %) and male hypogonadism (92 % versus 0 %), with no difference in diabetes, hypertriglyceridaemia or steatosis; the authors designate the p.(Ser605del) form as typical MDPL and the missense form as atypical [24]. Keppen–Lubinsky syndrome, due to de novo variants of KCNJ6 (GIRK2 potassium channel), combines severe psychomotor delay and intellectual disability, hypertonia, hyperreflexia, microcephaly, large prominent eyes, tightly adherent skin with an aged appearance and severe generalised lipodystrophy [43]; a patient with NM_002240.5:c.512T>G p.(Leu171Arg) had a hyperkinetic movement disorder and developmental delay without lipodystrophy, and other variants at codon 154 were associated with infantile spasms and axial hypotonia [25]. MFN2-related multiple symmetric lipomatosis is associated with distal axonal neuropathy (section 2.12) [19, 90]. In PCYT1A-related lipodystrophy there is no neurological or retinal involvement, unlike the allelic disorder with spondylometaphyseal dysplasia and cone-rod dystrophy (section 2.6) [10, 89].

In the progeroid syndromes with lipodystrophy, neurological involvement is vascular or allelic. In Hutchinson–Gilford progeria, motor and cognitive development is normal and neurological morbidity results from atherosclerotic cerebrovascular disease [134]. In Werner syndrome, there may be cerebrovascular disease with stroke, but cognitive changes are not typical [135]. Wiedemann–Rautenstrauch syndrome, due to POLR3A, belongs to the same allelic spectrum as POLR3A-related hypomyelinating leukodystrophy and adolescent-onset spastic ataxia, and FBN1-related marfanoid–progeroid–lipodystrophy syndrome has no described neurological involvement [100, 136, 137]. SHORT syndrome, due to PIK3R1, enters the differential diagnosis of partial lipodystrophy of facial onset [54].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

The essential feature is generalised or regional absence of fat, and the 2016 guideline associates it with a set of physical signs and comorbidities that increase suspicion [60]. Physical signs are growth retardation in infants and children, prominent muscles, phlebomegaly, severe acanthosis nigricans, eruptive xanthomas and a cushingoid, acromegaloid or progeroid appearance. Comorbidities that should prompt consideration of lipodystrophy are diabetes with high insulin requirements (200 U/day or more, 2 U/kg/day or more, or a need for U-500 insulin), severe hypertriglyceridaemia (500 mg/dL or more, with or without treatment, or 250 mg/dL or more despite diet and drugs), acute pancreatitis due to hypertriglyceridaemia, steatohepatitis in a non-obese individual, early-onset cardiomyopathy and PCOS. Autosomal dominant or recessive transmission of similar physical or metabolic characteristics and significant hyperphagia are additional clues [60].

The ECLip consensus proposes a simple metabolic discriminator. In physiological leanness, the profile is concordant, with low insulin, low TG, no MASLD and no acanthosis; the combination of leanness, insulin resistance, low HDL, high TG and MASLD is a discordance that should raise suspicion, and is particularly useful in men, in whom prominent muscles and veins attract little attention [5]. Adiponectin rises in physiological leanness and even in advanced undernutrition, but is low in lipodystrophy, so high adiponectin in a person with little fat is a strong argument against the diagnosis [5]. Absence of metabolic signs does not exclude lipodystrophy when energy balance is very negative, because restriction masks functional deficiency [5]. Subcutaneous tissue is always palpable in individuals without lipodystrophy [62].

The French PNDS for CGL summarises in a diagram the elements that should raise the diagnosis, which are grouped as follows [58]:

4.2. Warning signs by age

In infants, suspicion of CGL arises from absence of fat with a muscular appearance, hepatomegaly, acanthosis, hyperphagia or irritability, accelerated growth, umbilical hernia and lipaemia; hypertriglyceridaemia may manifest as chylomicronaemia, eruptive xanthomas or acute pancreatitis [4, 60, 146]. Childhood photographs distinguish CGL, in which fat is absent from early life, from AGL, in which fat was normal, although some AGL cases have loss in the first few months [60]. A child with suspected Donohue syndrome or CGL should be assessed and followed by a metabolic disease physician, and examination should look for acanthosis in the axillae and groins, lipodystrophy, muscular hypertrophy and prominent veins [146]. In a child with CGL, normal HbA1c and fasting glucose do not exclude dysglycaemia: in a case of CGL2 with HbA1c of 5.2 %, the oral glucose tolerance test (OGTT) showed glucose of 202 mg/dL at 2 hours with insulin above 1000 μU/mL [116]. Elevated CK with generalised fat loss should prompt testing of CAVIN1 and CAV1 [4, 116].

In the newborn, according to the French PNDS, the reasons for consultation are mainly hepatomegaly, which is almost constant, and the “muscular”, hypertonic appearance, with a distended abdomen; lipoatrophy often goes unnoticed by the family and professionals, and children may be referred for indirect signs, such as very visible lymph node chains simulating polyadenopathy, a superficial venous network that appears hypertrophied, or suspected dehydration [58]. Diarrhoea, vomiting, feeding difficulties and poor weight gain are frequent reasons, polyuria and polydipsia (thirst, heavy nappies) are rare and reflect metabolic decompensation, and hyperphagia may be present in the absence of gastrointestinal symptoms [58]. In early childhood the signs become less marked and diagnosis is less frequent, whereas in adolescence lipoatrophy and acanthosis become evident again, with PCOS in girls [58]. Muscle weakness, regurgitation, dysphagia, sialorrhoea and intellectual disability point to particular forms of CGL [58]. The history should look for consanguinity or parents from the same village and for cases of lipoatrophy, diabetes, steatosis or hypertriglyceridaemia in siblings [58].

In adolescence, warning signs of FPLD are loss of limb and buttock fat from puberty, cervical and facial accumulation, PCOS, early hypertriglyceridaemia and acanthosis [11, 60]. Misdiagnosis as uncomplicated PCOS may lead to oral oestrogen prescription and precipitate pancreatitis: in a woman with FPLD2, a combined oral contraceptive at 28 years caused moderate to severe acute pancreatitis with splenic artery thrombosis and TG of 5400 mg/dL [116]. The transition from adolescence to adulthood is the period when delayed diagnosis has the greatest consequences [116].

In adults, suspicion arises with diabetes with insulin resistance disproportionate to BMI, severe hypertriglyceridaemia or recurrent pancreatitis, MASLD in a non-obese person, premature coronary disease, cervical lipomatosis and a similar familial pattern [11, 14, 60]. Lipodystrophy-associated diabetes is sometimes labelled type 1 diabetes; in a Greek woman with CGL1, diabetes at 14 years was classified as type 1 despite absence of autoantibodies and C-peptide, and molecular diagnosis was made only at 26 years [147]. In patients with autosomal dominant Emery–Dreifuss dystrophy, lipodystrophy and metabolic complications should be sought [105]. The Brazilian consensus also proposes considering screening at 10 years in girls from families with a pathogenic LMNA variant, because changes in body composition may precede puberty [11].

In adults, functional symptoms are rare and consultation is prompted mainly by diabetes, hypertriglyceridaemia, hepatic cytolysis, hirsutism or oligomenorrhoea; lipoatrophy is rarely the complaint and has to be sought in atypical diabetes (young patient, not overweight, without autoantibodies) [58]. Inspection is the most important step: it is performed in underwear, from the front and in profile with the arms alongside the body, from the front with the arms held out horizontally and in movement, with photographs to follow progression and measurement of waist, hip and limb circumferences and skinfolds [58]. BMI is normal or low (sometimes below 18 kg/m²), and hyperphagia, sometimes aggravated by decompensated diabetes, distinguishes lipodystrophy from undernutrition due to anorexia or from cachexia; clinical diagnosis is easier in women, because in men the muscular appearance is less surprising [58]. Voracious appetite with amenorrhoea, when lipoatrophy becomes apparent at puberty, may lead to a misdiagnosis of an eating disorder [58].

4.3. Urgent situations

Situations requiring immediate action are acute pancreatitis due to hypertriglyceridaemia, hyperglycaemic decompensation with extreme insulin requirements, heart failure due to HCM in infants with CGL, ventricular arrhythmias and syncope in CGL4 and laminopathies, oesophageal variceal haemorrhage in cirrhosis, severe infections and sepsis, and abrupt withdrawal of metreleptin in patients with hypertriglyceridaemia or previous pancreatitis, which may cause rebound hypertriglyceridaemia and pancreatitis [4, 60, 63, 64, 83]. In encephalopathy associated with BSCL2 exon 7, neurological regression in the early years is the warning sign [1, 20].

The French protocols insist that the patient should know the signs of pancreatitis (sudden “stabbing” abdominal pain, eruptive xanthomas), which require urgent consultation, and that abdominal pain and the polyuric-polydipsic syndrome should prompt immediate laboratory tests to exclude pancreatitis due to hypertriglyceridaemia or diabetic decompensation; pancreatic imaging by computed tomography (CT) or MRI is indicated in the presence of suggestive epigastric pain or raised lipase [58, 59]. In laminopathies with conduction disease and in CGL4, palpitations, presyncope and syncope require immediate cardiological assessment [58, 59].

4.4. Neonatal and population screening

There is no neonatal screening for genetic lipodystrophies in the sources consulted. The UK Biobank study, in which none of the pathogenic variant carriers had a clinical diagnosis, and the Geisinger cohort, in which only 4 of 16 carriers of LMNA p.Arg482Gln had a diagnosis despite metabolic abnormalities, demonstrate underdiagnosis but do not establish a population screening programme [57, 148]. An ongoing French study is seeking genetic syndromes of severe insulin resistance among women with classical PCOS [149].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. General principles

Diagnosis of lipodystrophy is based on history, physical examination, body composition and metabolic status (class I, level B); no serum leptin values establish or exclude the diagnosis (IIa, C); confirmatory genetic testing is useful in suspected familial forms (I, A) and should be considered in at-risk relatives (IIa, C); complement and autoantibodies may support diagnosis of acquired forms (IIa, B) [60]. In 2016 there were no firm diagnostic criteria [60]. The guideline algorithm begins with suspected regional or generalised lack of adipose tissue, records age at onset and comorbidities, examines the distribution of loss, muscles, veins, acanthosis, hepatomegaly, xanthomas and acromegaloid or progeroid appearance, performs metabolic assessment (insulin resistance, diabetes, dyslipidaemia, fatty liver) and anthropometry with skinfolds, with dual-energy X-ray absorptiometry (DXA) and whole-body MRI when available, and refers genetic forms for genotyping, genetic counselling and family screening [60]. The ECLip algorithm adds investigation of drugs associated with localised or systemic lipodystrophy and of progeroid and autoinflammatory signs (section 6) [5].

5.2. Clinical criteria for CGL

The historical GeneReviews criteria for Berardinelli–Seip syndrome require three major criteria, or two major and at least two minor criteria, and/or biallelic variants in AGPAT2 or BSCL2 [1]. A Brazilian reference work on genetic syndromes omits hepatomegaly from the major criteria; the GeneReviews list includes it [1, 80].

Source: GeneReviews, 2016 version, retired in 2026 and used as a historical reference [1, 80].

5.3. Clinical criteria for FPLD

The 2025 Brazilian consensus proposed suspicion and diagnostic criteria for FPLD, retrospectively validated in patients with a confirmed pathogenic variant [11]. Suspicion requires reduced or absent subcutaneous adipose tissue in the lower limbs, with or without accumulation in the trunk, face, supraclavicular region and pubis, and at least one of: TG above 150 mg/dL and/or HDL below 50 mg/dL in women or 40 mg/dL in men; diabetes, impaired fasting glucose or glucose intolerance, particularly before 40 years; MASLD; premature coronary disease (before 45 years); acanthosis or other signs of insulin resistance; PCOS [11].

Source: [11]. Applied to 94 patients with a confirmed pathogenic variant at four centres, 67 (71.3 %) met the mandatory criterion with two major criteria; in a subsample of 28 patients, all had at least one major and between 3 and 10 minor criteria [11]. The criteria are based on consensus and observational data and have not been validated prospectively or in non-Brazilian populations [11]. The BROADEN volanesorsen trial used another operational definition: anterior thigh skinfold ≤10 mm in men or ≤22 mm in women with a genetic diagnosis, or family history with one minor criterion, or two minor criteria with BMI below 35 [150].

5.4. Anthropometry and body composition

Skinfolds below the 10th percentile increase suspicion but are not diagnostic; a mid-thigh skinfold of 11 mm in men and 22 mm in women supports diagnosis in European, Middle Eastern, North African and South American patients, according to the experience of the authors of an expert review, and thresholds for Asian populations are undefined [62]. A Brazilian study of 37 women with FPLD and 74 controls suggested a threshold of 20 mm in women [11]. A Köb index, the ratio of subscapular to leg skinfolds, above 3.477 distinguishes FPLD1 from android obesity in women [11, 62].

DXA measures the fat percentage of the lower limbs, trunk and genital region and the FMR. In a Brazilian study of 18 patients with FPLD and 16 controls, an FMR above 1.2 identified women with FPLD, and a threshold of 1.7 was proposed for men (87th percentile of UK Biobank); the French PNDS for FPLD2 uses, in women, an FMR above 1.2 and/or lower-limb fat below 25 % of total fat [11, 59]. Lower-limb fat below the 1st percentile was reliable in 50 women and 6 men with FPLD2, but its value in boys and men has not been established [11, 62]. DXA “fat shadow” images had a sensitivity and specificity of 100 % in generalised lipodystrophy and of 85 % and 96 % in partial lipodystrophy, in a retrospective study that does not justify routine use [11, 62]. MRI shows intra- and extramyocellular lipids, liver fat, bone marrow and the “Dunnigan sign” (hypertrophy of mons pubis fat surrounded by subcutaneous lipoatrophy); pelvic MRI, with gluteal fat thickness and the pubic-to-gluteal fat ratio, was useful in women in a Turkish cohort [62]. Whole-body MRI distinguishes CGL1, with preserved mechanical fat, from CGL2 [6, 118].

The French protocols add supporting thresholds. In FPLD2, a triceps skinfold below 7 mm in a woman, measured with a skinfold caliper (Harpenden caliper), suggests lipoatrophy in the absence of undernutrition, and MRI with spectroscopy shows intra-abdominal fat of around 50 % of total abdominal fat, compared with around 25 % in the general population [59]. In CGL, total fat mass by bioimpedance or DXA is around 10 % to 20 % of body mass, and metabolic MRI, when available, quantifies intraperitoneal fat and hepatic steatosis [58].

ECLip recommends regional measures (lower-limb fat percentage, FMR and selected skinfolds) as supportive tools, but considers that heterogeneity between FPLD forms, sex, age and method still precludes generalised use of thresholds [5].

5.5. Biomarkers

Leptin is very low or undetectable in generalised lipodystrophy (median 0.7 to 1.1 ng/mL in the metreleptin registration trials) and low to normal in partial lipodystrophy, except in MFN2-related lipomatosis, in which it is very low [62–64]. Assays are not standardised and values overlap with those in the general population, particularly in partial forms, so leptin does not aid diagnosis but may guide treatment choice [60]. Leptin and adiponectin are influenced by breastfeeding, puberty, iron, ketones, fatty acids and hormones [62]. High-molecular-weight adiponectin is extremely low in generalised lipodystrophy and normal or high in anorexia nervosa [62]. Laboratory assessment includes a lipid profile with non-HDL cholesterol and apolipoprotein B, fasting glucose and HbA1c, OGTT if suspicion is high, full blood count with platelets and transaminases and gamma-glutamyltransferase for the FIB-4 index, CK if myopathy is suspected, androgens and 17-hydroxyprogesterone in PCOS, HIV serology and complement (C3, C4, CH50) in probands without a family history, late-night salivary cortisol or suppression with 1 mg dexamethasone if Cushing syndrome is suspected and IGF-1 if acromegaly is suspected [11]. Fasting insulin should be measured when there are signs of insulin resistance without obesity, and C-peptide when the patient is receiving insulin [103]. In APL, C3 is low and C3 nephritic factor may be present; in AGL, C4 may be low and anti-perilipin 1 autoantibodies are present in 37 % to 50 % [62]. CK is elevated in CGL3, CGL4, FPLD6 and laminopathies with dystrophy [1, 62].

The French PNDS specify some values. In CGL, leptin is in most cases below 4 ng/mL and sometimes below 1 ng/mL, adiponectin is very low except in CGL2, in which it is only moderately reduced, transaminases rise with ALT predominance, and hypertriglyceridaemia, sometimes with lactescent serum, makes LDL incalculable, so cardiovascular risk is assessed by directly measured LDL or by apolipoprotein B [58]. Type 1 diabetes autoantibodies (anti-glutamic acid decarboxylase, anti-IA2, anti-insulin and anti-ZnT8), tested as a matter of principle, are negative, and in insulin-treated diabetes C-peptide shows persistent secretion [58]. In FPLD2, the most frequent abnormalities are TG above 1.5 g/L, HDL below 0.5 g/L in women and 0.4 g/L in men and hyperinsulinaemia (interpreted according to pubertal stage and BMI); the 2-hour OGTT with glucose and insulin should be performed in all patients with suspected disease and no known diabetes, C-peptide is not usually collapsed, CK rarely exceeds 2 to 3 times normal and leptin is low relative to BMI [59]. Adrenal imaging (CT or MRI) may be performed in severe or rapidly progressive hyperandrogenism [58, 59].

The two PNDS propose a structured initial assessment, to be adapted to the context [58, 59]:

The initial CGL assessment described in GeneReviews includes full blood count, electrolytes, transaminases, urea, creatinine, insulin, C-peptide, TG and cholesterol, OGTT and, when appropriate, a clamp, liver ultrasound, echocardiography, renal ultrasound, orthopaedic examination (hip mobility, genu valgum), radiographs of the long bones for cysts, bone age and pubertal stage, slit-lamp ophthalmological examination, age-appropriate cognitive assessment and a genetics consultation [1, 80].

5.6. Genetic testing: strategy

Genetic testing confirms the diagnosis in the proband and enables testing of at-risk relatives; it is also useful in atypical acquired forms [60, 62]. A phenotype-based, gene-by-gene approach is limited by clinical overlap, variable expressivity, incomplete penetrance and new genes, and multigene panels are more cost-effective; exome or genome sequencing is reserved for specialist centres and panel-negative cases [1, 62]. When testing gene by gene in CGL, BSCL2 should be sequenced first if intellectual disability or cardiomyopathy is present, and the order may also be stratified by ethnic origin [1]. When lipodystrophy is associated with neurological disease, recurrent fever or panniculitis, the panel should cover the whole of BSCL2 (including exon 7), CAV1, the proteasome genes with POMP, POLD1 and KCNJ6, or exome sequencing is used; digenic proteasome disease may require study of both parents (section 3.10) [21, 23, 27]. The Brazilian consensus recommends a next-generation sequencing panel with AGPAT2, AKT2, ADRA2A, BSCL2, CAV1, CAVIN1, CIDEC, CTRC, LIPE, LMF1, LMNA, MFN2, PCYT1A, PLIN1, POLD1, PPARG and ZMPSTE24, with an optional expanded panel including monogenic hypertriglyceridaemia and pancreatitis genes (APOA5, APOC2, GPIHBP1, LPL, LMF1, PRSS1, SPINK1, CFTR), LMNB2, PSMB8, LIPA, SMPD1, CYP27A1 and ABCA1; a new variant should be confirmed by Sanger sequencing [11]. The Cambridge centre's panel identifies the reference transcripts in the report (for example, BSCL2 NM_032667.6 and CAV1 NM_001753.5) [151].

The result is interpreted together with clinical findings: a positive test with clinical criteria confirms diagnosis; a positive result without criteria requires clinical and metabolic follow-up; and a negative result with clinical criteria suggests FPLD1 or FPLD type X, possibly with a variant of uncertain significance (VUS), and warrants surveillance and family assessment [11]. The report should state the gene, reference transcript and version, variant in HGVS (Human Genome Variation Society) nomenclature at DNA and protein levels, zygosity, classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria and the criteria applied; in a Colombian family with LMNA p.(Arg482Trp), classification as pathogenic was based on PS3, PS4, PM1, PM2, PP1, PP2 and PP3 criteria and segregation by Sanger sequencing [113].

Entry through cardiology also leads to the diagnosis. The PNDS for laminopathies with cardiac presentation requires, in any LMNA variant carrier, an extracardiac assessment: personal and family history of myalgia, weakness, tendon contractures, atypical diabetes (non-autoimmune, in a young person who is not overweight), hypertriglyceridaemia, steatosis, acute pancreatitis or PCOS; examination looking for generalised or limb lipodystrophy with preserved or accumulated fat in the face, neck and supraclavicular regions, acanthosis nigricans, peripheral neuropathy, dysmorphic signs (early alopecia, sloping shoulders, sclerodermiform skin, abnormal pigmentation) and signs of atherosclerosis; and, systematically, CK, lipid profile with direct LDL, AST, ALT, gamma-glutamyltransferase and fasting glucose [125]. In case of any doubt and without known diabetes, an OGTT with 75 g of glucose is performed with glucose and insulin measured at 0, 30, 60, 90 and 120 minutes, together with liver ultrasound, a search for atherosclerosis and a gynaecology consultation, and the patient is referred to the metabolic (PRISIS) or neuromuscular reference centre [125]. An LMNA variant already described in other laminopathy phenotypes, found in a patient with cardiac presentation, requires the search to be extended to the corresponding metabolic, muscular and progeroid manifestations [125]. In the cardiology setting, the gene is studied by targeted (Sanger) sequencing when suspicion is strong or in panels of 40 to 80 cardiomyopathy and conduction disease genes, and the test can be performed post mortem on frozen tissue after sudden death [125].

The French PNDS describe the expected yield. In classical CGL a molecular aetiology is found in most cases, almost always a homozygous null variant of AGPAT2 or BSCL2 (nonsense, frameshift or canonical splice site), with known or suspected consanguinity; confirmation of heterozygosity in the parents is useful for counselling [58]. In FPLD2, most patients have a heterozygous missense variant of LMNA, and in more than half of cases the variant affects arginine 482 (p.(Arg482Trp) and p.(Arg482Gln), less often p.(Arg482Leu); HGVS notation in section 2.7); biallelic LMNA variants, linked mainly to consanguinity and to more severe forms, account for less than 5 % of cases in the UMD-LMNA database, which brings together variants, phenotypes and bibliography [59]. There is no routine functional test to demonstrate the pathogenicity of an LMNA variant in vitro [59]. In France, the request follows good practice in constitutional genetics (prescription, information, free and informed written consent, communication of the result and information of relatives) and requires a prior pedigree [58, 59].

5.7. Limitations of testing

A negative test does not exclude a genetic form, because additional loci remain to be identified [60, 62]. Among all patients referred for lipodystrophy or extreme insulin resistance, around half remain without a molecular aetiology after analysis of the known genes, according to the French PNDS for FPLD2, and not all patients with a picture suggestive of FPLD2 have an LMNA variant [59]. In the Portuguese series from Porto, 9 of 11 tested patients with FPLD had negative or inconclusive results [96]. Sequencing detects small deletions and insertions and missense, nonsense and splice variants, but does not usually detect exon or whole-gene deletions and duplications, which have been described in both CGL genes (deletion of AGPAT2 exons 3 and 4; a large deletion and a large insertion-deletion in BSCL2); the proportion of variants detectable by copy-number methods is unknown [1]. Deep intronic variants escape exon-focused panels, and in Wiedemann–Rautenstrauch syndrome, a differential diagnosis, many POLR3A variants are deep intronic [100]. In genome studies without parental data, compound heterozygotes cannot be identified reliably, and this was why UK Biobank detected no cases of generalised lipodystrophy [57]. In CGL, confirmation of the phase (cis or trans) of the two variants requires study of the parents [1, 57].

Interpretation depends on the mechanism. In PLIN1, only C-terminal frameshifts cause disease, and an early truncating variant should not be considered causal [15, 107]. In BSCL2, loss-of-function variants cause CGL in the biallelic state, whereas toxic gain-of-function variants in the glycosylation motif cause dominant neurological disease [20]. In PPARG, the common Pro12Ala variant is not causal [14]. In AKT2, the activating variant p.Glu17Lys may be mosaic, which is relevant to hypoinsulinaemic hypoglycaemia and not to FPLD [18]. The same variant may have different numbering depending on the transcript (BSCL2, PPARG), and a report without a transcript may be misread [94]. Two CAV1 variants (NM_001753.5:c.473C>T p.(Pro158Leu) and NM_001753.5:c.512G>T p.(Arg171Leu)) found in a patient with FPLD in the Portuguese series were classified as VUS, which illustrates that a VUS should not guide clinical decisions or cascade testing without segregation analysis and reassessment [94, 96].

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible once familial pathogenic variants have been identified [1]. In dominant neurological seipinopathies, prenatal diagnosis is possible but rarely requested [20]. Prenatal ultrasound is not a diagnostic method for CGL in the sources consulted, although severe forms may have IUGR [1].

In France, prenatal diagnosis is discussed case by case, at the couple's request, when the familial variant has been identified; in CGL, when both parents are carriers, and in FPLD2, when one parent is a carrier, particularly if the family has severe cardiomyopathy; the request is submitted to a multidisciplinary prenatal diagnosis centre (CPDPN), which validates the indication or not, in conjunction with medically assisted reproduction in FPLD2 [58, 59].

6. Differential Diagnosis

6.1. Fat loss that is not lipodystrophy

The first task is to exclude severe weight loss: malnutrition, anorexia nervosa, uncontrolled diabetes, thyrotoxicosis, adrenal insufficiency, cancer cachexia, HIV-associated wasting and chronic infections [60]. Uncontrolled diabetes with extreme hypertriglyceridaemia is the most difficult differential, but glycaemic control restores fat in non-lipodystrophic diabetes [60]. Leanness due to undernutrition, intensive training or catabolic disease is not lipodystrophy; the concordant metabolic profile and high adiponectin help distinguish it [5]. Generalised lipodystrophy may be confused with anorexia or malnutrition, and in generalised lipodystrophy forced feeding or high-calorie supplements prescribed following an erroneous diagnosis of “malnutrition” worsen complications [62].

The French PNDS for CGL adds to this differential constitutional thinness, weight loss, diabetes secondary to chronic calcifying pancreatitis and monogenic diabetes due to mitochondrial cytopathy, which is accompanied by marked thinness due to energy deficit; in children, autoimmune type 1 diabetes, type 2 diabetes, mitochondrial diabetes with deafness and the other monogenic forms of diabetes do not have lipodystrophy [58]. In FPLD, some partial forms with modest cervicofacial accumulation may mimic generalised lipoatrophy in very thin patients [58].

6.2. Differential by age

6.3. Comparative table

6.4. Progeroid syndromes and SHORT

Mandibuloacral dysplasia manifests between 3 and 14 years with postnatal short stature, prominent scalp veins, a thin beaked nose, mandibular hypoplasia with difficulty opening the mouth, short, bulbous distal phalanges with acro-osteolysis, dystrophic nails, joint stiffness, thin, mottled and hyperpigmented skin, early tooth loss, sparse hair, wormian bones, clavicular hypoplasia or osteolysis, a bell-shaped chest and osteoporosis [102, 145]. In type A (LMNA), fat loss is marked in the extremities, milder in the face and normal or slightly excessive in the neck and trunk; the most common variant is homozygous p.Arg527His, NM_170707.4:c.1580G>A (NC_000001.11:g.156137204G>A) [94, 145]. In type B (ZMPSTE24, which cleaves farnesylated prelamin A), lipodystrophy is generalised and affects the face more, onset is before the first year and the course is faster, with severe glomerulopathy, more extensive skeletal abnormalities and subcutaneous calcifications; residual enzyme activity explains a milder phenotype than restrictive dermopathy [102, 145]. Both are associated with metabolic syndrome, insulin resistance, diabetes and hypertriglyceridaemia, but without the premature arteriosclerosis of progeria and with patients described over 50 years of age [102, 145]. Lonafarnib (Zokinvy®) is indicated in the USA for processing-deficient progeroid laminopathies, including biallelic ZMPSTE24, from 12 months and with a body surface area of at least 0.39 m², with efficacy derived from progeria [153].

Mandibular hypoplasia, deafness and progeroid features with lipodystrophy syndrome (MDPL), due to heterozygous de novo POLD1 variants, has a course similar to mandibuloacral dysplasia but is distinguished by progressive generalised lipodystrophy with increased truncal deposition, absence of acro-osteolysis and clavicular hypoplasia, male hypogonadism, sensorineural deafness at the end of the first or in the second decade and better survival [31, 145, 154]. The recurrent variant is the in-frame deletion NM_002691.4:c.1812_1814del p.(Ser605del), at the polymerase active site, a mechanism opposite to that of polymerase proofreading-associated polyposis (missense in the exonuclease domain) [31, 94].

Wiedemann–Rautenstrauch syndrome (neonatal progeroid syndrome) is autosomal recessive, due to biallelic truncating and/or splice variants of POLR3A (many deep intronic), with growth retardation, generalised lipoatrophy, a triangular face, relative macrocephaly, prominent scalp veins, dental abnormalities and loculated fat over the buttocks [100]. C-terminal FBN1 variants, de novo CAV1 variants and SLC25A24 variants produce similar but not identical neonatal progeroid and lipodystrophic phenotypes [100]. In autosomal recessive cutis laxa type III (De Barsy syndrome), due to variants of ALDH18A1 (type IIIA) or PYCR1 (type IIIB), the aged appearance, thin translucent skin with prominent vessels and abnormal fat distribution over the buttocks and thighs may resemble a progeroid lipodystrophy; the loose, wrinkled skin, hernias, prenatal and postnatal growth restriction, cataract or corneal opacity and developmental delay with athetoid movements guide the diagnosis [155]. Marfanoid–progeroid–lipodystrophy syndrome (FBN1, OMIM 616914) combines neonatal progeroid appearance, macrocephaly, proptosis, downslanting palpebral fissures, retrognathia, extreme congenital absence of subcutaneous fat (except breast and iliac region), severe myopia, hyperextensibility and arachnodactyly, without metabolic disturbances [137, 138, 156].

SHORT syndrome (an English acronym for short stature, hyperextensibility, inguinal hernia, ocular depression, Rieger anomaly and teething delay) results from PIK3R1 variants, is autosomal dominant and de novo in 70 % [54]. It is associated with a facial gestalt (triangular face, broad forehead, deep-set eyes, narrow nasal tip, downturned mouth corners, chin dimple, prominent ears), mild IUGR (83 %), short stature (52 %), partial lipodystrophy beginning in the face and extending to the chest and upper limbs, often sparing the buttocks and legs (87 %), insulin resistance (73 %) and diabetes (60 %; 9 of 9 patients over 18 years), with a mean age at diabetes diagnosis of 17 years (9 to 32) [54, 157]. Growth hormone worsens insulin resistance and should be avoided, and in three patients metformin worsened insulin resistance [54]. ECLip classifies SHORT as H3B, without unequivocal adipose failure [5]. The ECLip algorithm also lists drugs associated with localised lipodystrophy (insulin, injectable corticosteroids, pegvisomant, long-acting exenatide, tumour necrosis factor alpha antagonists (anti-TNF-α), recombinant growth hormone and somatrogon, subcutaneous medroxyprogesterone) and systemic lipodystrophy (programmed death receptor 1, PD-1, inhibitors and antiretrovirals), and autoinflammatory signs (recurrent fever, erythematous oedematous plaques, nodular panniculitis, arthralgia, microcytic anaemia, elevated acute-phase reactants) [5].

6.5. Acquired forms

AGL (Lawrence syndrome) affects more women than men (3:1), usually begins before adolescence, with progressive loss including the palms and soles, and is associated with autoimmune disease (myositis, type 1 diabetes, autoimmune hepatitis); lymphomas, particularly peripheral T-cell lymphomas, have a prevalence of approximately 7 % [60]. Generalised lipodystrophy may be a paraneoplastic manifestation of pilocytic astrocytoma, with recovery of fat following treatment in three children, so the guideline suggests considering brain tumour screening in children with idiopathic AGL or atypical CGL [60]. APL (Barraquer–Simons) mainly affects women (4:1), with craniocaudal loss from the face, neck, shoulders, arms and trunk and accumulation in the hips, buttocks and legs, the reverse of the FPLD pattern; metabolic complications are uncommon, C3 is low in most, C3 nephritic factor may be present, approximately 20 % have membranoproliferative glomerulonephritis and retinal drusen have been described [60, 62, 152]. Hereditary lipodystrophy is generally total or predominant in the limbs and gluteal region, whereas acquired lipodystrophy tends to be patchy, in the face, shoulders and arms [103].

The French PNDS for CGL summarises the arguments that, in generalised lipoatrophy beginning in adolescence or adulthood, especially in a woman, point to an acquired form: old photographs showing normal fat, absence of consanguinity and familial cases, markers of autoimmune disease (lupus, scleroderma, Sjögren syndrome, rheumatoid arthritis, juvenile dermatomyositis), low complement and negative molecular testing, with a possible role for anti-perilipin 1 autoantibodies [58]. These forms have metabolic complications similar to those of CGL [58]. Common variable immunodeficiency and autoimmune polyendocrinopathy syndrome type 1 (APECED) may be complicated by autoimmune generalised lipoatrophy without antibodies, and there are acquired forms after immunotherapy with nivolumab or after total body irradiation before allogeneic bone marrow transplantation [58]. In acquired partial forms, the FPLD2 PNDS draws attention to the association with childhood panniculitis and autoimmune hepatitis [59].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no cure or treatment that regenerates adipose tissue [60]. Treatment broadly follows that of complicated obesity (dietary optimisation, exercise, intensive management of diabetes and dyslipidaemia, hepatic, cardiovascular and reproductive surveillance), with the difference that BMI carries very little weight in decisions: many patients are denied treatment before diagnosis because they are not obese [5]. The metabolic burden of FPLD is equivalent to a BMI 10 to 12 points higher than measured, according to an expert review, and target weight should be lower in all forms [62]. Metreleptin is the only authorised specific replacement therapy; the remaining interventions treat complications [63, 64, 88]. Patients with suspected CGL or Donohue syndrome should be followed by a metabolic disease physician, and management is multidisciplinary, involving endocrinology, nutrition, hepatology, cardiology, nephrology, gynaecology, genetics and mental health [11, 93, 146].

7.2. Diet and exercise

The 2016 guideline recommends a balanced diet (IIa, C), with 50 % to 60 % of energy from carbohydrate, 20 % to 30 % from fat and approximately 20 % from protein; simple sugars should be restricted in favour of fibre-rich complex carbohydrates, spread throughout the day and combined with protein or fat, and fat should be predominantly cis monounsaturated and long-chain omega-3 [60]. Energy-restricted diets improve metabolic abnormalities and may be appropriate in adults (I, C); in acute pancreatitis due to chylomicronaemia a very-low-fat diet is indicated (I, C), with bowel rest followed by less than 20 g of fat per day; a dietitian should provide support particularly for infants and young children; overfeeding should be avoided (IIa, C); and medium-chain triglyceride (MCT) formulas may provide energy and lower TG in infants (IIa, C) [60]. Population reference weight-for-length or BMI should not be used as a target: low BMI is acceptable if linear growth is maintained, and overfeeding to achieve a “normal weight” worsens complications and steatosis [60]. The 2016 GeneReviews stated that restricting fat to 20 % to 30 % of total energy is often sufficient to maintain normal TG and prevents hypertriglyceridaemia [1, 4]. In severe hyperglycaemia and pancreatitis due to chylomicronaemia, an expert review proposes fat below 15 % of energy [62]. The Japanese guideline recommends 25 to 35 kcal per kg of standard weight for height, adjusted for age, sex and activity, without energy restriction in children (with monitoring of albumin and cholinesterase) and with fat restriction in hypertriglyceridaemia [65]. Abstinence from tobacco and particularly alcohol is recommended in moderate to severe hypertriglyceridaemia [11, 62].

The French PNDS detail the diet by age. In CGL, the child's intake must cover growth requirements without worsening metabolism, and sufficient lipid intake is important for brain development: in the neonatal period, special MCT-rich formulas are proposed exclusively, with MCT-rich oils by mouth; in childhood and adolescence, limitation of saturated fats and possible MCT enrichment (oils or powders), especially with hypertriglyceridaemia [58]. MCT are rapidly used for energy and little stored in peripheral tissues [58]. Instituted as early as possible, this diet generally corrects or prevents, on its own, the metabolic abnormalities of early childhood, and dietary diversification proceeds as in other children; in adolescence, drugs often become necessary [58]. Increasing the intake of a child with a low BMI is not desirable, because it precipitates metabolic complications and steatosis, but the restriction proposed for adults does not apply either, so as not to compromise linear growth [58].

In adults, the CGL PNDS adopts a distribution of 50 % to 60 % carbohydrate, mainly complex and fibre-rich, 20 % to 30 % lipid with a preference for monounsaturated and omega-3 polyunsaturated fats, and 20 % protein, with simple sugars limited to 5 % of intake, low glycaemic index foods (below 55), such as legumes, quinoa, wholegrain rice and pasta, and vegetables for fibre [58]. The FPLD2 PNDS follows the French references for the general population (National Agency for Food, Environmental and Occupational Health Safety, ANSES, and National Nutrition and Health Programme, PNNS), with 40 % to 55 % carbohydrate, 35 % to 40 % lipid and 10 % to 20 % protein, a distribution with more fat than that of the 2016 guideline and the CGL PNDS (section 7.14) [59, 60]. Both protocols limit or exclude alcohol and sugary drinks, strongly advise against smoking, adapt the recommendations to pregnancy, breastfeeding, BMI, diabetes and hypertriglyceridaemia and, in severe hypertriglyceridaemia, prescribe a strict diet without rapid sugars, without alcohol, low in fructose, with limited unrefined carbohydrate and fat below 20 % of energy, accepting that caloric restriction improves metabolism [58, 59]. In FPLD2, undernourished children and adults may receive MCT preparations, oils and margarines to cover energy requirements [59]. Both protocols warn of bulimia-type eating disorders, favoured by leptin deficiency and the psychological impact of lipodystrophy [58, 59].

Very-low-energy diets currently have proof-of-concept evidence: a 38-year-old woman with FPLD2 receiving 800 kcal/day for 4 months had a 40 % fall in TG and a 1.4-point reduction in HbA1c, with reproductive benefit [11, 62]. A Cambridge study is assessing total diet replacement for 12 weeks, followed by 6 weeks of reintroduction, in approximately 20 patients with FPLD and diabetes, with HbA1c at 12 weeks as the primary endpoint [158].

Exercise should be encouraged in the absence of contraindications (IIa, C), with cardiac assessment before starting in subtypes predisposed to cardiomyopathy; strenuous exercise should be avoided in cardiomyopathy and contact sports in severe hepatosplenomegaly and CGL with lytic bone lesions [60, 116]. The Brazilian consensus recommends aerobic exercise, following assessment for structural heart disease, and resistance exercise [11]. The Japanese guideline draws attention to reduced physical endurance, difficulty maintaining temperature in the cold (for example, when swimming) and plantar calluses [65].

The French PNDS require a cardiovascular examination before any physical activity programme and recommend at least 3 hours and 30 minutes per week in adults and 1 hour per day in children, according to the 2020 PNNS references, with stretching exercises and a type of activity adapted to cardiovascular complications, musculotendinous pain and muscle fatigability [58, 59]. Muscle contraction increases glucose uptake through pathways independent of insulin signalling, so exercise lowers glucose even with severe resistance, and the CGL protocol places diet and physical activity ahead of drugs [58].

The PNDS for laminopathies with cardiac presentation adds a restriction that covers patients with FPLD2: in LMNA-related lipodystrophies it recommends an appropriate diet and regular non-intensive exercise, after a cardiovascular examination, but contraindicates competitive sport when there is cardiac expression, especially with dilated cardiomyopathy or ventricular hyperexcitability, advises limiting sustained high-intensity activities throughout life and generally advises against competition in carriers still without cardiac expression, in a case-by-case decision that avoids a sedentary lifestyle [125]. The basis is observational and experimental: intense physical activity brought forward cardiomyopathy in a mouse model, competition was associated with sudden death and heart failure events, and cumulative lifetime activity was associated with systolic dysfunction and higher NT-proBNP [125].

7.3. Diabetes

Metformin is first-line treatment for diabetes and insulin resistance (IIa, C) [60]. The Japanese guideline differs, considering that metformin efficacy has been demonstrated only in HIV-associated lipodystrophy [65], and in SHORT syndrome, a differential diagnosis, metformin worsened insulin resistance in three patients [54]. Insulin is effective but may require concentrated preparations and high doses (IIa, C) [60]. Available concentrated preparations include lispro U-200, glargine U-300 and regular insulin U-500, five times more concentrated than U-100, with pharmacokinetics similar to NPH (neutral protamine Hagedorn) insulin and two to three administrations daily [62]. Glargine and degludec have altered kinetics when injected into lipodystrophic areas, and in generalised lipodystrophy the intramuscular route may be necessary [60]. In the Japanese guideline, high-dose insulin is frequently ineffective and secretagogues alone have little efficacy [65]. Insulin requirements may be extreme: two Belgian sisters with CGL1 received 1200 and 3000 U/day before metreleptin, and a Brazilian patient with CGL2 reached 1600 IU/day [112, 159].

The French PNDS consider metformin acceptable, in children and adults, as soon as there is an abnormality of glucose metabolism, even without diabetes: fasting glucose above 1 g/L (5.6 mmol/L) or 2-hour OGTT glucose above 1.40 g/L (7.8 mmol/L), a prescription outside the marketing authorisation (MA) but validated, intended to delay metabolic deterioration; the CGL protocol acknowledges that efficacy may be limited by the severity of steatosis [58, 59]. Sulfonylureas stimulate insulin secretion in recent-onset lipoatrophic diabetes, with efficacy reduced by multitissue resistance [58]. GLP-1RA, DPP-4 inhibitors and SGLT2 inhibitors have very limited published data and, in children, may be used under monitoring despite the lack of a paediatric MA [58, 59]. Insulin, including concentrated formulations (U-200; U-500, in France under a temporary authorisation for use) and continuous subcutaneous infusion, is given under the supervision of a specialist team; thiazolidinediones are not marketed in France [58, 59]. In FPLD2, GLP-1RA improved glycaemic control, insulin requirements and hunger in case reports; in patients of normal weight, weight loss should be monitored, and the risk of pancreatitis depends mainly on pre-existing hypertriglyceridaemia, although a meta-analysis in type 2 diabetes did not show an increase in this risk [59]. The CGL protocol concludes the strategy with a stepwise scheme: diet and exercise, gradual addition of glucose-lowering drugs as hyperglycaemia develops, metreleptin if necessary, and annual assessment of microvascular and macrovascular complications [58].

Thiazolidinediones may improve metabolic complications in partial lipodystrophy, but should be used only with caution in generalised lipodystrophy (IIb, B); in the partial form they improved HbA1c, TG, liver volume and steatosis, but may increase excessive regional fat and lipomas [60, 62]. They act on PPARγ and have a theoretical advantage in FPLD3 [11, 14]. The Japanese guideline considers them effective in partial forms but not in generalised lipodystrophy [65]. Pioglitazone (Actos®) is authorised in the USA only for adult type 2 diabetes and carries a boxed warning for causing or worsening congestive heart failure; its use in FPLD with diabetes falls under the type 2 diabetes indication, without authorisation for lipodystrophy [14]. Fluid retention and heart failure warrant caution, and safety in generalised lipodystrophy is unestablished [62].

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) had efficacy and safety comparable to matched type 2 diabetes in a retrospective study of 14 patients with FPLD (13 FPLD1, 1 FPLD2), and in the French network 57 patients with FPLD improved BMI, HbA1c and TG at one year, with one episode of pancreatitis with severe hypertriglyceridaemia in a non-adherent patient [11, 62]. In a larger French series, 76 adults with FPLD receiving GLP-1RAs reduced BMI, HbA1c and TG at 12 ± 6 months and at 18 months or more, with gastrointestinal effects in 34 % [116]. Caution concerns previous pancreatitis and abrupt withdrawal, which may cause rebound hypertriglyceridaemia and pancreatitis [62]. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors, was studied in two observational series. In the first (17 patients, 14 with FPLD; 8.7 months), BMI fell by 1.7 kg/m², HbA1c by 1.1 points, TG by 65 mg/dL and insulin by 109 U/day (medians) [11, 160]. In the Cambridge series (40 patients with partial lipodystrophy, 65 % with an FPLD1-like phenotype, all with diabetes, 77.5 % with previous GLP-1RA use), tirzepatide started at 2.5 mg weekly, off-label in the United Kingdom, up to a maximum of 15 mg (median dose 7.5 mg), with a deficit of 500 to 1000 kcal/day, reduced weight from 91.0 to 82.8 kg, HbA1c from 65 to 52 mmol/mol, TG from 2.80 to 1.83 mmol/L and insulin from 177.5 to 58.0 IU/day over 9.5 months; six patients (15 %) discontinued, five because of gastrointestinal intolerance and one because of pancreatitis [151]. In two patients with CGL1, tirzepatide 15 mg weekly as monotherapy had results described as substantial [11]. An open-label randomised trial of tirzepatide versus usual care in adults with FPLD is recruiting [161].

Sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) were assessed in the French PRISIS network in 59 patients (57 FPLD, 2 CGL; 86 % women): after 29.0 ± 10.7 months, BMI fell from 25 to 23.9 kg/m², HbA1c from 7.8 % to 7.3 %, systolic blood pressure from 130 to 126 mmHg and liver stiffness from 6.8 to 5.8 kPa, with discontinuation in 7 %, mainly due to vaginal fungal infections, and no serious adverse effects [162]. In a smaller series (22 patients in the safety analysis, 12 in the efficacy analysis), HbA1c fell from 9.2 ± 2.0 % to 8.4 ± 1.8 % at 12 months, with cases of ketoacidosis in a patient not adhering to insulin and pancreatitis in a patient with a previous history [11, 62]. Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) are an option, since DPP-4 is elevated in FPLD [11]. Mecasermin (IGF-1) is effective in diabetes with severe insulin resistance, but does not affect appetite and may worsen HCM, so it has not been tested broadly [65].

Bariatric surgery (Roux-en-Y gastric bypass) brought metabolic and weight improvement in most of a small group of patients (two LMNA, two PLIN1 and four with probable FPLD1); in two patients with a C-terminal PLIN1 frameshift and poor control, benefit was marked [15, 62, 163]. Data are scarce and there is no randomised trial [11].

7.4. Dyslipidaemia and pancreatitis

Statins, with lifestyle modification, are first-line treatment for dyslipidaemia (I, C), taking account of age, reproductive status and tolerance; fibrates and/or long-chain omega-3 are indicated with TG above 500 mg/dL and may be considered above 200 mg/dL (IIb, C) [60]. Statins and fibrates require caution because of myopathy, particularly with myositis or muscular dystrophy (CGL3, CGL4, FPLD2 and FPLD6) [17, 60]. Stricter targets may be considered, even without diabetes: low-density lipoprotein (LDL) cholesterol below 100 mg/dL, non-HDL below 130 mg/dL and TG below 200 mg/dL [60]. The Brazilian consensus proposes high-potency statins with ezetimibe as first-line treatment to meet LDL targets, with non-HDL and apolipoprotein B as secondary targets, and fibrates and omega-3 in hypertriglyceridaemia of 500 mg/dL or more [11]. An expert review considers omega-3 efficacy unproven and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors not systematically studied, and indicates fenofibrate when the response is insufficient [62]. Plasmapheresis has been used in extreme hypertriglyceridaemia, but requires frequent repetition [60]. In the Japanese guideline, hypertriglyceridaemia is treated with fibrates, statins, eicosapentaenoic acid (EPA) and ezetimibe, often with difficult control [65]. Withdrawal of oral oestrogens, a diet low in fat and sugar, a fibrate, omega-3 (4000 mg/day), metformin, dapagliflozin, a statin and MCT oil enabled control of diabetes and lipids in a woman with FPLD2 following pancreatitis with TG of 5400 mg/dL [116]. Therapies targeting apolipoprotein C-III (APOC3) are addressed in section 7.8.

The French PNDS set their own LDL targets, aligned with the 2019 European dyslipidaemia recommendations and treating patients as being at high cardiovascular risk: LDL below 1 g/L (2.6 mmol/L) in primary prevention, even without diabetes, below 0.70 g/L (1.8 mmol/L) with diabetes, hypertension or another risk factor, and below 0.55 g/L (1.4 mmol/L) in secondary prevention; the FPLD2 protocol adds a non-HDL cholesterol below 1.30 g/L (3.35 mmol/L) in primary prevention [58, 59]. A statin is the first choice, with dose and molecule adjusted to the target; ezetimibe is added if the target is not reached or replaces the statin in intolerance, and PCSK9 inhibitors are reserved, after specialist advice, for patients who meet the reimbursement criteria [58, 59]. A fibrate is the drug for severe hypertriglyceridaemia, above 5 g/L (5.65 mmol/L), resistant to lifestyle measures, to prevent pancreatitis; it reduces TG by 20 % to 50 % on average and increases HDL by 5 % to 25 %, and is contraindicated in pregnancy, breastfeeding and severe renal or hepatic impairment [58, 59]. If hypertriglyceridaemia persists, omega-3 fatty acids may be added at a supraphysiological dose, at least 2 to 4 g per day, which are not reimbursed in France [58]. In FPLD2, a fibrate may also be considered with TG of 2 g/L (2.26 mmol/L) or more and low HDL (below 0.50 g/L in women and 0.40 g/L in men) after the LDL target has been reached [59]. The combination of statin and fibrate should be started by a specialist, with fenofibrate, and gemfibrozil is contraindicated with statins [58, 59]. Lipid and liver profiles, and CK if there are muscle complaints, are checked before and 2 to 3 months after starting a lipid-lowering drug and then once or twice a year; transaminases above 3 times normal contraindicate statins and fibrates, especially if they rise on treatment [58, 59]. The two protocols diverge on CK: in CGL, its frequent elevation does not contraindicate treatment provided there is clinical and laboratory monitoring, whereas in FPLD2 a lipid-lowering drug should not be started with CK above 5 times normal [58, 59].

7.5. Hypertension, liver, kidney and heart

Angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are first-line treatment for hypertension with diabetes (IIa, C) [60]. Cholic acid did not reduce steatosis in FPLD in a double-blind, crossover, placebo-controlled trial; vitamin E and pioglitazone have histological benefit in MASLD without lipodystrophy but have not been studied in lipodystrophy [60]. Obeticholic acid was studied in a small phase 2 trial in FPLD2 with results available in the registry [62, 164]. Metreleptin reduces steatosis, transaminases and steatohepatitis scores within 6 to 12 months, and one case of severe recurrent steatosis after liver transplantation improved with the drug [60]; the Japanese guideline states that it reduces hepatic lipid accumulation without altering fibrosis in two studies [65]. Elastography and assessment of portal hypertension guide follow-up (section 11). The French PNDS prohibit alcohol in the presence of hepatomegaly, abnormal liver tests, steatosis or suspected cirrhosis, and then complete the aetiological work-up with a review of hepatotoxic drugs, hepatitis B and C serology, caeruloplasmin, ferritin, anti-smooth muscle, antinuclear, anti-LKM, antimitochondrial and IgA anti-transglutaminase antibodies, thyroid-stimulating hormone and elastography [58, 59]. They refer to hepatology, preferably to the rare liver diseases network, to discuss diagnostic and prognostic biopsy, patients with FIB-4 above 2.67 (CGL protocol) or above 4 (FPLD2 protocol), F2 fibrosis on elastography, cytolysis above 2 times normal or ultrasound signs of cirrhosis or portal hypertension [58, 59]. In CGL, hepatomegaly with abdominal lipoatrophy makes the umbilicus protrude, which should not be mistaken for a true umbilical hernia, which has also been described [58]. Proteinuria should be treated according to diabetic nephropathy standards, and the group that described LMNA p.(Arg349Trp) nephropathy recommends early renoprotection in these carriers [104]. Treatment of HCM and arrhythmias and prevention of sudden death in laminopathies follow those of familial dilated cardiomyopathy, progressive cardiac conduction disease and left ventricular noncompaction; in FPLD2, the decision to implant a cardioverter-defibrillator or pacemaker was necessary in 5 of 11 patients with Emery–Dreifuss overlap [13, 105].

The French PNDS treat hypertension according to general population recommendations, but advise caution with beta-blockers and rate-slowing calcium channel blockers when the ECG shows conduction disease, which concerns mainly CGL4 and the laminopathies [58, 59]. In CGL, HCM is followed by cardiologists of the rare cardiac diseases network, and prevention of sudden death in CGL4, especially with long QT, is planned in specialist centres [58]. In LMNA-related lipodystrophies, rhythm and conduction disturbances may precede structural myocardial damage, so implantation of a cardioverter-defibrillator for primary prevention is generally early in the cardiomyopathy, and the FPLD2 protocol refers to the laminopathy malignant ventricular arrhythmia risk calculator (https://lmna-risk-vta.fr); coronary revascularisation in secondary prevention is left to specialist cardiologists [59, 124]. Cardiac MRI with late gadolinium enhancement, especially septal, may detect early fibrosis and have prognostic value for conduction disease and arrhythmias, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), raised in ventricular dysfunction or dilatation, is associated with ventricular arrhythmias [59].

The indication for an implantable cardioverter-defibrillator (ICD) in FPLD2 follows the rules for laminopathies with cardiac presentation [125]. In secondary prevention (resuscitated cardiac arrest, sustained ventricular arrhythmia), the indication is formal; in primary prevention, the ejection fraction criterion of below 35 % used in dilated cardiomyopathy is not sufficiently sensitive, and the 2022 PNDS combines two strategies [125]. The first counts four independent risk factors for malignant ventricular arrhythmia: male sex, non-sustained ventricular tachycardia (NSVT) on Holter, left ventricular ejection fraction (LVEF) below 45 % and a non-missense LMNA variant (truncating, insertion or deletion, or splicing); with two or more factors, the risk justifies an ICD and, with zero or one, surveillance suffices (European cohort of 269 carriers; French validation in 101 patients, with a C-index of 0.76), except in a man with a non-missense variant and no other factor, in whom the decision is individual [125]. The second is the LMNA-risk-VTA calculator (https://lmna-risk-vta.fr), which estimates the absolute 5-year risk of malignant ventricular arrhythmia from sex, atrioventricular block (absent, first-degree or high-grade), NSVT (three or more ventricular beats at 120/min or more), LVEF and variant type; it was developed in 444 patients (C-index 0.776, with a calibration slope of 0.827) and externally validated in 145 (C-index 0.800); in the original study, an estimated 5-year risk of 7 % or more captured 96.2 % of severe arrhythmias; direct comparison with the recommendations favoured the model, and most teams use the 10 % 5-year threshold [124, 125]. The PNDS presents the value of 0.827 as the validation C-index, whereas in the study it corresponds to the calibration slope of the derivation sample [124]. The 2022 European Society of Cardiology (ESC) recommendations, cited by the PNDS, propose a prophylactic ICD with a 5-year risk of 10 % or more combined with LVEF below 50 %, atrioventricular block or NSVT [125]. A transvenous ICD is preferred to a subcutaneous one, because high-grade conduction disease is frequent, and, when there is an indication for permanent pacing, an ICD rather than a pacemaker, because 10 of 84 pacemaker carriers died suddenly in a meta-analysis; the pacemaker follows the usual criteria for conduction disease [125]. Around 30 % of ICD carriers have complications at 5 years (inappropriate shocks, infections, lead fracture), so the patient's informed choice carries particular weight at intermediate risk [125].

In atrial fibrillation or flutter, paroxysmal or permanent, the laminopathy PNDS requires therapeutic anticoagulation regardless of the CHA₂DS₂-VASc score, prefers maintenance of sinus rhythm because of the risk of ventricular deterioration and warns of the lower efficacy of ablation (early recurrence in 7 of 8 patients in one series); antiarrhythmic drugs respect the contraindications of ventricular dysfunction, conduction disease and ventricular hyperexcitability [125]. Refractory ventricular tachycardia responds poorly to ablation (91 % recurrence, 44 % progression to end-stage heart failure and 26 % mortality in a multicentre series), and rhythm treatment should not delay a transplant plan [125]. Heart failure with reduced ejection fraction is treated with beta-blockers, ACE inhibitors or ARBs, sacubitril-valsartan and gliflozins according to general recommendations, without demonstrated specific efficacy in laminopathies; resynchronisation produced a response in 38 % to 62 % of patients, and progression faster than in other cardiomyopathies justifies early referral to a heart failure centre for circulatory support or transplantation [125]. The increased venous thromboembolic risk advises proactive thromboprophylaxis in at-risk situations and weighs in the choice of anticoagulation in secondary prevention [125]. The detail of these decisions belongs to laminopathy cardiology.

7.6. Appearance, mental health and pain

Appearance-related distress should be assessed, with referral to mental health and plastic surgery services (IIa, C): autologous fat (particularly in APL), dermal fillers and muscle grafts for facial lipoatrophy; liposuction or surgical reduction of excess fat in the head, neck or vulva; breast implants [60]. Deoxycholic acid has been used for submental fat in certain FPLD subtypes [62]. Adipose expansion with adipose-derived stem cells lacks evidence [65]. Acanthosis improves with treatment of insulin resistance [60]. Psychological support and a pain team should form part of follow-up, given the burden of anxiety, depression and chronic pain [11, 62, 93]. Adherence to daily metreleptin injections fluctuates with psychological distress, musculoskeletal pain and treatment burden [116, 159].

The French PNDS distinguish plastic surgery in the two forms. In CGL, the almost total absence of subcutaneous fat precludes liposuction combined with lipoinjection; what remains are procedures on bony or muscular contours, with an exceptional aesthetic indication and sometimes with functional consequences, facial, breast or gluteal prosthetic implants and fillers, mainly facial, with hyaluronic acid, minimally invasive but of temporary effect, and in practice these methods are rarely used because medical problems take priority [58]. In FPLD2, the loss of breast tissue, muscular hypertrophy of the limbs and the cushingoid face have a strong psychological impact, often experienced as an attack on femininity; areas of adipose hypertrophy (face, limb roots, pubic region) are treated by liposuction or dermolipectomy, atrophic areas (breasts, limbs) by autologous fat transfer from the hypertrophic areas, often in several stages, and breast prostheses are another option [59]. Reconstructive surgery has no known effect on metabolism, requires controlled diabetes and risk factors and smoking cessation before the procedure so as not to compromise healing, and carries risks (haematoma, hypoaesthesia) and a possibility of long-term recurrence; metreleptin, through loss of fat mass, may reduce facial adipose volume in FPLD2, but may also accentuate facial lipoatrophy in CGL [58, 59]. In France, plastic surgery, laser hair removal for marked hirsutism and other services are reimbursed at 100 % under the off-list long-term condition scheme (ALD 31), subject to prior agreement of the Social Security medical adviser [58, 59].

Psychological support, according to the same protocols, should be offered at defined moments: at disclosure of the diagnosis and of new complications (for example, the onset of diabetes), in adolescence (body image, the gaze of others, dietary restrictions), before the transition to adult services and in the face of a pregnancy plan, with attention to parental guilt and anxiety and to the impact on siblings, and with group therapeutic education workshops, where they exist, for peer sharing [58]. In adults, quality of life, self-esteem, social relationships and educational and occupational consequences are assessed systematically, as they are altered by hyperphagia, appearance, hirsutism and infertility, and psychological assessment is part of therapeutic education programmes [58, 59].

Musculoskeletal and neuromuscular pain has its own approach. In CGL, because diabetes is difficult to control, non-pharmacological options should be exhausted before corticosteroid injections, oral non-steroidal anti-inflammatory drugs depend on renal function and cardiovascular risk, and rehabilitation is based on regular physical activity, work on joint range of motion and combating contractures, with physiotherapy, balneotherapy and self-exercises; a fracture through a focal lytic lesion is a fracture in locally weakened bone and does not in itself justify anti-osteoporotic treatment, but physical activity and vitamin D and calcium intake are reinforced, and patients should be reassured about the low fracture risk of the bone lesions, sometimes overestimated by those unfamiliar with the disease [58]. In FPLD2, myalgia and cramps are treated with stepwise analgesics, muscle relaxants, massage and metabolic optimisation; in forms with muscle degeneration, without pathophysiological treatment, the neuromuscular clinic coordinates physiotherapy with stretching and gentle strengthening, technical aids (crutches, orthoses, walking frame, wheelchair) and surgery for contractures (mainly Achilles) and severe scoliosis after assessment of respiratory function, with respiratory physiotherapy, cough assistance and non-invasive ventilation if necessary, and influenza and pneumococcal vaccines should be up to date in patients with respiratory involvement [59]. Neuropathic pain may be treated with gabapentin, pregabalin, antidepressants (clomipramine, imipramine, amitriptyline, duloxetine) and lidocaine plasters for localised pain, and entrapment syndromes may have a surgical, endoscopic indication [59]. The PNDS does not give doses; in the US labels for neuropathic pain of adult diabetic neuropathy, pregabalin starts at 50 mg three times daily (150 mg/day) and may be increased to 300 mg/day within the first week, maximum 300 mg/day with creatinine clearance of at least 60 mL/min, and duloxetine is used at 60 mg once daily, with a lower starting dose and gradual increase in renal impairment [165, 166].

7.7. Metreleptin

Mechanism and presentation

Metreleptin is a methionylated recombinant human leptin, produced in Escherichia coli, with 147 amino acids, non-glycosylated, one disulphide bridge between Cys97 and Cys147 and approximately 16.15 kDa; it activates the leptin receptor, a member of the class I cytokine receptor family, through the JAK/STAT pathway (Janus kinases and signal transducers and activators of transcription) [63]. Peak plasma concentration occurs approximately 4 hours after subcutaneous injection, half-life is 3.8 to 4.7 hours in healthy volunteers and elimination is predominantly renal; anti-drug antibodies delay clearance, and leptin assays measure endogenous leptin and metreleptin together [63, 64]. In the USA, Myalept® is supplied as an 11.3 mg vial of lyophilised powder, reconstituted with 2.2 mL of bacteriostatic water for injections (with 0.9 % benzyl alcohol) to 5 mg/mL, usable for 3 days in the refrigerator (2 to 8 °C, protected from light), or with preservative-free water for injections for immediate use, mandatory in neonates and infants [63]. In the EU, Myalepta® is available in 3 mg, 5.8 mg and 11.3 mg vials, reconstituted with 0.6, 1.1 and 2.2 mL of water for injections to 5 mg/mL, for single, immediate use [64]. Injection is subcutaneous into the abdomen, thigh or arm, at 45° with a skinfold, avoiding the intramuscular route, particularly with little subcutaneous tissue, and never intravenous; doses above 1 mL may be divided into two injections, and metreleptin should not be mixed with insulin [63]. The first dose is administered under the supervision of a doctor or nurse [63, 64].

Dosage

The dose is administered once daily, at the same time, independently of meals; a missed dose should be administered as soon as noticed, resuming the schedule the following day [63]. In the EU, the dose is calculated from actual weight at initiation, prescribed in mg and in mL, and the self-administration technique should be reviewed every 6 months [64]. Dose increases should be no more frequent than every 4 weeks, and only after at least 6 months of treatment when the response is incomplete, whereas reductions for excessive weight loss may be weekly; the maximum tolerated dose may be below the maximum dose because of weight loss, even with an incomplete metabolic response [64]. In children, HbA1c and TG may not change, because there are no baseline abnormalities, and most will need an increase in dose per kilogram, particularly during puberty, adjusted for weight change [64]. Small paediatric volumes have led to medication errors; an infant who received ten times the dose for 8 months because of a calculation error developed severe anorexia, vitamin and zinc deficiencies, iron-deficiency anaemia, protein–energy malnutrition and poor weight gain, resolved with support and adjustment [63]. In the EU, for patients up to 25 kg a 0.3 mL U100 insulin syringe is used, rounding down to 0.01 mL (for example, 15 kg: 0.9 mg = 0.18 mL = 18 units; after an increase of 0.02 mg/kg, 1.2 mg = 0.24 mL = 24 units); for doses between 1.5 and 5 mg a 1 mL syringe is used, and above 5 mg a 3 mL syringe [64]. The Brazilian consensus proposes an initial dose of 0.05 mg/kg in FPLD, with a maximum of 10 mg, different from the US and EU labels, and the Japanese guideline uses target doses by sex and age; the first NIH trial, which included two Belgian sisters with CGL1, started with 0.015 mg/kg/day in boys and 0.02 mg/kg/day in girls under 18 years, approximately 50 % of estimated physiological replacement, with escalation up to 200 % [11, 65, 159]. In European and American practice the labels take precedence.

Monitoring, response and withdrawal

The 2016 guideline recommends clinical and laboratory assessment every 3 to 6 months and dose adjustment according to metabolic parameters and weight [60]. The European summary of product characteristics (SmPC) defines a minimum clinical response as a reduction in HbA1c of at least 0.5 points and/or a reduction in insulin requirements of at least 25 % and/or a reduction in TG of at least 15 %; without a response at 6 months, technique, dose and dietary adherence should be checked and a dose increase considered before discontinuation [64]. The Japanese guideline assesses efficacy by 2 months, with possible improvements from 2 weeks in HbA1c, fasting glucose, insulin, the HOMA (homeostasis model assessment) index, liver enzymes, TG, liver imaging, appetite (particularly postprandial satiety), acanthosis and gonadal function, and considers discontinuation in the absence of effect [65].

The risk of hypoglycaemia requires reductions in insulin and secretagogues at initiation: the European SmPC provides for reductions of 50 % or more in basal insulin in the first 2 weeks, the 2016 guideline suggests reducing insulin by approximately 50 % in patients with well-controlled diabetes, and non-severe hypoglycaemia may be managed with food [60, 63, 64]. Withdrawal in patients at risk of pancreatitis (previous pancreatitis or severe hypertriglyceridaemia) should be gradual, over 1 week according to the USA label and 2 weeks, with a low-fat diet, according to the European SmPC, with TG monitoring and initiation or adjustment of lipid-lowering agents; if pancreatitis develops during metreleptin treatment, the European SmPC advises against stopping treatment, because abrupt withdrawal may worsen it [63, 64]. Pancreatitis has been described in patients who abruptly stopped or reduced the drug [60].

Efficacy

In the USA registration trial (NIH, open-label, single-arm; 48 patients with generalised lipodystrophy, 32 CGL and 16 AGL; median age 15 years; median baseline leptin 0.7 to 1.0 ng/mL; median duration 2.7 years), at 12 months HbA1c fell by 2.0 points from 8.5 % (n = 35), fasting glucose by 49 mg/dL from 174 mg/dL (n = 37) and TG by 55 % from a median of 348 mg/dL (n = 36); in the subgroup with TG of 500 mg/dL or more (n = 12), the median of 1527 mg/dL fell by 1117 mg/dL [63]. In the European analysis of the same programme (66 patients with generalised lipodystrophy, 45 CGL; median duration 4.2 years), HbA1c fell by 2.2 points from 8.6 % (n = 59; p < 0.001) and TG by 32.1 % from 14.7 mmol/L (n = 58; p = 0.001); 16 of 39 patients (41 %) discontinued insulin, 7 of 32 (22 %) oral antidiabetic agents and 8 of 34 (24 %) lipid-lowering agents, proteinuria fell by 906 mg/24 h from 1676 mg/24 h (n = 24) and alanine aminotransferase (ALT) by 53 U/L from 112.5 U/L [64]. In the partial lipodystrophy subgroup defined by the European Medicines Agency (EMA) (31 patients with TG of 5.65 mmol/L or more and/or HbA1c of 6.5 % or more; 27 FPLD and 4 APL; 97 % women; median age 38 years; median leptin 5.9 ng/mL), HbA1c fell by 0.9 points from 8.8 % (n = 27; p < 0.001) and TG by 37.4 % from 15.7 mmol/L (n = 27; p < 0.001); with baseline TG of 5.65 mmol/L or more (n = 15) the fall was 53.7 %, and with HbA1c of 8 % or more (n = 18) it was 1.3 points [64]. In 53 patients under 18 years treated at the NIH, fasting glucose fell from 176 to 121 mg/dL, HbA1c from 8.3 % to 6.5 % and median TG from 374 to 189 mg/dL at 12 months [116].

Metreleptin reduces hyperphagia, often with weight loss, improves glycaemia from the first week, reduces LDL and total cholesterol without altering HDL, reduces steatosis and transaminases, decreases proteinuria in most patients (four patients had worsening renal function, so pre-existing renal disease requires monitoring), normalises gonadotrophins, puberty and menstruation in women, reduces testosterone without altering ovarian morphology and increases testosterone in men [60]. It attenuates cardiac hypertrophy and improves septal e′ velocity [62]. It does not alter subcutaneous fat distribution [64]. In the NIH study, treatment initiation before severe complications was associated with better long-term control of diabetes, proteinuria and TG and less fibrosis progression [116]. In Japanese post-marketing surveillance (48 patients in the safety analysis, 15 in the efficacy analysis; mean observation 4.3 years), HbA1c and TG fell at 2 to 4 months and remained stable for up to 7 years, with less improvement in the partial form [167]. A discrete choice experiment estimated a gain of 0.313 quality-adjusted life-years (QALYs) at 12 months in generalised lipodystrophy and 0.117 in partial lipodystrophy, corresponding to an approximately 59 % and 31 % reduction in the deficit relative to perfect health [128].

In partial lipodystrophy, response is smaller and heterogeneous. In one study, metreleptin reduced TG and improved glycaemia in patients with HbA1c above 8 %, TG above 500 mg/dL and leptin below 4 ng/mL; in another, it improved TG and insulin sensitivity and secretion in FPLD2 with moderate to severe hypoleptinaemia; in a third, it did not improve glycaemia in FPLD2 with leptin below 7 ng/mL [60]. FPLD2 with severe hypoleptinaemia (below the 7th percentile) or moderate hypoleptinaemia (7th to 20th percentiles) had a similar reduction in serum and hepatic TG, without improvement in hyperglycaemia, and no leptin threshold reliably predicts response [11, 62]. Over 12 months, 7 patients with FPLD3 went from HbA1c 9.2 % to 7.7 % and TG 1377 to 680 mg/dL, and 22 with FPLD2 from 7.8 % to 7.3 % and from 332 to 293 mg/dL; the probability of TG reduction above 30 % and HbA1c reduction above 1 point was greater with baseline TG of 500 mg/dL or more and HbA1c above 8 % [11]. In the Japanese experience, patients with the partial form and leptin of 4 ng/mL or more (21 patients) did not improve significantly, whereas those with HbA1c of 8 % or more or TG of 500 mg/dL or more improved regardless of leptin [65]. These open-label data are subject to the Hawthorne effect and regression to the mean [62].

Adverse effects

Adverse effects with a frequency of 5 % or more in the USA trial were headache, hypoglycaemia and weight loss (13 % each), abdominal pain (10 %), arthralgia, dizziness, otitis, fatigue, nausea, ovarian cyst and upper respiratory tract infection (8 % each), and anaemia, low back pain, diarrhoea, paraesthesia, proteinuria and fever (6 % each) [63]. The European list also includes decreased appetite, tachycardia, deep vein thrombosis, pleural effusion, alopecia, myalgia and menorrhagia as common effects [64]. Japanese surveillance recorded adverse reactions in 15 of 48 patients, mainly decreased appetite and neutralising antibodies, and one clearly related anaphylactic reaction; two deaths (infarction in a patient with three previous infarctions and pleural effusion) were not clearly related, and no lymphomas, hypoglycaemia or pancreatitis were reported [167]. In a patient with CGL1, loss of control after 14 years of treatment was associated with antibodies with neutralising activity (titre 1:30), and control improved with the same total dose divided between two sites and better adherence, despite persistent antibodies [159]. Leptin may alter cytochrome P450 enzymes and induce CYP3A, so narrow-therapeutic-index drugs (warfarin, ciclosporin, theophylline) should be monitored and hormonal contraceptives may lose efficacy, requiring an additional non-hormonal method [63, 64]. In the USA, metreleptin is contraindicated in general obesity without congenital leptin deficiency and in previous severe hypersensitivity; in the EU, only in hypersensitivity [63, 64].

Comparative regulatory status

In Brazil, metreleptin was approved by the National Health Surveillance Agency (ANVISA) in 2023 for generalised lipodystrophy from 2 years and partial lipodystrophy from 12 years without adequate control on standard treatment, according to Brazilian authors; access is government-controlled, case by case, and the patient with CGL2 described by Sued Leão started treatment through named-patient use before registration and experienced a 36-month interruption because of lack of access [66, 112]. In Canada, the indication covers generalised lipodystrophy from 2 years and partial lipodystrophy from 12 years with persistent significant metabolic disease, according to the authors of an international case series [116]. In Greece, metreleptin became available only after European approval [147]. The sources consulted contain no data on metreleptin access or reimbursement in Portugal; in the Porto series, three patients with generalised lipodystrophy were receiving treatment [96].

French framework (PNDS)

The French PNDS consider metreleptin the only specific treatment of lipodystrophic syndromes and, in generalised lipodystrophy, a first-line treatment of the metabolic complications, with effects of around −2 points in HbA1c and −60 % in TG, improvement in liver volume and liver enzymes, control of hyperphagia (with fewer hyperglycaemic peaks), reduction of left ventricular hypertrophy even after adjustment for hypertension, reduction of proteinuria, and improvement in quality of life and gonadotrophic function, with a fall in testosterone in women [58]. The drug does not reconstitute adipose tissue and, through weight loss, may accentuate facial lipoatrophy; the suggestion of increased life expectancy rests on an observational study that compared treated patients with untreated, less severe patients with FPLD and CGL [58]. In partial lipodystrophy, efficacy was observed mainly in patients with complications not controlled by standard treatment and with low leptin for BMI [59]. In France, metreleptin has a marketing authorisation, as an adjunct to diet, in confirmed generalised lipodystrophy from 2 years of age and in confirmed partial lipodystrophy from 12 years of age with metabolic complications insufficiently controlled by standard treatment; it is a hospital-only prescription, initiated and renewed by specialists in paediatrics or in endocrinology, diabetology and nutrition, in conjunction with the hospital pharmacist [58, 59].

Both protocols require the indication to be validated, and then reassessed at least once a year, at a multidisciplinary team meeting (RCP) of the PRISIS reference centre, baseline leptin to be documented and the prescription to be reassessed every 6 months for efficacy, tolerability and adherence [58, 59]. The physician gives and explains to the patient the package leaflet, the instructions for use and a card with the prescribed dose, provided by the National Agency for Medicines and Health Products Safety (ANSM), and trains the patient in extemporaneous reconstitution of the powder with water for injections and daily subcutaneous self-administration at the same time [58, 59]. The initial dose given as an example, 5 mg (1 mL) per day in women over 40 kg, coincides with that of the European SmPC and is adjusted after 1 month according to efficacy (HbA1c, TG, liver abnormalities) and tolerability (weight); follow-up includes a visit after 1 month and quarterly visits in the first year [58, 59, 64]. According to the protocols, around 30 % of patients have adverse effects, mainly hypoglycaemia in those treated with insulin, weight loss and injection-site reactions (erythema, urticaria); anti-metreleptin antibodies are frequent but rarely neutralising and should be sought in the event of significant loss of efficacy; and there are rare cases of lymphoma in autoimmune forms of generalised lipodystrophy, of pancreatitis (in patients with previous pancreatitis, especially on discontinuation) and of renal or hepatic worsening [58, 59]. Metreleptin requires effective contraception in women [58]. At each visit, lipodystrophy at insulin and metreleptin injection sites is looked for [58].

7.8. Therapies targeting APOC3 and the leptin receptor

Volanesorsen (Waylivra®) is an antisense oligonucleotide against APOC3 messenger RNA. In the BROADEN trial (phase 2/3, randomised, triple-blind), 40 adults with FPLD, type 2 diabetes (HbA1c 7 % to 12 %), TG of 500 mg/dL or more and steatosis received 300 mg of volanesorsen sodium weekly or placebo for 52 weeks; at month 3, TG fell by 88.5 % with volanesorsen and 21.6 % with placebo (difference −66.8 percentage points; 95 % CI −104.2 to −29.5; p = 0.0009), and at month 12 liver fat fraction on MRI fell by 51.9 % versus a rise of 1.5 % (difference −53.3; 95 % CI −87.7 to −19.0; p = 0.0039), without a difference in HbA1c; serious adverse effects occurred in 6 of 21 treated patients and 3 of 19 receiving placebo [150, 169]. The trial was terminated early when data were sufficient to decide on development [150]. In the EU, volanesorsen has had conditional authorisation since 3 May 2019 only for genetically confirmed familial chylomicronaemia syndrome (FCS) with a high risk of pancreatitis and inadequate response; each syringe contains 285 mg of volanesorsen in 1.5 mL, equivalent to 300 mg of volanesorsen sodium, explaining the two expressions of the same dose [168, 170]. It is not authorised in the USA [62, 168]. In Brazil, ANVISA approved Waylivra® in December 2022 as the first FPLD treatment, the first worldwide approval for this indication, according to the marketing authorisation holder's announcement, consistent with an expert review; the official label was not consulted, and the drug, with active registration, has not been submitted to the National Commission for the Incorporation of Technologies into SUS (CONITEC) and is not on the Unified Health System (SUS) lists [62, 171, 172]. The Brazilian consensus proposes considering volanesorsen 285 mg weekly in FPLD with acute or recurrent pancreatitis, or high risk due to refractory TG of 500 mg/dL or more, with weekly platelet counts and maintenance above 140,000/μL [11]. The European SmPC, for FCS, provides for weekly administration for 3 months and then fortnightly, discontinuation if TG do not fall by at least 25 % or below 22.6 mmol/L at 3 months, and a more detailed platelet schedule: with 140 × 10⁹/L or more, fortnightly monitoring; with 100 to 139, weekly monitoring and fortnightly dosing; with 75 to 99, interruption for at least 4 weeks; with 50 to 74, interruption and monitoring every 2 to 3 days; below 50, discontinuation, daily monitoring, glucocorticoids and haematology consultation [170]. Thrombocytopenia is the principal adverse effect [11, 170].

Olezarsen (Tryngolza®), another anti-APOC3 oligonucleotide, was approved in the USA on 19 December 2024 for FCS (80 mg monthly) and, through a supplement on 24 June 2026, to reduce TG and the risk of acute pancreatitis in adults with severe hypertriglyceridaemia (TG of 500 mg/dL or more), at 50 mg monthly, increasable to 80 mg [173]. In the severe hypertriglyceridaemia trials (1061 patients, 63 % with type 2 diabetes, 15 % with pancreatitis in the previous 10 years), TG fell at month 6, relative to placebo, by between 49 % and 72 % depending on trial and dose, and adjudicated acute pancreatitis was reduced by 85 % with the combined doses (relative risk 0.15; 95 % CI 0.05–0.40), with the effect concentrated in patients with TG of 880 mg/dL or more and previous pancreatitis [173]. Warnings include hypersensitivity, increased liver enzymes and fat (elevation of 3 times the upper limit or more in 7 % with 80 mg) and a mean platelet decrease of 6 % to 10 % [173]. The label contains no lipodystrophy data; a patient with FPLD and TG of 500 mg/dL or more falls within the American severe hypertriglyceridaemia indication, an interpretation that no lipodystrophy guideline has validated [173]. In the EU, olezarsen was authorised on 17 September 2025 only for genetically confirmed FCS [168]. Plozasiran (Redemplo®), an anti-APOC3 interfering RNA, was approved in the USA on 18 November 2025 and in the EU on 19 June 2026, only for FCS, at 25 mg subcutaneously every 3 months; hyperglycaemia is among the most frequent adverse effects, with an HbA1c rise of up to 0.36 points, which matters in lipodystrophic patients with diabetes, and there are no lipodystrophy studies in the sources consulted [168, 174]. Vupanorsen (antisense against angiopoietin-like protein 3, ANGPTL3) had positive lipid effects in FPLD and gemcabene was studied in FPLD, with results in the registry [62].

Mibavademab (REGN4461) is a human monoclonal agonist antibody to the leptin receptor, structurally unrelated to leptin, which activates the receptor in the presence or absence of leptin and does not induce antibodies neutralising endogenous leptin [175]. In the phase 2 trial in generalised lipodystrophy (16 patients aged 12 years or more, HbA1c of 7 % or more and/or TG of 250 mg/dL or more), the low dose had no effect at 8 weeks relative to placebo (fasting glucose difference 38.1 mg/dL; 95 % CI −21.3 to 97.5; TG difference 17.8 %; 95 % CI −67.6 to 103.2); in the open-label high-dose phase, eight patients had a mean HbA1c fall of 2.12 points and a median TG fall of 74.6 % after 52 weeks, with good tolerability and no deaths [175, 176]. In FPLD, a phase 2 trial with 20 adults was terminated by sponsor decision; in cohort A, at 12 weeks, TG fell by 39 % with mibavademab (n = 6) and 11.3 % with placebo (n = 5), without formal statistical testing [177]. A study of transition from metreleptin to mibavademab in 9 patients with generalised lipodystrophy ended in July 2026 without published results, and the phase 3 LAGO trial, randomised and placebo-controlled in generalised lipodystrophy from 2 years (approximately 28 patients), started in March 2026 and is recruiting [178, 179]. An expanded access programme exists [180].

7.9. Treatment trials and studies

Metreleptin studies are open-label and single-arm, with concomitant medication not held constant, and do not allow separation of the drug effect from regression to the mean, the Hawthorne effect and changes in background therapy [62, 63]. Results of different studies should not be compared with one another, because populations differ in baseline leptin, HbA1c, TG and lipodystrophy type, and percentage TG reductions should be read with absolute starting values (for example, 32 % from 14.7 mmol/L in the European generalised form) [64]. The only randomised metreleptin trial in the partial form has no published results. BROADEN was positive for TG and liver fat but not HbA1c, and the mibavademab trial in FPLD was stopped without formal analysis [150, 177]. Tirzepatide and SGLT2 inhibitor series are retrospective, without a control group and, in the Cambridge case, with adverse-effect data in 28 of 40 patients [151, 162].

7.10. Developments in the last 12 months

METRE-PL (NCT05164341) randomised 1:1 69 patients with FPLD aged 12 years or more, at 22 centres in 7 countries, to metreleptin (up to 10 mg/day) or placebo for 12 months; at baseline, mean HbA1c was 8.6 %, mean TG 696 mg/dL, median leptin 8.3 ng/mL, 93 % had diabetes, 29 % previous pancreatitis and 96 % took at least one antidiabetic drug [181, 182]. Primary completion was scheduled for 21 July 2026; an investigator stated that data were expected in autumn 2026, but by 10 October 2026 no results in the registry, top-line results announcement, extension application or FDA decision for partial lipodystrophy had been found, in a search that does not prove their non-existence [181, 182]. An open-label extension [184] and a European phase 4 study in PL [185] continue. Also ongoing are studies of pegvisomant in severe insulin resistance [186], pregnancy natural history with and without metreleptin [187], the MEASuRE registry [188], the ECLip registry [189] and NIH compassionate-use programmes [190]. Preclinically, gene therapy with an adeno-associated viral vector restored white adipose tissue and metabolic health in adult seipin-deficient mice [62]. Setmelanotide had no metabolic benefit in a patient with partial lipodystrophy and leptin deficiency with autoimmunity [62].

7.11. Agents to avoid

Oral oestrogens are contraindicated because of the risk of severe hypertriglyceridaemia and pancreatitis (IIa, C) [60, 116]. Overfeeding and excessive fat intake worsen complications [1, 60]. The 2016 GeneReviews recommended avoiding fenfluramine and other drugs without proven efficacy [1]. Abrupt withdrawal of metreleptin and GLP-1RAs may cause rebound hypertriglyceridaemia and pancreatitis [62, 64]. Statins and fibrates require caution in forms with myopathy [17, 60]. Growth hormone should be avoided in SHORT syndrome [54]. Thiazolidinediones require caution in generalised lipodystrophy and heart failure [14, 60].

7.12. Contraception, pregnancy and lactation

Contraception should be progestogen-only or non-hormonal (IIa, C); if oestrogen replacement is necessary, the transdermal route should be used (IIa, C), and there is safe experience with oral progestogens and progestogen-containing intrauterine devices [60]. Metreleptin may restore luteinising hormone release and increase fertility, with a risk of unplanned pregnancy, and may reduce hormonal contraceptive efficacy [64]. Pregnancy should be monitored by an obstetrician experienced in diabetes and a physician experienced in lipodystrophy (IIa, C) [60], in a high-risk pregnancy unit with fetal medicine [1]. Insulin resistance worsens during pregnancy, hypertriglyceridaemia may worsen with a risk of pancreatitis, and lipodystrophy in pregnancy is associated with gestational diabetes, macrosomia, eclampsia, IUGR, intrauterine death and miscarriage [11, 60, 63]. In eight women with FPLD2, 37.5 % had spontaneous miscarriages, 25 % gestational diabetes and 50 % macrosomia [11].

The French PNDS treat PCOS in these patients as in the general recommendations (lifestyle and exercise; weight loss only if there is excess weight), with metformin to regularise cycles and possibly hyperandrogenism, and antiandrogens for disabling hirsutism or acne; the combined oestrogen-progestogen pill is not the first choice, because oral oestrogen is contraindicated by hypertriglyceridaemia, and depending on the intensity of hyperandrogenism an antigonadotrophic progestogen with transdermal oestrogen may be used [58, 59]. If this progestogen is cyproterone acetate, the patient receives oral and written information on the risk of meningioma, signed by the physician and the patient, and undergoes brain MRI before starting; spironolactone, off-label, requires associated contraception and blood pressure monitoring [58, 59]. The PNDS do not give doses; those of the Endocrine Society guideline for hirsutism in premenopausal women are followed, extrapolated from the general population with hirsutism (including PCOS) to these patients as an analogous condition, without specific studies in lipodystrophies [191]. Spironolactone (Aldactone®) is used orally at 100–200 mg/day in two divided doses, with a maximum of 200 mg/day, added to hormonal treatment when hirsutism persists after 6 months and never as monotherapy without effective contraception, because of the teratogenic risk; it is not used in renal impairment and may cause hyperkalaemia [191]. For cyproterone acetate (Androcur®, 50 mg tablets; not marketed in the USA), the same guideline indicates 50–100 mg/day orally on days 5–15 of the cycle, combined with ethinylestradiol on days 5–25 [191]; in these patients oral oestrogen is replaced by transdermal oestradiol, because of hypertriglyceridaemia [58, 59], and, since the 2020 European referral, formulations of 10 mg/day or more are reserved for patients in whom other options have failed, at the lowest effective dose, with permanent discontinuation if a meningioma develops [192]. The recommended hormonal assessment includes LH, FSH and oestradiol in menstrual irregularity, and total testosterone, SHBG and AMH at the start of the cycle in hyperandrogenism; because SHBG is low due to insulin resistance, total testosterone underestimates androgen excess and bioavailable testosterone is preferable, and pelvic ultrasound, preferably transvaginal, shows multifollicular and/or enlarged ovaries, with a BMI generally below 25 kg/m², lower than in common PCOS [58, 59]. In men with erectile dysfunction or reduced libido, the gonadotrophic axis is assessed (LH, FSH, total testosterone and SHBG) [58, 59].

Infertility is mainly anovulatory and, as a rule after genetic counselling, may be treated with metformin or clomifene citrate, which the FPLD2 PNDS considers more effective for inducing follicular recruitment; the benefit of metreleptin on fertility was not assessed in the protocols [58, 59]. In the US label, clomifene starts at 50 mg per day for 5 days, increases to 100 mg per day for 5 days only if ovulation does not occur, should not exceed 100 mg per day or 5 days, and after three cycles without ovulation or pregnancy treatment should be reassessed; the same label describes hypertriglyceridaemia, sometimes with pancreatitis, especially with pre-existing hyperlipidaemia, high doses or long treatment, and recommends TG measurement before starting and periodic monitoring, a precaution that carries weight in these patients [193].

In pregnancy, the French PNDS require a preconception consultation with a team experienced in lipodystrophy and gestational diabetes and joint follow-up with a specialist lipodystrophy centre and a level 3 maternity unit (CGL) or a level 2 or 3 unit (FPLD2) [58, 59]. Before conception, potentially teratogenic drugs (statins, fibrates, antihypertensives) are stopped, an HbA1c below 6.5 % is targeted in pre-existing diabetes and baseline triglyceride levels are measured; metformin is stopped when pregnancy is diagnosed and may be resumed from the second trimester if insulin, sometimes in concentrated formulations and at very high doses especially from the second trimester, is not sufficient [58, 59]. In pregnant women with FPLD2 without known diabetes, fasting glucose is measured at the very beginning of pregnancy [59]. Monitoring includes regular fetal biometry to detect macrosomia, blood pressure at least monthly to detect gestational hypertension or pre-eclampsia, and monthly TG when they were above 5 g/L before pregnancy; above 10 g/L, the risk of pancreatitis justifies an adapted diet without reducing lipids below what is recommended in pregnancy, omega-3 fatty acids and advice from a specialist centre [58, 59]. In FPLD2, pregnancy may be complicated by miscarriage, gestational diabetes, hypertension, pre-eclampsia, intrauterine fetal death and prematurity, with a higher risk than in women with PCOS without lipodystrophy [59]. In 2022, the CGL PNDS found only one published case of pregnancy, complicated by highly insulin-resistant diabetes and obstetric complications linked to macrosomia; since then the cases of a Greek patient and of two Belgian sisters with CGL1 have been published (section 10.1) [58, 147, 159].

On the cardiac side, the PNDS for laminopathies with cardiac presentation has few data: five women at an early stage of cardiomyopathy, without heart failure, had pregnancies without severe arrhythmias, and in a series of 89 pregnant women with an LMNA variant new arrhythmias occurred in 9 %, without severe maternal or fetal complications and without an unfavourable effect of previous pregnancies [125]. The protocol recommends close cardiological follow-up, with echocardiogram (dimensions and LVEF), Holter and NT-proBNP at intervals dictated by symptoms and clinical status, and possible adaptation of treatment and mode of delivery [125]. These series describe carriers with cardiac presentation; in FPLD2 the metabolic and obstetric risks described above are added.

Sources differ on metreleptin in pregnancy. The 2016 guideline allows treatment continuation if withdrawal could harm mother and fetus, informing the patient that pregnancy effects are unknown, because withdrawal is associated with rebound hypertriglyceridaemia and pancreatitis [60]. The European SmPC does not recommend use during pregnancy or in women of childbearing potential without contraception, reports miscarriages, stillbirths and preterm births in exposed women without evidence of causality, and requires a decision between stopping breastfeeding or metreleptin [64]. The USA label states insufficient data, a pregnancy exposure registry, prolonged gestation and dystocia with maternal death in mice from approximately the maximum clinical dose, no teratogenicity at 7 to 15 times that dose, placental transfer of approximately 1 %, a preference for reconstitution with water for injections without benzyl alcohol and no lactation data [63]. Case series show varied outcomes: in a Greek patient with CGL1, metreleptin enabled spontaneous conception after 13 months of treatment, was stopped at 6 to 8 weeks and pregnancy proceeded uneventfully with an insulin pump [147]; in two Belgian sisters with CGL1, one pregnancy on metreleptin ended in caesarean section for suspected pre-eclampsia and the other required insulin up to 210 U/day and ended in a difficult delivery of a macrosomic neonate, and both breastfed on metreleptin without apparent effects in the infants (section 10) [159]. The Belgian case authors suggest considering caesarean section because of pelvic anatomical changes in CGL [159]. Most pregnant women need additional insulin, particularly in the third trimester [62]. Pregnancies have been described in women with CGL1 and few with CGL2 [1].

The French PNDS take an intermediate position: metreleptin is not recommended in pregnancy, because teratogenicity is unknown, but the CGL PNDS accepts considering continuation when the metabolic benefit justifies the risk, given that discontinuation exposes the patient to extreme insulin resistance and rebound hypertriglyceridaemia; continuation, or introduction during pregnancy in the face of diabetes or hypertriglyceridaemia that is difficult to control, is decided at an RCP with the reference centre [58, 59]. Follow-up is monthly during pregnancy, in parallel with obstetric follow-up [58, 59].

7.13. Children, transition and the perioperative setting

Metreleptin may be considered in children with generalised lipodystrophy to prevent comorbidities (IIb, C), without an age limit for initiation in the 2016 guideline and with children treated from 6 months [60]. In the EU, safety and efficacy are unestablished below 2 years (generalised) and 12 years (partial), and data below 6 years are very limited [64]; the European study in children under 6 years was terminated with one patient [183]. Injection technique without subcutaneous tissue, anxiety, distressing weight loss and polypharmacy compromise adherence in children and adolescents [116]. Hyperphagia may have a major social impact: a 10-year-old girl with CGL2 stole food at school and was treated with aripiprazole for aggression [116]. The transition from adolescence to adulthood concentrates late FPLD diagnoses and the risk of oral oestrogen prescription, and special education should be ensured for children with intellectual disability [1, 116].

The French PNDS require visits every 3 to 6 months at the paediatric reference centre during the peripubertal period, when metabolic abnormalities appear or worsen, with HbA1c at each visit, and a transition prepared with the adult centre, supported by therapeutic education and, for example, by a first joint consultation [58]. In FPLD2, this period requires close metabolic and hepatic monitoring, contraindication of combined oestrogen-progestogen contraceptives and psychological support for body image [59]. Without intellectual disability, schooling of a child with CGL requires few adaptations: with the dietary rules followed at home, the child may have lunch in the school canteen with attention to the menus or bring a meal from home under an individualised care plan (PAI), especially in early childhood or with poor metabolic balance, and with diabetes the PAI details treatment and monitoring [58, 59]. Recognition of disability by the Maison départementale des personnes handicapées (MDPH) may be requested when the burden of care, intellectual disability or sequelae require non-reimbursed rehabilitation or have social and financial consequences for the family, and adults may apply for disabled worker status [58, 59].

The only specific anaesthetic recommendations in the sources consulted are those of the French PNDS for FPLD2 and for laminopathies with cardiac presentation, which agree: in laminopathies with muscle involvement, suxamethonium and volatile anaesthetics (halothane, isoflurane) should be avoided, because of the theoretical risk of malignant hyperthermia [59, 125], and surgery for contractures and scoliosis requires prior assessment of respiratory function [59]. The remaining data highlight points to consider: discontinuation of metreleptin, including prolonged fasting without administration, may precipitate hypertriglyceridaemia and pancreatitis, insulin requirements may be very high and subcutaneous absorption altered, HCM and arrhythmias (CGL4 and laminopathies) require cardiac assessment, atlantoaxial instability has been described in CGL3 and CGL4, and MFN2-related cervical lipomatosis may compress the airway [19, 60, 64, 83, 119].

7.14. Guideline recommendations and divergences

Sources: [11, 14, 60, 63–65, 170]. The 2026 Hellenic position statement recommends metreleptin in eligible patients, GLP-1RA and SGLT2 inhibitors as adjuncts in selected cases, and psychosocial support [93].

The two French PNDS, from the same reference centre, diverge from each other and from the other sources on several points; where they diverge, the recommendation of the guideline applicable to the clinical context is the reference and the label serves as a comparison:

7.15. Lipodystrophies with neurological involvement: targeted therapy

In the seipinopathies, the CAV1-related forms and the progeroid syndromes there is no therapy targeting the neurological mechanism. Dominant neurological seipinopathy is treated with early physiotherapy, orthopaedic footwear, orthoses and surgical correction of foot deformities, with annual neurological assessment [20]. In the encephalopathy associated with BSCL2 exon 7, treatment is that of the progressive myoclonic epilepsies, with antiepileptic drugs and, in one case, a ketogenic diet; metreleptin, indicated for generalised lipodystrophy when present (section 7.7), has been associated in isolated reports with later regression or better seizure control, without controlled demonstration [21]. In the neonatal form of FPLD7, PAH is treated according to paediatric PAH guidelines, without specific therapy for the CAV1-related form; in the 2026 Chinese case, sequential therapy with a phosphodiesterase 5 inhibitor, an endothelin receptor antagonist, a prostacyclin receptor agonist and a subcutaneous prostanoid did not halt progression [140]. In CGL3, achalasia responded to endoscopic myotomy in the two patients described [120]; the generalised lipodystrophy follows the metreleptin indications in section 7.7.

In CANDLE/PRAAS, the 2021 EULAR/ACR recommendation states that the aim is to control systemic and organ inflammation to prevent or limit damage, with the lowest possible dose of glucocorticoids (level of evidence 2B in the general part and 4C in the part on glucocorticoids), that JAK inhibitors improve symptoms (2B; level of agreement 9.3 out of 10), that treated patients should be screened for treatment-associated comorbidities, including BK virus load in urine and blood (4C), and that glucocorticoids improve symptoms (4C) [23]. Monitoring of BK viral load and renal function is recommended before starting the JAK inhibitor and at each visit; there are no data justifying routine antiviral prophylaxis, and routine vaccines, live and inactivated, are indicated when the patient is not receiving immunosuppressants or glucocorticoids, with a case-by-case decision (5D) [23]. Glucocorticoids control fever and skin lesions, but not the muscle and fat lipodystrophy, and the disease relapses with dose reduction; methotrexate, calcineurin inhibitors and other conventional immunosuppressants give partial or minimal benefit, tumour necrosis factor antagonism may worsen the disease and interleukin 1 blockade generally fails in the interferonopathies [27, 131].

Baricitinib (Olumiant®), a JAK1 and JAK2 inhibitor, is the drug with most data. In the National Institutes of Health (NIH) expanded access programme (2011 to 2017), 18 patients with monogenic interferonopathies, 10 with CANDLE, were treated for a mean of 3.0 years: the median daily symptom score fell from 1.3 to 0.25, prednisone in the 14 patients receiving it fell from 0.44 to 0.11 mg/kg/day and 5 of the 10 patients with CANDLE achieved lasting clinical remission, with permanent discontinuation of glucocorticoids and normalisation of inflammatory markers and of the interferon signature [143]. In the 13 patients with growth potential, the height Z-score went from −4.03 to −3.19, with catch-up growth in the 9 who reduced prednisone below 0.16 mg/kg/day, and bone mineral density increased [143]. Baricitinib did not improve pre-existing hepatic steatosis in two patients or prevent it in three with baseline hyperlipidaemia, which points to a mechanism intrinsic to proteasome dysfunction [23].

None of these studies is randomised or has a comparison group; the patients in the NIH programme and the systematic review partly overlap, the systematic review is based mainly on series and case reports, and the Japanese study has five patients with CANDLE and was terminated early, so the figures do not allow drugs to be compared or the magnitude of effect to be estimated precisely [143, 144, 194].

Pharmacokinetics explains the doses. The half-life of baricitinib in patients under 40 kg is shorter than in adults, which requires up to four daily doses, clearance depends on the estimated glomerular filtration rate (eGFR) and mean therapeutic exposure (area under the curve 2388 nM·h) was 1.83 times higher than that of adults with rheumatoid arthritis treated with 4 mg once daily [67]. The proposed regimen, stratified by weight and eGFR and adopted in subsequent studies, is as follows [23, 67, 196]:

Baricitinib should not be used with eGFR below 30 mL/min/1.73 m², and the programme excluded patients with eGFR below 40, weight below 8.5 kg or active chronic infection (herpes, hepatitis, HIV, tuberculosis) [67]. In the Japanese study, the final optimised doses in patients with CANDLE were 8 to 12 mg/day, as tablets or oral suspension [195]. Because clearance per kilogram decreases with growth, the dose has to be reviewed as the child gains weight, but reductions should be slow and gradual: reductions greater than 25 % triggered a flare in all cases, and the authors proposed clinical and subclinical flare criteria, to which the interferon score adds sensitivity [196]. These doses lie outside the label conditions: in the USA, baricitinib is approved in adult rheumatoid arthritis (2 mg once daily; 1 mg with eGFR 30 to <60; not recommended below 30), hospitalised COVID-19 and severe alopecia areata from 12 years; in the EU, in rheumatoid arthritis (4 mg once daily; 2 mg in defined situations), atopic dermatitis from 2 years and juvenile idiopathic arthritis from 2 years (4 mg if ≥30 kg; 2 mg between 10 and <30 kg), and alopecia areata from 12 years, with half the dose if creatinine clearance is between 30 and 60 mL/min and no use below 30 [197, 198].

The most frequent adverse effects in the NIH programme were upper respiratory tract infections, gastroenteritis and BK viruria and viraemia, observed only in this population; there were two cases of herpes zoster, no deaths, and one patient with undifferentiated interferonopathy developed femoral osteonecrosis [143]. Tofacitinib and ruxolitinib have also been used, without a validated dosing regimen in the sources consulted for this disease [23, 144]. In the dominant-negative PSMB8 forms, the response to JAK inhibition and to interferon α/β receptor blockade with anifrolumab was only partial (patient series, without an approved indication) [142]. In PSMB10-related PRAAS5, JAK1 inhibitors produced significant clinical improvement or remission; in two children, baricitinib was started at 2 mg/day at 6 years (with methotrexate) and at 3 mg/day at 1 year and 8 months, with suppression of the lesions and fever and discontinuation of glucocorticoids, doses from case reports and not from a validated regimen [30, 39]. In PSMG2-related PRAAS4, ruxolitinib was associated with clinical improvement in one case [38]. In POMP-related PRAAS2, with progressive neutrophilic dermatosis, autoimmunity and combined immunodeficiency, two patients received haematopoietic progenitor cell transplantation, with 100 % donor chimerism, improved proteasome assembly and activity and absence of autoinflammation, autoimmunity, lipodystrophy and recurrent infections at 36 and 52 weeks; experience is limited to these two cases [36].

Developments in the last 12 months include the systematic review of 46 patients treated with JAK inhibitors (2026; low-level evidence, mainly series and cases) [144], the description of monoallelic PSMB8 forms with immunodeficiency and of the dominant-negative mechanism through failure of immunoproteasome assembly (2026; series of seven patients and functional studies) [133], the characterisation of the dominant-negative variant p.(Gly209Arg) with a partial response to baricitinib and anifrolumab (2026; patient series) [142] and the identification, in brain organoids, of polyamine excess as a mechanism of the neurodevelopmental deficit, reversible in vitro by ornithine decarboxylase inhibition (2026; preclinical evidence) [132]. No JAK inhibitor is authorised for CANDLE/PRAAS in the USA or the EU at the date of this update [197, 198].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by mode of inheritance

Generalised forms (CGL1 to CGL4, biallelic PPARG, PCYT1A) and partial forms due to CIDEC, LIPE and MFN2 are autosomal recessive. Parents of an affected individual are obligate heterozygotes; each sibling has a 25 % risk of being affected, 50 % of being an asymptomatic carrier and 25 % of being neither affected nor a carrier, irrespective of sex, pregnancy order, parental age and ethnicity; children of an affected individual are obligate heterozygotes; and the parents' siblings have a 50 % risk of being carriers [1, 80]. Consanguinity suggests autosomal recessive inheritance and was found in 72.4 % of a cohort of 44 patients from Rio Grande do Norte [62, 66].

FPLD due to LMNA, PPARG, PLIN1 and AKT2 is autosomal dominant, with a 50 % risk for each child; FPLD7 and MDPL usually result from de novo variants, as do 70 % of SHORT syndrome cases [8, 13, 14, 54, 145]. In the three probands with the neonatal form of FPLD7, the variant was absent from the parents tested; the recurrence risk for siblings is low, but not zero, because of germline mosaicism, which the sources consulted do not quantify for CAV1, and the familial form with an inherited variant is transmitted with a 50 % risk per child and variable expressivity [22, 32, 139, 140]. In FPLD3, ClinGen considers inheritance semidominant, with more severe biallelic cases, which should be considered when a second variant is found in trans [14]. Severe lipodystrophic laminopathy is likewise semidominant [51]. The neurological seipinopathies are autosomal dominant, with a 50 % risk per child and reduced penetrance: 24.4 % of the 90 p.Asn88Ser carriers were asymptomatic or had only subclinical signs [20]. If the variant is not detected in the blood of either parent of a proband with neurological seipinopathy, the risk for siblings is estimated at around 1 % because of the possibility of germline mosaicism, and a parent in whom the variant arose may have somatic mosaicism with minimal disease [20]. BSCL2-related progressive encephalopathy is autosomal recessive, as is CGL2 [20, 21]. In CANDLE/PRAAS, autosomal recessive inheritance (PSMB8, PSMB4, PSMG2, PSMB10), digenic inheritance (PSMB8 with PSMA3 or PSMB4; PSMB4 with PSMB9), in which the recurrence risk depends on the segregation of the two genes and requires study of both parents, and autosomal dominant inheritance, almost always de novo (POMP, PSMB9 p.(Gly156Asp), dominant-negative PSMB8), coexist; EULAR/ACR recommends formal genetic counselling for patients, parents and siblings [23, 29, 35–37, 133]. The de novo CAV1 forms, MDPL and Keppen–Lubinsky syndrome have, when neither parent is a carrier, a low but non-zero risk for siblings, because of the possibility of germline mosaicism, and a 50 % risk for each child of the affected person [22, 25, 31].

8.2. Carriers

An increased incidence of diabetes has been suggested in heterozygous CGL carriers, but never confirmed [1]. The parents of a child with CGL2 are heterozygous for null variants, which do not cause neurological seipinopathy, because this results from a toxic gain of function of specific variants [20]. In the largest family with CGL3, the nine CAV1 heterozygotes were asymptomatic and without metabolic abnormalities; heterozygous loss-of-function CAV1 variants cause heritable PAH with reduced penetrance, but the sources consulted do not quantify the PAH risk in carriers from CGL3 families [8, 120]. Heterozygotes for the Amish LIPE founder variant tend towards insulin resistance and higher TG [87, 88]. These data justify informing carriers, without supporting a surveillance programme.

8.3. Cascade testing and expressivity

Genetic testing of at-risk relatives should be considered (IIa, C) and is particularly important in families with LMNA variants associated with cardiomyopathy and arrhythmia [60]. The Brazilian consensus recommends cascade genetic screening of all first-degree relatives and clinical and metabolic follow-up of carriers without clinical criteria [11]. In the Colombian family with LMNA p.(Arg482Trp), the 68-year-old mother, with fat loss from all four limbs, prominent veins, steatosis, unstable angina at 65 years and osteoporosis, was diagnosed only through cascade testing initiated from her son, and the same variant had different expressions in the two dizygotic twins [113]. As natural history is incomplete and some genotypes have mild phenotypes, counselling should explain uncertainty; in affected families, premarital counselling with carrier detection may be considered [60]. Carrier testing requires prior identification of familial variants [1].

In France, the physician who prescribed the test organises with the patient the information of adult relatives, as provided for in the Public Health Code (article L1131-1-2); if the patient does not wish to inform the family personally, the physician offers to send a letter that communicates the existence of a familial disease and invites relatives to a genetics clinic, without revealing the name of the proband, the variant or the associated risks [58, 59]. In CGL, identification of the heterozygous variants in the parents confirms the 1 in 4 risk for siblings [58]. In FPLD2, family screening must take into account men with few symptoms, and, when the family has heart disease, at-risk relatives undergo surveillance by ECG, echocardiogram and Holter from 10 years of age [59]. Without genetic testing, at-risk relatives are offered regular clinical and laboratory surveillance, in particular glucose and lipids, and before contraception is prescribed [58, 59].

In FPLD2 families with cardiac expression, the laminopathy PNDS organises cardiological screening of first-degree relatives, who have a 50 % risk, with ECG, echocardiogram and 24-hour Holter from 10 to 12 years of age; if the relative does not undergo genetic testing, screening is repeated every 2 to 3 years between 10 and 20 years and every 2 to 5 years thereafter, as a rule until 60 [125]. Predictive testing for the familial variant (class 4 or 5) is recommended from 10 to 12 years, or earlier if there is an early-onset form in the family; a relative without the variant leaves specific surveillance, and those who do not wish to know their status remain under cardiological surveillance [125]. In France, the team contacts relatives only through the proband, whose refusal to inform them may engage their civil liability (decree no. 2013-527), and predictive testing is prescribed by a multidisciplinary team declared to the Agence de la biomédecine, with a clinical geneticist [125].

8.4. Prenatal and preimplantation diagnosis and timing of counselling

Once familial variants are identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. The optimal time for counselling is before pregnancy, and it should be offered to young adults who are affected, carriers or at risk; in the absence of a confirmed molecular diagnosis, DNA from the affected individual may be stored [1]. Distinguishing CGL1 from CGL2 assists counselling, particularly when the child is too young for cognitive development to be characterised, given the difference in risk of intellectual disability (≈10 % versus ≈80 %) and the existence of the BSCL2 exon 7 variant associated with lethal encephalopathy [1]. In neurological seipinopathies, prenatal diagnosis is technically possible but rarely requested [20].

In France, prenatal and preimplantation diagnosis follow the same law (article L2131-1 of the Public Health Code), and the multidisciplinary prenatal diagnosis centres (CPDPN) rarely accept them in cardiomyopathies and more readily in myopathies and complex laminopathies, case by case [125].

8.5. Counselling minors and women of childbearing potential

Testing asymptomatic minors has a clinical justification in FPLD, because metabolic and body composition changes may begin before or during puberty and preventive measures exist (diet, contraception without oral oestrogen, lipid and glycaemic surveillance); the Brazilian consensus proposes considering screening at 10 years in girls from families with a pathogenic LMNA variant [11, 116]. In women of childbearing potential, counselling should cover contraception without oral oestrogen, pregnancy planning, pancreatitis and gestational diabetes risks and the divergent positions of sources on metreleptin during pregnancy (section 7.12) [60, 64, 126].

The French PNDS follow the same logic. In FPLD2, the almost complete penetrance, the anticipation described and the silent cardiometabolic complications justify the physician being able to offer presymptomatic testing of minor children from the prepubertal age (10 years), depending on the family context and the clinical form; the onset of signs at puberty and the choice of contraception weigh in this decision, and in the absence of testing non-alarming information on prevention and surveillance is given [59]. In CGL, in which the first signs appear early, the question arises in few situations, but presymptomatic testing may be offered from birth, depending on the severity of the form and the family context, to adapt surveillance to the aetiology [58]. In both cases, French law requires an individual consultation with a physician from a multidisciplinary team with clinical and genetic expertise declared to the Agence de la biomédecine [58, 59].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

Lipodystrophy prevalence estimates differ by several orders of magnitude because they measure different things: clinically diagnosed cases in registry databases, cases known to patient associations in a region, or carriers of pathogenic variants in genomic cohorts. Before genomic databases, estimates ranged from approximately 0.1 to 90 per million [56].

The UK Biobank figure is approximately ten times higher than phenotypic estimates and approximately five times lower than that of the DiscovEHR cohort, in which the founder effect of LMNA p.Arg482Gln accounted for 16 of 30 cases and mean BMI was 31.2 kg/m² [57]. There was no difference in prevalence between sexes in UK Biobank (0.0076 % versus 0.0053 %; p = 0.37), contrasting with the female predominance of more than 80 % in clinical series and the European registry [57, 127]. Because volunteers were healthier, predominantly of European ancestry and over 40 years, and because it does not detect compound heterozygotes, UK Biobank underestimates recessive and severe forms [57].

9.2. Congenital generalised lipodystrophy by country and region

Orphanet attributes the Brazilian prevalence of 3.23/100 000 to an article that is actually the protocol of the Brazilian rare diseases network; the primary source is the 2017 study by Medeiros and colleagues, which measures prevalence in the state of Rio Grande do Norte rather than Brazil [2, 55]. GeneReviews counted more than 300 published cases in 2016, and Orphanet records approximately 500 cases or families of CGL2, 126 of CGL1 and 5 of CGL3 [1, 201–203].

9.3. Founder populations and gene distribution

CGL1 due to AGPAT2 has been described worldwide, with clusters in sub-Saharan Africa, Brazil, the Maghreb (Morocco, Algeria, Tunisia), occasionally the Middle East (Turkey) and Northern Europe; in a US series, 26 of 45 patients had AGPAT2, and almost all patients of African origin have the c.589-2A>G variant [1]. CGL2 due to BSCL2 predominates in patients from Europe, the Middle East and sub-Saharan Africa in the Berardinelli–Seip study group; the c.317_321del variant (historical) is a founder variant in the Lebanese population, p.Ala212Pro (historical numbering in NM_032667.6, c.634G>C; = NM_001122955.4:c.826G>C p.(Ala276Pro)) has been described in Norwegian patients, and other variants have been found in patients of European, Middle Eastern, Asian or Portuguese ancestry [1, 78]. In Brazil, 18 of 26 patients had BSCL2 variants in one series, and a second described ten families with new BSCL2 and AGPAT2 variants [1, 73, 204]. In Japan, three of four patients were homozygous for BSCL2, and CGL4 was identified in five Japanese patients [1, 82]. The BSCL2 exon 7 variant was described in five Spanish infants [1, 97]. The Rio Grande do Norte cluster, with municipal prevalences up to 498/100 000, is attributed to a founder effect and parental consanguinity [55, 66]. In Turkey, a nationwide study brought together 33 patients from 22 families, with AGPAT2, BSCL2 and CAVIN1 variants [95]. CGL4 has been described in families from Oman [83].

In FPLD, the LMNA p.Arg482Gln variant has a founder effect in Canadian families and rural Pennsylvania [57, 76]. Réunion island has a sufficiently large FPLD2 population for a study of 64 non-diabetic individuals [205]. The LIPE null variant is a founder variant in the Old Order Amish [17, 87]. A Brazilian multicentre cohort included 424 individuals with FPLD, 106 of them with genetic confirmation (25 %), with diabetes in 57.5 %, severe hypertriglyceridaemia in 35 %, established atherosclerotic disease in 10.4 % and pancreatitis in 8.5 % [11].

In the lipodystrophies with neurological involvement, the founder populations are those of CANDLE/PRAAS: JMP syndrome was defined in families from Portugal and Mexico with the PSMB8 variant p.(Thr75Met), also recurrent in other patients with CANDLE, and Nakajo–Nishimura syndrome is concentrated in the Kansai region of Japan, with a single founder p.(Gly201Val) and consanguinity in 19 of 27 compiled patients [27, 131, 141]. Among the few patients with PSMB10-related PRAAS5 described are three unrelated Brazilian boys, born to non-consanguineous parents, with annular lesions from the first days of life [39]. BSCL2-related progressive encephalopathy has been described mainly in patients from Spain, Italy and China, with the c.974dup variant recurrent in Italian, Spanish and Chinese patients [21]. There are no prevalence estimates for these entities in the sources consulted; Orphanet records PRAAS as a disease with isolated cases or families [27].

9.4. Portugal and Brazil

In Portugal, in addition to the estimate of 1:500,000 for CGL and the presence of BSCL2 variants in patients of Portuguese ancestry [1], the series from the Unidade Local de Saúde de Santo António (Porto) included 21 patients (90.5 % women; median age at diagnosis 49 years; median follow-up 61 months): 16 with FPLD, 2 with CGL, 2 with AGL and 1 with a complex syndrome [96]. Overall, 71.4 % had diabetes, 57.1 % hypertriglyceridaemia, 14.3 % HCM, 33.3 % MASLD and 14.3 % cirrhosis; in the four generalised forms, diabetes and proteinuria were present in all, and one patient with CGL2 had the BSCL2 variant c.325dup p.(Thr109AsnfsTer5) (NM_032667; c.517dup on MANE). In FPLD, only 2 of 11 tested patients had a positive molecular result or a result of uncertain significance, including the likely pathogenic PPARG variant c.581G>A p.(Arg194Gln) (PPARγ2) and two CAV1 VUS [94, 96]. The sources consulted do not identify a specific Portuguese patient association.

In Brazil, where CGL was described, Rio Grande do Norte has the highest known prevalence [55, 66]. In an international care pathway study, first symptoms appeared earlier in Brazilian patients (12.8 years; n = 52) than in Turkish (18.3; n = 80) and American patients (23.4; n = 98), and in a Brazilian cohort with 23 CGL, 25 FPLD, 2 AGL and 2 APL, 29 % had diabetes or insulin resistance, 50 % TG above 500 mg/dL, 71 % liver abnormalities, 48 % renal abnormalities and 23 % cardiac abnormalities [66]. Brazil has a national FPLD consensus, the BRAZLIPO group and a national registry; integration of genomic testing into SUS remains undefined [11, 66]. In a group of 13 Brazilian women with FPLD2, the body adiposity index was lower than in controls (24.6 versus 30.4; p < 0.001) [66].

9.5. Special populations

Men with FPLD have a less evident phenotype, later diagnosis and smaller metabolic differences from non-carriers, making them more difficult to identify [5, 11, 57]. In men in the European registry, CGL is almost as frequent as FPLD [127]. Anthropometric thresholds were derived mainly in European, Middle Eastern, North African and South American populations, and are undefined for Asian populations; in a study of eight Asian women with FPLD1, the mid-thigh skinfold was 19.5 mm versus 48.2 mm in controls [62, 66]. The LipoDDx® (approximately 80 % accuracy in subtype recognition) and DEEPLIPO applications (deep learning from photographs, with mean accuracy of 91 % in a pilot of 337 images) are supportive tools, not diagnostic tools [62, 66].

9.6. Reference networks and patient associations

The European reference network Endo-ERN includes lipodystrophy in thematic group MTG3, dedicated to rare genetic disorders of glucose and insulin homeostasis, and the ECLip centres in Ulm, Pisa, Bologna, Paris (Saint-Antoine, PRISIS network) and Lille are Endo-ERN centres [5, 68]. ECLip (https://www.eclip-web.org/) brings together 175 clinicians and researchers from 30 countries and maintains a European registry (https://eclip-registry.com) [5, 189]. Patient associations cited by the European consensus are AELIP (Spain, https://aelip.es/), Lipodystrophy UK (https://lipodystrophyuk.org), AFLIP (France, https://aflip.org), AILIP (Italy, https://ailip.it), NetLip (https://netlip.org) and Lipodystrophy United (USA, https://lipodystrophyunited.org) [5]. In Brazil there are BRAZLIPO (https://brazlipo.org/) and the Associação Brasileira de Síndrome de Berardinelli e Outras Lipodistrofias [66]. In the USA, the metreleptin REMS programme (https://www.myaleptrems.com) and pregnancy exposure registry complete these resources [63].

In France, the organisation is based on the PRISIS reference centre, coordinated at Hôpital Saint-Antoine (Assistance Publique – Hôpitaux de Paris, AP-HP), and its regional competence centres published in the Journal Officiel of 15 December 2017 (including paediatric centres and Réunion Island), integrated into the FIRENDO rare endocrine diseases network [58, 59]. The attending physician completes, at diagnosis, the application for 100 % reimbursement as ALD 31, coordinates follow-up with the centre and liaises with school and occupational medicine; the metreleptin indication goes through the PRISIS RCP [58, 59]. Therapeutic education, also for parents in early childhood, covers the disease and warning signs, transmission and family screening, administration and adverse effects of treatments, follow-up, daily life and travel, social rights and institutional resources [58, 59]. The associations mentioned by the protocols are AFLIP (Association Française des Lipodystrophies), Vaincre Dunnigan, AELIP, Aide aux Jeunes Diabétiques (AJD) and the Fédération Française des Diabétiques, and the institutional sources of information are Orphanet and the PRISIS website [58, 59]. The FIRENDO quality-of-life questionnaires support applications to the MDPH [58].

For the cardiac aspect of the laminopathies, the French organisation is based on the CARDIOGEN network (https://www.filiere-cardiogen.fr) and on the reference and competence centres for hereditary or rare cardiomyopathies and rhythm disorders (CEREFCOEUR, https://www.cerefcoeur.fr; coordinated at Hôpital Pitié-Salpêtrière), with the FILNEMUS neuromuscular network when there is muscle involvement; the associations cited are the Ligue contre la cardiomyopathie and AFM-Téléthon, and therapeutic education covers heart failure and the ICD [125].

10. Illustrative Clinical Case

10.1. Congenital generalised lipodystrophy type 1: twenty years of metreleptin

Van der Borght and colleagues described in 2026 two Belgian sisters with CGL1 (AGPAT2 deficiency; the variant is not specified in the article), now aged 39 and 42 years, with absence of adipose tissue from birth [159]. Both were diagnosed at 10 and 12 years of age because of poorly controlled diabetes. Before metreleptin, the younger sister (case 1) required 1200 U/day of insulin and the older sister (case 2) 3000 U/day; leptin was 1.1 and 0.8 ng/mL, they had steatosis with hepatomegaly and neither had reached menarche at 15 and 17 years of age [159]. They were enrolled in the NIH trial, which required leptin below 4.0 ng/mL in women and used starting doses of around 50 % of estimated physiological replacement, and subsequently in the expanded access programme; in case 2, a hypertensive episode after the first injection led to the starting dose being halved [159].

Source: Table 1 of [159].

Both menstruated within the first 6 months of treatment. Case 1 had an unplanned pregnancy at 22 years of age, which was terminated, and a planned pregnancy at 33 years, after 16 years of metreleptin and without insulin; hypertension developed at 36 weeks and proteinuria at 37 weeks, with suspected pre-eclampsia, and labour was induced and ended in caesarean section for a fetal indication, with a healthy boy weighing 3785 g [159]. Case 2 became pregnant during the trial; metformin was discontinued and metreleptin maintained at the preconception dose; the OGTT at 24 weeks was abnormal and insulin increased from 75 U/day to 210 U/day in the third trimester; labour was induced at 37 weeks because of a large fetus and was complicated by shoulder dystocia, with a newborn weighing 4350 g who had Erb palsy, two cardiac arrests, pneumothorax and three weeks of ventilation, and was left only with residual weakness of the left arm [159]. Both breastfed while receiving metreleptin, case 2 for 6 months, with no apparent effects on the infants [159]. After 14 years, case 2 lost metabolic control, with anti-metreleptin antibodies (titre 1:1250) with neutralising activity (titre 1:30); splitting the dose between two sites and improving adherence restored control with the same total dose, despite persistent antibodies [159]. Adherence fluctuated with psychological distress, musculoskeletal pain and the burden of daily injections [159]. Figures 1 and 3 of the article, consulted on the PubMed Central page, follow the clinical course (https://pmc.ncbi.nlm.nih.gov/articles/PMC13216765/figure/f1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC13216765/figure/f3/) [159].

The case demonstrates the sustained metabolic, renal and reproductive response to metreleptin in CGL1, the persistence of obstetric risks and the role of adherence and antibodies in loss of efficacy. Continuing metreleptin during pregnancy and breastfeeding followed the research protocol and the 2016 guideline, but differs from the European SmPC, which does not recommend use during pregnancy; the article refers to pregnancy as a contraindication and dates European approval to 2016 in the discussion, whereas the SmPC states “not recommended” and authorisation dates from July 2018 [60, 64, 159]. The authors' suggestion to consider caesarean section is an opinion based on two cases [159].

10.2. Familial partial lipodystrophy type 2: variable expressivity in a family

Duque-Córdoba and colleagues described in 2026 a Colombian family with the heterozygous LMNA variant c.1444C>T p.(Arg482Trp) (NM_170707.4), classified as pathogenic (ACMG/AMP criteria PS3, PS4, PM1, PM2, PP1, PP2 and PP3) by exome sequencing and confirmed by Sanger sequencing, transmitted by the mother to dizygotic twins [94, 113]. The proband, a 29-year-old man born to non-consanguineous parents and with IUGR, presented at 16 years of age with a “webbed neck” due to a lipoma and returned seven years later with hypertension, dyslipidaemia, steatosis and hydronephrosis. He had a square, asymmetrical face, extensive posterior cervical lipomatosis, non-infiltrative on MRI, with restricted mobility, truncal adiposity with relative loss of limb fat, hepatomegaly and overweight (96.5 kg, 182 cm, BMI 29.1 kg/m², waist-to-hip ratio 0.96), osteopenia and grade II to III steatosis; total cholesterol was 122 mg/dL, HDL 37, LDL 36.8 and TG 241 mg/dL, fasting insulin 21.8 μU/mL with a HOMA-IR index of 4.3 and borderline HbA1c, and ALT 68 U/L; he was treated with losartan, amlodipine and atorvastatin, followed annually by endocrinology and genetics and referred to plastic surgery [113]. His twin sister (59.5 kg; BMI 22.7 kg/m²; waist-to-hip ratio 0.87) had loss of lower limb fat with marked muscular definition, untreated TG of 698 mg/dL, persistently low HDL of 30.5 mg/dL on lipid-lowering treatment, HOMA-IR of 3.7, normoglycaemia, polycystic ovarian morphology without hyperandrogenism, regular cycles and grade III steatosis [113]. Their mother, aged 68 years (43.5 kg; BMI 17 kg/m²), had thinning of all four limbs, visible superficial veins, distal muscle wasting, mild dyslipidaemia on treatment, steatosis at 62 years, unstable angina with catheterisation at 65 years, hypertension and osteoporosis, and was diagnosed through cascade testing initiated from her son [113]. The figures in the article show frontal and lateral views of the proband, with dorsocervical lipomatosis and truncal adiposity (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC12911963/figure/f0001/), and the mother, with loss of fat from all four limbs and prominent veins (Figure 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC12911963/figure/f0003/) [113].

The case illustrates the expressivity of the same codon 482 variant, modulated by sex, age and hormonal status: cervical lipomatosis and overweight in the man, severe hypertriglyceridaemia with normal BMI in the young woman, and lipoatrophy with coronary disease in the elderly mother [113]. The man's presentation, with a BMI of almost 30 kg/m², explains why diagnosis may be delayed when only thinness is sought [5]. The management described (antihypertensives, a statin and annual follow-up) is consistent with general recommendations, but the guidelines also recommend ECG and echocardiography at diagnosis in LMNA-related FPLD, and for hypertriglyceridaemia of 698 mg/dL the guideline indicates a fibrate and/or omega-3 [11, 60].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without specific treatment, CGL shortens life expectancy by 30 years or more, and most patients die from liver disease or infection [4, 129]. In Rio Grande do Norte, the mean age at death was 27.1 years and potential years of life lost were 35.6 ± 16.6 [129]. HCM causes early mortality, around 30 years of age, and has caused death at 19 months [1]. In CGL4, sudden cardiac death in adolescence was described in five members of eight families [83]. The 2016 guideline identifies the main causes of death in lipodystrophies as heart disease (cardiomyopathy, heart failure, myocardial infarction, arrhythmia), liver disease (liver failure, gastrointestinal haemorrhage, hepatocellular carcinoma), renal failure, acute pancreatitis and sepsis [60]. BSCL2-related encephalopathy usually leads to death in the first decade [1, 7].

In FPLD, the median age at death was 72 years in the European registry, compared with 27 years in the generalised forms, with deaths mainly due to cardiovascular causes and cancer [127]. Even among carriers identified by genotype in the UK Biobank, mortality was four times higher than in non-carriers, with more frequent heart failure, coronary disease and diabetes [57]. LMNA variants outside codon 482 increase the risk of arrhythmias and conduction disease [61]. Mandibuloacral dysplasia, a differential diagnosis, is progressive but does not necessarily reduce survival [102].

Metreleptin changes these trajectories: in the two Belgian sisters with CGL1, HbA1c, TG, albuminuria and transaminases remained controlled for 20 years [159]. In a Brazilian patient with CGL2, a 36-month interruption because of lack of access caused HbA1c to return to 11.0 %, insulin requirements to 750 IU/day, and albuminuria and HCM to recur (septum of 19 mm, after having regressed to 12 mm), with progression to cirrhosis with portal hypertension; resumption improved control and reduced steatosis [112]. These data come from individual cases and open-label series, and the estimated 65 % reduction in mortality comes from an observational comparison between non-equivalent groups [11, 62].

11.2. Surveillance

In APL, which has a low metabolic risk, follow-up is based on clinical judgement [60]. At each visit, the French PNDS assess weight, height, BMI, blood pressure and smoking, appetite, diet and physical activity, pubertal stage, adherence and adverse effects, glucose self-monitoring, lipodystrophy at injection sites, signs of hepatocellular failure and portal hypertension, signs of hypertriglyceridaemia flares (xanthomas, abdominal pain), cardiovascular symptoms (dyspnoea by New York Heart Association class, chest pain, palpitations, presyncope, heart failure, peripheral arterial disease), myalgia, arthralgia, neuropathy and muscular dystrophy, menstrual cycles, hyperandrogenism, contraception and fertility, and the psychological distress of the patient and family; DXA, bioimpedance and whole-body MRI are generally performed at the reference or competence centre [58, 59]. The Brazilian consensus adapts surveillance according to subtype: intensive cardiovascular follow-up in FPLD2, close hepatic surveillance in FPLD3 and individualised follow-up in FPLD1 and type X; it also recommends elastography at diagnosis as a first-line approach, because FIB-4 alone (threshold 1.3) probably underestimates risk in FPLD, and screening for subclinical atherosclerosis by exercise testing, scintigraphy, stress echocardiography or coronary CT angiography with calcium scoring in selected cases [11]. Patients with FPLD2 should also be followed according to the cardiological recommendations for laminopathies; in the context of LMNA-related cardiomyopathy, carriers with any electrocardiographic abnormality undergo ECG, 24 to 48-hour Holter monitoring and assessment of ventricular function at least annually, and asymptomatic carriers undergo history-taking, examination, echocardiography and ECG every 1 to 2 years [13]. In Emery–Dreifuss dystrophy, the metabolic overlap warrants a lipid profile, HbA1c and glucose every 2 to 3 years [13, 105]. In SHORT syndrome, GeneReviews proposes monitoring growth every 6 to 12 months, OGTT every 5 years in the absence of diabetes, fasting glucose, insulin and HbA1c annually from 10 years of age, intraocular pressure annually, oral health every 6 months and hearing every 2 to 3 years [54].

12. Summary and Final Considerations

Genetic lipodystrophies result from the inability to develop or maintain functional adipose tissue, and their clinical expression is that of complicated obesity without obesity: insulin resistance, diabetes, hypertriglyceridaemia with pancreatitis, MASLD progressing to cirrhosis, renal disease, reproductive dysfunction and cardiovascular disease [5, 60]. CGL is autosomal recessive and manifests from birth with near-total absence of fat, muscular hypertrophy, acromegaloid features, hepatomegaly and hyperphagia; AGPAT2 and BSCL2 account for the vast majority of cases, CGL2 is associated with intellectual disability and earlier cardiomyopathy and cirrhosis, CGL1 with bone cysts and preservation of mechanical fat, and CGL3 and CGL4 with myopathy with elevated CK, the latter with potentially fatal arrhythmias [1, 4, 83]. The BSCL2 exon 7 variant, c.985C>T in the MANE transcript and c.793C>T in historical numbering, causes a lethal encephalopathy, and toxic gain-of-function variants in the same gene cause dominant neurological disease without lipodystrophy [20, 94]. The lipodystrophies with neurological involvement also include the heterozygous CAV1 forms, with cataracts and, in the de novo neonatal form, PAH, and CANDLE/PRAAS, in which lipodystrophy is secondary to panniculitis, the central nervous system shows calcifications and cognitive impairment, and JAK inhibitors, off-label and at doses higher than those in the labels, induce remission in some patients [22, 23, 132, 143].

FPLD manifests from puberty with loss of fat from the limbs and buttocks and cervicofacial and pubic accumulation; LMNA predominates in clinical series and adds arrhythmic risk, particularly with variants outside codon 482, whereas PPARG predominates in genomic cohorts and is associated with less visible lipoatrophy with more severe metabolic involvement [11, 57, 61]. Forms due to PLIN1, CIDEC, LIPE, AKT2 and MFN2 are rare and have differing levels of evidence, which the ECLip consensus and ClinGen help to weigh; CIDEC, rather than CIDEA, is the gene for FPLD5 [5, 85]. The minimum genetic prevalence of monogenic FPLD in the UK Biobank, 1 in 15,820 adults, none of whom had a clinical diagnosis, and the fourfold higher mortality in these carriers show that the disease is underdiagnosed, particularly in men [57].

Diagnosis is clinical and metabolic, supported by anthropometry, DXA and MRI, and confirmed by a multigene panel with copy-number analysis; a negative result does not exclude the disease, leptin neither establishes nor excludes the diagnosis, high adiponectin argues against it, and the reference transcript should be stated in the report, because BSCL2 and PPARG have historical numbering that differs from MANE numbering [5, 11, 60, 94]. Treatment is based on a balanced diet without overfeeding, exercise after cardiac assessment, intensive management of diabetes (metformin, concentrated insulins, thiazolidinediones in partial forms, GLP-1RA, tirzepatide and SGLT2 inhibitors with observational data) and dyslipidaemia, and avoidance of oral oestrogens [60, 151, 162]. Metreleptin is first-line treatment in generalised lipodystrophy, with an indication in the USA, the EU, Japan and Brazil, and is authorised for the partial form in the EU from 12 years of age after failure of standard therapy, but not in the USA, where the randomised METRE-PL trial still has no published results [63, 64, 181]. Anti-APOC3 therapies reduce TG, but in FPLD only volanesorsen is authorised, and only in Brazil, and the leptin receptor agonist mibavademab is in phase 3 in the generalised form [171, 173, 179].

Annual surveillance of glucose, lipids, liver, kidney, blood pressure and, in CGL, the heart, specific cardiological follow-up for laminopathies, genetic counselling with cascade testing, contraception and pregnancy planning and psychological support complete care, which should be organised in experienced centres linked to Endo-ERN and ECLip [5, 11, 60, 68]. The 2021 and 2022 French protocols give this care an operational form, with metformin from prediabetes, LDL targets stratified by risk, hepatic referral thresholds, metreleptin validated at a multidisciplinary meeting, genotype-directed cardiac surveillance (Holter in CGL4 and in LMNA variants outside codon 482) and pregnancy rules, but they diverge from each other on the FIB-4 threshold, the macronutrient distribution and management of elevated CK [58, 59].

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