Abetalipoproteinaemia, Familial Hypobetalipoproteinaemias and Adult Refsum Disease

Two families of inherited lipid disorders with no genetic relationship to each other, brought together by a single clinical principle: the pigmentary retinopathy and neuropathy that characterise them can be prevented by a targeted nutritional intervention started before the lesion is established — high-dose fat-soluble vitamins with fat restriction in the hypobetalipoproteinaemias due to secretion defects, and phytanic acid restriction with prevention of catabolism in adult Refsum disease.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

Hypocholesterolaemia due to loss of function of PCSK9 (FHBL-EC2; PCSK9 gene, OMIM 607786, included in OMIM 603776 as an LDL cholesterol quantitative trait locus; ORPHA:727932) and familial combined hypolipidaemia due to ANGPTL3 (FHBL-EC1; OMIM 605019; ORPHA:727925), which cause neither malabsorption nor vitamin deficiency, are covered as differential diagnoses and as part of the classification [11, 27–31]. Infantile Refsum disease belongs to the Zellweger spectrum; PEX7-related rhizomelic chondrodysplasia punctata type 1 belongs to the chondrodysplasia punctata group.

1. Introduction

1.1. Two families of diseases, one therapeutic principle

Abetalipoproteinaemia, the related hypobetalipoproteinaemias and adult Refsum disease share neither genes nor metabolic pathways. The former result from defects in the assembly or secretion of apolipoprotein B (apoB)-containing lipoproteins, the chylomicrons formed in the intestine and the very low-density lipoproteins (VLDL) formed in the liver; the main clinical consequence is the inability to absorb and transport fat-soluble vitamins, especially vitamin E [2, 11]. Adult Refsum disease results from a block in the peroxisomal α-oxidation of phytanic acid, a branched-chain fatty acid of exclusively dietary origin that accumulates in the retina, myelin, adipose tissue and other organs [7, 25]. The common denominator is clinical: in both groups the pigmentary retinopathy and peripheral neuropathy are preventable, or at least can be stabilised, by a targeted nutritional intervention, and in both, diagnostic delay is paid for with functional loss that treatment can no longer recover [2, 25].

1.2. Abetalipoproteinaemia and hypobetalipoproteinaemias: from clinical description to mechanistic classification

In 1950, Bassen and Kornzweig described, in a patient with atypical retinitis pigmentosa, a malformation of the red blood cells that would come to be called acanthocytosis (from the Greek acantha, thorn) [32, 33]. In 1958, Jampel and Falls recorded low serum cholesterol in these patients, and in 1960 Salt and colleagues documented the absence of β-lipoproteins in the plasma of a child with acanthocytosis and steatorrhoea, which gave the syndrome its name [11, 34]. OMIM notes that Salt's patient actually had familial hypobetalipoproteinaemia, because the parents had markedly low plasma cholesterol, a detail that anticipates the main differential difficulty in this family of disorders [4]. In 1992, Wetterau and colleagues showed that the activity of microsomal triglyceride transfer protein (MTP) and its 88-kDa component were present in intestinal biopsies from eight controls and absent in four patients with abetalipoproteinaemia [35]; in 1993, Sharp and colleagues cloned the cDNA of the large subunit of MTP and identified a frameshift variant and a nonsense variant in the homozygous state in two patients [36]. In 2003, Jones and colleagues identified eight variants in the gene for the GTPase Sar1b (then SARA2) in patients with chylomicron retention disease, Anderson disease and Marinesco-Sjögren syndrome with chylomicron retention, showing that chylomicrons, much larger than the usual vesicles, are recruited by the COPII-coated vesicle machinery [37]; genotyping showed that Anderson disease and chylomicron retention disease were the same entity [24].

The traditional terminology distinguished abetalipoproteinaemia, homozygous and heterozygous familial hypobetalipoproteinaemia and chylomicron retention disease. In 2021, the medical panel of the Abetalipoproteinemia and Related Disorders Foundation (ABLRDF) proposed a mechanistic nomenclature, developed in the 2022 guide: class I brings together the familial hypobetalipoproteinaemias due to assembly and secretion defects (familial hypobetalipoproteinemia due to secretion defects, FHBL-SD), with FHBL-SD1 for abetalipoproteinaemia (MTTP), FHBL-SD2 for the APOB-related form (biallelic or monoallelic) and FHBL-SD3 for chylomicron retention disease (SAR1B); class II brings together the forms due to enhanced catabolism (FHBL-EC), with FHBL-EC1 for familial combined hypolipidaemia due to ANGPTL3 and FHBL-EC2 for loss of function of PCSK9 [11, 38]. Class I causes malabsorption, vitamin deficiency and neurological and retinal damage and requires lifelong treatment and surveillance; class II causes no disease and confers cardiovascular protection [11]. The classification allows for new members, such as an LDLR variant with truncation of the 3′ untranslated region associated with low lipids, or a class for defects of intestinal cholesterol absorption if the role of LIMA1 is confirmed [11].

1.3. Adult Refsum disease: from the clinical tetrad to phytanic acid

Sigvald Refsum, a Norwegian neurologist (1907–1991), described in 1946 an autosomal recessive neurological entity which he called heredopathia atactica polyneuritiformis [7, 8]. The classical tetrad — retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and raised cerebrospinal fluid (CSF) protein without pleocytosis — is rarely complete in a single patient [8, 39]. In 1963, Klenk and Kahlke discovered that patients with hereditary ataxia and Refsum-type polyneuritis accumulate phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), an unusual branched-chain fatty acid, in tissues and body fluids, a finding common to all patients [8]. In 1966, Eldjarn and colleagues showed that a diet low in phytol and phytanic acid reduced serum phytanate and improved the clinical picture, and plasmapheresis was introduced in the following decades [8]. In 1997, two groups identified the gene for phytanoyl-CoA hydroxylase (PHYH, also called PAHX): Jansen and colleagues purified the enzyme from rat liver peroxisomes, described a 338-amino-acid protein with a peroxisomal targeting signal type 2 (PTS2) and found variants in five patients, and Mihalik and colleagues showed that the enzyme is an iron- and 2-oxoglutarate-dependent dioxygenase, targeted by the PEX7 receptor and encoded in a region of 10p13 previously indicated by homozygosity mapping [40, 41]. In 2003, van den Brink and colleagues showed that patients with a clinical diagnosis of Refsum disease without variants in PHYH had variants in PEX7, the gene usually associated with rhizomelic chondrodysplasia punctata type 1 [42]; the disease was thus defined as genetically heterogeneous, with two known genes [43].

The term "infantile Refsum disease" was applied to a congenital disease with phytanate accumulation that turned out to be a peroxisome biogenesis disorder of the Zellweger spectrum; the only feature shared with the adult disease is phytanate accumulation, and GeneReviews and OMIM recommend abandoning the term, preferring "adult Refsum disease" or "classic Refsum disease" for the entity described by Refsum [7, 8]. In 2026, the medical and scientific committee of the Global DARE Foundation published the first guideline dedicated to the diagnosis and metabolic management of adult Refsum disease, aligned with the GRADE system [25].

1.4. Definitions of the entities in this article

Abetalipoproteinaemia (FHBL-SD1) is defined by absent or extremely low LDL cholesterol, triglycerides and apoB with biallelic pathogenic variants in MTTP [2]. APOB-related familial hypobetalipoproteinaemia (FHBL-SD2) is defined, in the biallelic form, by hypocholesterolaemia, low LDL cholesterol and apoB with clinical manifestations in untreated patients and biallelic variants that compromise the structural integrity of apoB, and, in the monoallelic form, by usually asymptomatic hepatic steatosis with a heterozygous variant, generally truncating [3]. Chylomicron retention disease (FHBL-SD3) is defined by the inability to secrete chylomicrons after fat ingestion, with biallelic variants in SAR1B [5]. Adult Refsum disease is defined by phytanic acid accumulation with retinitis pigmentosa of onset in late childhood or later and variable combinations of anosmia, polyneuropathy, deafness, ataxia and ichthyosis, due to biallelic variants in PHYH or, in a minority, in PEX7 [7].

2. Molecular Genetics and Pathophysiology

2.1. Assembly and secretion of apoB-containing lipoproteins

There is a single APOB gene. In the liver it is translated into apoB100, a polypeptide of about 4560 amino acids; in the intestine, post-transcriptional C→U editing of the mRNA creates a stop codon and gives rise to apoB48, which corresponds to the amino-terminal 48% of apoB100 [11]. Particle assembly begins in the endoplasmic reticulum and depends on two proteins: apoB, which serves as the structural scaffold, and MTP, a chaperone that transfers triglycerides, cholesteryl esters and phospholipids to nascent apoB [2, 11]. The particles move to the Golgi apparatus in specialised transport vesicles, in a step that depends on the GTPase SAR1B, and are then secreted by exocytosis [11]. Chylomicrons consist of 80–95% triglycerides, have apoB48 as their structural protein and are secreted into the lymph; in the circulation they are hydrolysed by lipoprotein lipase, anchored to the endothelium by GPIHBP1, and the remnants are taken up by the liver [44]. In the fasting state, the liver assembles VLDL with apoB100, which give rise to IDL and LDL; LDL carry more than 75% of plasma cholesterol [44]. Lipolysis is inhibited by apoC-III and by angiopoietin-like proteins 3 and 4 (ANGPTL3, ANGPTL4), and PCSK9 binds to the LDL receptor and promotes its lysosomal degradation [11].

Vitamin E has no specific plasma transport protein and depends almost entirely on apoB-containing lipoproteins for intestinal absorption and transport to the tissues; the same applies to β-carotene, whereas vitamins A, D and K depend on these particles only partially [11, 33]. This difference explains the hierarchy of the deficiencies: vitamin E is the most affected, remains low in plasma even with supplementation and is mainly responsible for the neurological and retinal damage [2, 24].

2.2. MTTP and abetalipoproteinaemia (FHBL-SD1)

Active MTP is a heterodimer formed by the large subunit, of 97 kDa and 894 amino acids, encoded by MTTP, and by the 55-kDa protein disulphide isomerase (PDI), encoded by P4HB, which keeps the complex soluble [2, 33, 45]. The large subunit has an 18-residue signal peptide and three domains: an amino-terminal β-barrel (amino acids 22–297), which interacts with the amino terminus of apoB; a central α-helical region (298–603), which interacts with apoB and PDI and is required for transfer activity; and a carboxy-terminal domain (604–894), which mediates lipid binding and transfer [2, 33]. The MANE Select transcript is NM_001386140.1; the c. numbering of the variants described coincides with that of NM_000253.3 used in GeneReviews [10]. Without MTP, apoB is not lipidated and is degraded, apoB-containing lipoproteins practically disappear from plasma and lipids accumulate in enterocytes and hepatocytes [2, 33]. MTTP is also expressed in cardiomyocytes, which has been proposed as an explanation for the arrhythmias and heart failure described in some patients; in cardiomyocytes and hepatocytes derived from induced pluripotent stem cells (iPSCs) from a patient homozygous for NM_001386140.1:c.136C>G p.(Arg46Gly), both lineages reproduced the defect — absent apoB secretion, intracellular lipid accumulation and hypersensitivity to metabolic stress with increased cell death — which was reversed by correcting the variant with CRISPR/Cas9 editing (preclinical model) [10, 46].

More than 60 (GeneReviews) to 74 (Takahashi) pathogenic variants have been described, scattered throughout the gene and not concentrated in any ethnic group, most of them inactivating (nonsense, splicing and small insertions or deletions) [2, 33, 47]. Among the functionally studied missense variants, p.(Arg540His) prevents interaction with PDI and leaves MTTP as an insoluble aggregate; p.(Leu435His) and p.(Ser590Ile) have negligible transfer activity; p.(Gly746Glu) and p.(Asn780Tyr) interact with PDI but do not transfer lipids [2]. About one third of patients are born of consanguineous marriages [33]. Homozygosity may result from uniparental disomy, as in a Japanese patient homozygous for NM_001386140.1:c.1237-1G>A [10, 33]. Genotype–phenotype correlation data are insufficient; biochemical penetrance is complete in homozygotes and compound heterozygotes, but clinical penetrance is variable, increases with age and may be incomplete, as shown by the case of two cousins, one typical and the other atypical [2]. There are atypical forms without malabsorption, such as that of a 27-year-old Japanese man homozygous for p.(Asn780Tyr) with only mild steatosis and acanthocytosis, or that of a 25-year-old man homozygous for the in-frame deletion p.(Ser615del), with no signs of malabsorption or neurological signs [33, 48]. Heterozygotes have a normal lipid profile and do not develop the disease, although steatosis has been described in carriers of a single variant [2, 11]. No allelic disorders of MTTP are known [2]. The French protocol describes the gene as having 18 exons, expressed mainly in the enterocyte and the hepatocyte and, to a lesser extent, in the kidney and the cardiomyocyte, and counts more than 50 variants, most leading to a truncated protein; large rearrangements (copy number variations) have also been described in MTTP, as in APOB and SAR1B [23].

2.3. APOB and familial hypobetalipoproteinaemia (FHBL-SD2)

Most variants that cause FHBL-SD2 are frameshift, nonsense or splicing variants and give rise to a truncated apoB, designated by the percentage of the length of apoB100 [3]. Severity is inversely proportional to the length of the peptide: truncations of 30% or less cause more severe disease than those of 32% or more; proteins smaller than apoB30 are not detectable in plasma by Western blot, and truncations shorter than apoB48 also affect chylomicrons, bringing the phenotype closer to that of abetalipoproteinaemia [3, 11]. Longer truncations retain some capacity to bind lipids and form lipoproteins, but these are rapidly cleared from the circulation [3, 11]. Rarely, missense variants produce peptides smaller than apoB48 [11]. The mechanism is loss of function [3]. The French protocol counts more than 120 deleterious variants and summarises the correlation by peptide length: below 48% of normal length, secretion of chylomicrons and VLDL is compromised, with fat malabsorption and steatosis; between 48% and 100% only VLDL secretion decreases, and the consequences are mainly hepatic [23].

Inheritance is described in two ways, both correct depending on the phenotype considered. GeneReviews and OMIM classify clinically manifest FHBL as autosomal recessive, because symptoms require two variants [3, 4]; the ABLRDF and Lee and Hegele describe it as semidominant or codominant, because heterozygotes have an intermediate biochemical phenotype, with apoB100 and LDL cholesterol at about 24% of normal, and the parents of a biallelic patient have about half the normal levels of apoB-containing lipoproteins [11, 12]. Saudubray classifies it as autosomal dominant [19]. The APOB variants that cause familial hypercholesterolaemia are, by contrast, missense variants, concentrated in exon 26 and in the LDL receptor-binding domain (region of codon 3527, such as NM_000384.3:c.10580G>A p.(Arg3527Gln)), and raise LDL cholesterol [3, 10, 49]. The monoallelic form confers cardiovascular protection: in 12 case–control studies with 57,973 individuals, an apoB truncation was associated with a 72% reduction in coronary heart disease (odds ratio 0.28; 95% CI 0.12–0.64) [50].

2.4. SAR1B and chylomicron retention disease (FHBL-SD3)

SAR1B is a small GTPase of the Sar1-ARF family which, in its GTP-bound form, forms the COPII coat with the Sec23/24 and Sec13/31 heterodimers, initiates vesicle budding and captures the cargo to be exported from the endoplasmic reticulum to the Golgi; chylomicron retention disease is therefore classified among the disorders of cellular vesicular trafficking [5, 24, 51]. Without functional SAR1B, the pre-chylomicron transport vesicles do not fuse with the Golgi and accumulate in the cytoplasm of the enterocyte; chylomicrons are selectively absent from plasma, whereas hepatic secretion of triglyceride-rich lipoproteins is relatively preserved, which explains the normal plasma triglycerides [5, 24]. SAR1B is also expressed in the liver, muscle, brain and myocardium, which secretes apoB-containing lipoproteins; this distribution is the proposed explanation for the steatosis, CK elevation and cardiomyopathy described in the disease [24]. The MANE Select transcript is NM_016103.4, whose numbering coincides with that of NM_001033503.3 in GeneReviews [10]. By 2010, 14 variants had been described in about 30 patients, most of them missense; the variant with the greatest impact on lipids and growth in the French-Canadian cohort was a missense variant, NM_016103.4:c.409G>A p.(Asp137Asn), and the description of an asymptomatic homozygous mother suggests the existence of modifier genes [5, 24]. GeneReviews identifies no genotype–phenotype correlations or germline allelic disorders [5].

2.5. Class II: ANGPTL3 and PCSK9

In FHBL-EC1, loss-of-function variants of ANGPTL3 (1p31.3) no longer inhibit lipoprotein lipase, increasing lipolysis of chylomicrons and VLDL and clearance of remnants; there is a gene dosage effect, with a more marked reduction of LDL cholesterol, triglycerides, HDL cholesterol, apoB and apoA-I in biallelic individuals [11, 29]. In FHBL-EC2, loss of function of PCSK9 increases recycling of the LDL receptor and reduces LDL cholesterol by 21–40% [11]. Neither affects the absorption of fat or vitamins, and both have inspired lipid-lowering drugs [11]. The French protocol quantifies the protective effect with two population studies. In the ARIC study, the 2.6% of 3363 Black participants with PCSK9 nonsense variants had a 28% lower mean LDL cholesterol and 88% less coronary heart disease over 15 years (hazard ratio 0.11; 95% CI 0.02–0.81), whereas in the 9524 White participants the PCSK9 variant found in 3.2% reduced LDL by 15% and coronary risk by 47% (hazard ratio 0.50; 95% CI 0.32–0.79); the protocol presents the values of the first group as general for heterozygotes [23, 52]. Heterozygotes for ANGPTL3 loss-of-function variants (about 1 in 309 people; 21,980 cases of coronary heart disease and 158,200 controls) had 17% lower triglycerides and 12% lower LDL and a lower coronary risk (odds ratio 0.66; 95% CI 0.44–0.98; p = 0.04; the French protocol gives the upper limit as 0.9) [23, 53]. In the French protocol, hepatic triglyceride content and the prevalence of steatosis are not increased in carriers of these variants, although cases of steatosis have been described in patients with other risk factors [23]. The same protocol warns that ischaemic cardiovascular events have been described in patients with monoallelic and biallelic FHBL-SD2, so a low LDL cholesterol is not enough to protect against atherosclerosis when diabetes, obesity or low HDL cholesterol coexist [23].

2.6. Peroxisomal α-oxidation and PHYH

Phytanic acid derives only from the diet, mainly from dairy products, ruminant fat and certain fish, from phytanate or from phytol esterified in phytyl esters; the free phytol of the chlorophyll of green vegetables is not released in humans [7, 25, 39]. The methyl group at position 3 prevents direct β-oxidation; peroxisomal α-oxidation removes the terminal carboxyl as CO2 and produces pristanic acid (2,6,10,14-tetramethylpentadecanoic acid), which then proceeds to β-oxidation [7, 39]. The system involves phytanoyl-CoA 2-hydroxylase (PHYH), 2-hydroxyacyl-CoA lyase 1 (HACL1) and a pristanal dehydrogenase; of the enzymes of the pathway, only PHYH deficiency has been associated with human disease [39]. PHYH catalyses the hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA, is an Fe(II)- and 2-oxoglutarate-dependent dioxygenase and has a PTS2 [7, 41, 54]. The MANE Select transcript is NM_006214.4 [10]. The block leads to the accumulation of phytanate to toxic concentrations; most is stored in adipose tissue, but there is a rapidly mobilisable compartment, and decompensations correlate with circulating phytanate [7, 25]. The exact mechanism of toxicity has not been elucidated [25]. An alternative hepatic ω-oxidation pathway, dependent on cytochromes P450, metabolises about 6.9 mg/day of phytanate (estimates up to 30 mg/day), a much smaller amount than that released by rapid weight loss: phytanate accounts for 0.2–1.5% of abdominal fat, so each kilogram of fat lost can release 200–1500 mg [25].

GeneReviews identifies no clinically relevant genotype–phenotype correlations; the variability within the same family, comparable to that observed between families, has been attributed to phytanate intake and accumulation [7]. Functional studies showed that variants at residue Arg275 compromise 2-oxoglutarate binding and that others uncouple 2-oxoglutarate conversion from phytanoyl-CoA oxidation, so the diagnosis should not rest on these enzyme assays alone [55]. The variant NM_006214.4:c.678+5G>T, with conflicting interpretations in ClinVar and an allele frequency of about 1/1000 in the general population (more than 4/1000 in South Asians and Ashkenazi Jews), causes in-frame skipping of exons 5 and 6 in 31–88% of transcripts and is associated with attenuated disease, sometimes with isolated retinitis pigmentosa and normal phytanate [56]. The 2024 study concludes that the variant is pathogenic and that any biallelic genotype that includes it justifies measurement of phytanate [56].

2.7. PEX7 and the spectrum of PTS2 receptor disorders

The PEX7 receptor, stabilised by the long isoform of PEX5 (PEX5L), imports into the peroxisome the proteins with PTS2, including alkyl-dihydroxyacetone phosphate synthase (AGPS), required for plasmalogen synthesis, and PHYH [18, 39, 57]. Severe loss of function of PEX7 causes the combined deficiency of plasmalogens and α-oxidation typical of rhizomelic chondrodysplasia punctata type 1, whereas hypomorphic variants — missense variants on the surface of the protein, such as p.(His285Arg), p.(Ser25Phe), p.(Thr14Pro), p.(Ile245Phe), p.(Ser116Ile), p.(Tyr40Cys) and p.(Asp177Glu), or alleles that allow residual protein production, such as NM_000288.4:c.-45C>T and NM_000288.4:c.340-10A>G — cause mild forms of chondrodysplasia or an adult Refsum disease phenotype [18]. The PEX7 variants that cause adult Refsum disease have minimal effect on plasmalogen biosynthesis [25]; van den Brink's patients had phytanate between 142 and 1950 µmol/L, normal pristanate β-oxidation and deficient plasmalogen synthesis [9]. GeneReviews anticipates a continuum of PEX7 phenotypes, from the severe rhizomelic form to Refsum-like disease [18]. The variant p.(His285Arg) is proposed as a founder variant of Dutch origin and is the most frequent hypomorphic variant in the mild forms [18].

2.8. Standardised variants cited in this article

3. Clinical Spectrum and Manifestations by System

3.1. Abetalipoproteinaemia: natural history without treatment

Abetalipoproteinaemia usually presents in infancy, after breastfeeding has started, with faltering growth, diarrhoea, vomiting, abdominal distension and pain, and steatorrhoea, whose intensity follows the fat content of the diet, including breast milk [2, 11, 33]. With age, patients learn to avoid fat and the steatorrhoea lessens; adults from regions with low fat intake may have escaped severe diarrhoea in childhood [2, 11]. Endoscopy on an unrestricted diet shows a whitish duodenal mucosa (gelée blanche), and biopsy shows lipid-laden enterocytes [2]. The liver usually shows hepatomegaly and steatosis with aminotransferases 1–1.5 times the upper limit, stable for years; steatohepatitis, fibrosis or cirrhosis occur rarely and have led to liver transplantation in a few patients [2, 11]. Supplementation with medium-chain triglycerides (MCT) has been associated with fibrosis, so the causality of the liver disease should be assessed carefully [33].

The extraintestinal manifestations result from fat-soluble vitamin deficiency. Without treatment, neuromuscular disease begins in the first or second decade with progressive axonopathy of the posterior columns, spinocerebellar tracts and peripheral nerves: reduction and then loss of tendon reflexes is often the first sign, followed by loss of vibration and position sense, Romberg sign, dysmetria, dysarthria, broad-based gait and, in the young adult, a Friedreich-type ataxia [2, 11, 33]. Tremor, paraesthesiae, weakness with a myopathic component, pes cavus, kyphoscoliosis and, in untreated cases, loss of ambulation may occur [11, 33]. Electrophysiological changes have been detected from 7 months [11]. Saudubray highlights, among the paediatric warning signs, progressive gaze abnormalities with a characteristic pattern of dissociated nystagmus [59]. Intellectual disability has been described in some patients, without demonstrated causality [33].

The cardinal ocular manifestation is an atypical pigmentary degeneration of the retina, attributed to vitamin E and A deficiencies; night blindness precedes loss of colour and peripheral vision, with ring scotomas and macular sparing, and most untreated patients reach legal blindness at around 40 years [2, 11, 33]. Ptosis, ophthalmoplegia (including posterior internuclear ophthalmoplegia), anisocoria, strabismus and corneal ulcers, the latter linked to vitamin A deficiency, occur rarely [2, 11, 33].

In the blood, acanthocytosis affects 50% or more of red cells and results from the altered lipid composition of the membrane; the erythrocyte sedimentation rate is low because the red cells do not form rouleaux; there is anaemia (mild, with haemolysis and reticulocytosis, sometimes aggravated by iron, folate or vitamin B12 deficiency) and hyperbilirubinaemia [2, 11, 33]. Vitamin K deficiency reduces factors II, VII, IX and X, prolongs the prothrombin time and may cause bleeding, including gastrointestinal bleeding [11, 33]. Cardiomegaly and cardiomyopathy, sometimes fatal, and subclinical or overt hypothyroidism of unclear cause occur rarely [2, 11]. In the past, without high-dose vitamins, patients rarely survived beyond the third decade, dying with severe neuromyopathy and respiratory failure [2, 33].

The French protocol adds details on the extraintestinal complications. Severe neurological complications begin before 20 years, and in paediatric experience the most severe forms occur in patients with the lowest vitamin E at diagnosis [23]. Rare cases of severe non-obstructive cardiomyopathy have been described, with deaths before 50 years [23]. In bone, vitamin D deficiency favours hypocalcaemia and raised parathyroid hormone, with bone resorption, osteoporosis in children and osteomalacia in adults; the low-fat diet is often also low in calcium, and vitamin K is involved in mineralisation, but there is no systematic densitometry study demonstrating an increased risk of fracture [23]. In the endocrine sphere, two patients had normal basal corticosteroid production but a reduced response to prolonged corticotrophin (ACTH) stimulation, delayed puberty has been described, and the lack of LDL is associated with reduced maximal progesterone production by the corpus luteum [23]. There are no objective data on the effect of the severe forms (abetalipoproteinaemia and biallelic FHBL-SD2) on intellectual and cognitive performance [23].

3.2. Treated abetalipoproteinaemia

With lifelong high-dose oral supplementation, survival into the seventh and eighth decades with relatively minimal symptoms has been described [2, 33]. Two Canadian patients treated since childhood reached the fifth decade with apparently stabilised neuropathy [60]. Combined vitamin A and E supplementation started before 2 years markedly attenuates retinal degeneration [61, 62]. Treatment does not fully restore function: growth potential may not be reached, retinal changes may appear despite early treatment, with pigmentary changes and subnormal cone–rod electroretinogram (ERG) amplitudes on long follow-up, and patients who start vitamins with electrophysiological changes already present tend to stabilise, not recover [2, 11, 33]. The French protocol is more guarded regarding the retina: it reports ophthalmological involvement, mainly retinitis pigmentosa, in 60% of patients with abetalipoproteinaemia, possible from childhood and progressing to blindness at around 40 years even with high-dose vitamins, and associates with retinal protection, in addition to vitamins A and E, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and other fat-soluble antioxidants [23]. This statement contrasts with the marked attenuation of retinal degeneration described when vitamins A and E are started before 2 years, and the protocol does not separate patients by age at start of treatment [23, 62].

3.3. APOB-related familial hypobetalipoproteinaemia

The biallelic form can present from infancy to adulthood and, although it may be clinically indistinguishable from abetalipoproteinaemia, it is on average milder: the mean age at diagnosis was 21 years, compared with 3.8 years in abetalipoproteinaemia [3]. Almost all patients have hepatomegaly, steatosis, fat-soluble vitamin deficiency and acanthocytosis (present from birth); steatohepatitis or fibrosis, steatorrhoea, faltering growth, ophthalmological involvement and peripheral neuropathy are common; cirrhosis is infrequent and hepatocellular carcinoma exceptional [3]. Without intervention, height and weight usually remain below the 10th centile, there is reduced bone mineral density and bruising or bleeding due to vitamin K deficiency [3]. The ocular and neuromuscular manifestations — loss of reflexes and deep sensation, muscle pain or weakness, dysarthria, broad-based ataxia and tremor — can be halted but not reversed by the vitamins, and prevented by early diagnosis [3].

The monoallelic form is usually asymptomatic, with mildly raised transaminases and a hepatic fat content 3 to 5 times higher than that of the general population; in one study, 54% of heterozygotes had steatosis, which takes years to develop, and about 5–10% develop non-alcoholic steatohepatitis requiring care, rarely with progression to cirrhosis, especially with alcohol, caloric excess or other liver injury [3]. Families with short truncations developed steatosis and cryptogenic cirrhosis [11]. Oral fat intolerance and intestinal malabsorption are infrequent [3]; Saudubray describes partial fat malabsorption in heterozygous children and adults and gallstones in adults [19]. Heterozygotes do not have clinically relevant vitamin deficiencies [11], but Saudubray suggests vitamin E to prevent an adult-onset neuropathy [19]. In a study of more than 800 adult psychiatric inpatients, lipid profiles compatible with heterozygosity were more frequent than expected, with statistical associations between low LDL cholesterol and schizophrenia, aggression towards others and developmental disorders, without genetic testing or demonstration of causality [3]; according to the French protocol, this is the retrospective HYPOPSY study, with 839 adults, in which the prevalence of LDL cholesterol below 0.5 g/L was 4 times higher than in the control population, and the developmental disorders included autism [23].

The French protocol adds three points on the monoallelic form. No major neurological complications have been described, but some patients report paraesthesiae or dysaesthesiae of the feet and hands attributed to moderate hypovitaminosis E, relieved by supplementation [23]. Cases of steatohepatitis with fibrosis or cirrhosis requiring liver transplantation have been published in carriers of deleterious APOB variants, including heterozygotes without an additional risk factor; the risk increases with the lipogenesis and oxidative stress of type 2 diabetes and the metabolic syndrome [23]. In a retrospective cohort of 740 children followed for non-alcoholic fatty liver disease, 58 (8%) had hypobetalipoproteinaemia; the protocol presents this figure as a proportion of FHBL-SD2, but the Cincinnati study (2010–2017) defined the group only by LDL cholesterol below 50 mg/dL, without genetic testing, and found no difference in inflammation or fibrosis compared with children with normal or raised LDL, despite a leaner phenotype [23, 63]. The monoallelic form, and sometimes the biallelic form, is diagnosed incidentally on a lipid profile or in the investigation of steatohepatitis, and the diagnosis is justified in order to monitor the liver and screen relatives [23].

3.4. Chylomicron retention disease

The disease presents between the first and sixth months with chronic malabsorptive diarrhoea, present in all patients in the Lyon and Montreal cohort (16 patients with a molecular diagnosis, median follow-up of 5 and 10 years), faltering growth in 80%, abdominal distension in 65% and vomiting in 60% [24]. Consanguinity is frequent and there is no intrauterine growth restriction [24]. Digestive symptoms improve within days to weeks on a low-fat diet, but diarrhoea returns when fat is reintroduced, even in adults, and steatorrhoea does not improve during follow-up, which does not support the hypothesis of intestinal adaptation [24]. Hepatomegaly occurs in about 20% and moderate macrovesicular steatosis is common, with no cases of cirrhosis described; liver enzymes do not correlate with steatosis [5, 11, 24]. Bone mineralisation and maturation are reduced [5].

Neurological involvement is later and less severe than in abetalipoproteinaemia: areflexia and proprioceptive changes appear in older children and adolescents, with a mean age of 12 years in children with manifestations compared with 4 years in asymptomatic children; four of the 16 patients in the cohort had electromyographic abnormalities, the youngest aged 6.5 years, and the most affected were those with the lowest vitamin E at diagnosis [24]. Ataxia, myopathy and sensory neuropathy have been described in adults aged 21 and 55 years [24]. Ophthalmological involvement is generally mild — micronystagmus, mild blue–yellow axis deficit, slow dark adaptation, abnormal visual evoked potentials and scotopic ERG — and the absence of pigmentary retinopathy and severe neurological involvement in a child is compatible with the diagnosis [5, 24]. Cardiomyopathy with an ejection fraction of 40% has been described in adults, of unknown prevalence; in the Canadian cohort there was no cardiomyopathy before 23.5 years [5, 24]. Myalgia and cramps are rare [24]. The French protocol puts the usual CK elevation at about 5 times normal, reports one patient with CK 10 times normal and reduced left ventricular ejection fraction, stresses that CK values do not correlate with muscle involvement and that, in a cohort of patients under 25 years, echocardiography was normal; in the liver, it describes hepatomegaly in 20%, aminotransferases 1.5 to 3 times normal without correlation with steatosis and three published cases of steatohepatitis, without cirrhosis [23]. With early diagnosis and lifelong supplementation, the long-term prognosis is favourable [5].

3.5. Adult Refsum disease

Patients are asymptomatic at birth and grow and develop normally [39]. Onset ranges from 7 months to more than 50 years, with most first symptoms between 10 and 20 years, insidiously [7]. In the CoRDS–Global DARE registry survey, the mean age at diagnosis of retinitis pigmentosa was 22.8 years and that at diagnosis of Refsum disease 35.5 years [64]. The following table brings together the frequencies from the main series.

Retinitis pigmentosa is present in all patients with Refsum disease biochemistry and begins with night blindness, often in childhood, years before constriction of the visual fields and loss of central acuity; visual function is preserved until late, with markedly concentrically reduced fields [7]. In a series of 23 patients, the delay between the first ophthalmology consultation and the diagnosis was 1 to 28 years (mean 11) [7, 25]; in the registry, 50% had a diagnosis of retinitis pigmentosa by 20 years and only 9% of Refsum disease [25]. Cataracts appear earlier, are posterior subcapsular as well as corticonuclear, and surgery is made difficult by poor pupillary dilation (miosis with a sluggish reflex) and zonular fragility; acute angle-closure glaucoma and, in 2026, macular dystrophy associated with two new PHYH variants have also been described [7, 25, 65].

The polyneuropathy fluctuates at the outset and then affects the distal lower limbs with wasting and weakness, and may spread to the trunk; almost all patients have impaired distal deep sensation [7, 39]. Conduction studies show abnormal sensory conduction with normal or slightly reduced motor velocity, and sural nerve biopsy shows a reduction in myelinated fibres without onion bulbs [25]. Oxford Desk Reference stresses that the disease may mimic other hereditary demyelinating neuropathies (HMSN2 and HMSN3), being distinguished by night blindness and pigmentary retinopathy [66]. The deafness is bilateral and symmetrical, mild to profound, and auditory neuropathy may cause hearing difficulty with a normal audiogram [7]. Short metatarsals characteristically cause dorsal displacement of the fourth toe; a short, conical distal phalanx of the thumb was present in all patients with skeletal abnormalities in a radiographic series, and there are epiphyseal chondrodysplastic changes at the knee and elbow, variable within the same family [7, 25]. CSF protein is markedly raised (101 mg/dL in an Arab family, normal 15–50 mg/dL) and 20% of patients with PHYH variants have mildly raised pipecolic acid [7]. The kidney may show a reduced glomerular filtration rate and tubulopathy with hypokalaemia, kaliuresis, aminoaciduria and proteinuria, especially during decompensations [25].

GeneReviews and the Global DARE guide distinguish a chronic form, in which retinitis pigmentosa dominates and the other signs are subtle, from acute decompensations [7, 25]. The latter present with rapid sensorimotor polyneuropathy with demyelinating features, proximal and distal weakness, worsening of limb and truncal ataxia, neuropathic pain, sudden visual and hearing deterioration, generalised ichthyosis, tubulopathy, raised CK, aminotransferases and bilirubin, arrhythmias and heart failure, with sudden death described [7, 25]. They are part of the differential diagnosis of Guillain-Barré syndrome [25, 67]. They are triggered by weight loss, fasting, intercurrent illness, stress and trauma, and are usually associated with phytanate above 500 µmol/L and often above 1000 µmol/L [7, 25]. In the British series of 25 patients, six had significant ventricular dysrhythmia at acute presentation, all with phytanate above 1500 µmol/L [25]. Cardiomyopathy, hypertrophic or dilated, occurs mainly in advanced stages and may be fatal without heart transplantation [39, 68]. A 38-year-old Moroccan man was diagnosed following decompensated heart failure with dilated cardiomyopathy and an ejection fraction of 15%, bradycardia with complete right bundle branch block, an apical thrombus and phytanate of 324 µmol/L, in a context of blindness due to retinitis pigmentosa, hearing loss, anosmia, amyotrophy and ataxia not investigated since the age of 20 [69].

PEX7-related Refsum disease has an overlapping phenotype, sometimes milder; a 55-year-old Norwegian man diagnosed by Refsum himself, with retinitis pigmentosa, polyneuropathy, ichthyosis and hearing loss, developed cardiomyopathy at 53 years and was only later shown to have a PEX7 defect [7, 9]. The overlap with the mild forms of rhizomelic chondrodysplasia punctata (cataracts, epiphyseal changes, learning difficulties in 87%, seizures in 43% and heart defects in 31% in a series of 16 patients) defines a clinical continuum [18, 39]. In treated disease, the frequency and severity of exacerbations decrease over time, the neuropathy, cardiac symptoms and skin improve, ocular and auditory progression may slow, and there is no improvement in the bone changes nor, to any relevant extent, in the sense of smell [25]. Depressive symptoms were reported by 86.2% of registry respondents [64].

4. Clinical Recognition and Red Flags

4.1. Infant and young child

Chronic diarrhoea with steatorrhoea and faltering growth in the first months, especially when aggravated by breast milk or by formulas rich in long-chain triglycerides, calls for a fasting lipid profile with apoB; hypocholesterolaemia accompanied by diarrhoea is non-specific and easily attributed to malnutrition, which delays the diagnosis [11, 24]. The lipid pattern is a guide: almost undetectable lipids and apoB with very low triglycerides suggest abetalipoproteinaemia or biallelic FHBL, whereas total, LDL and HDL cholesterol reduced to about half with normal triglycerides and raised CK suggest chylomicron retention disease [11, 24]. Acanthocytosis on a peripheral blood film, a very low erythrocyte sedimentation rate, a prolonged prothrombin time or bleeding due to vitamin K deficiency in an infant with malabsorption are additional warning signs [2, 33]. In the Saudubray table of digestive signs, the combination of abdominal distension, ataxia, acanthocytosis, neuropathy and retinitis pigmentosa points to abetalipoproteinaemia, and that of cardiomyopathy, retinopathy and micronystagmus in an infant without splenomegaly to chylomicron retention disease [59]. According to the French protocol, more than 80% of patients with abetalipoproteinaemia or chylomicron retention disease have signs before 1 year, but the diagnosis is late in 60%, with a mean age of 4 years in abetalipoproteinaemia and 6 years in chylomicron retention disease; the first diagnoses assigned are often cow's milk protein allergy or coeliac disease, and the hypocholesterolaemia is attributed to malnutrition [23]. The same document advises suspecting these diseases, from the first months, in the presence of chronic diarrhoea or vomiting, abdominal pain that is sometimes severe, distension, fat malabsorption, spontaneous avoidance of fatty foods and growth delay, without intrauterine growth restriction [23].

4.2. Older child, adolescent and adult

In the hypobetalipoproteinaemias, the warning signs are progressive ataxia with areflexia and loss of deep sensation, an atypical pigmentary retinopathy, LDL cholesterol below 15 mg/dL or apoB below 15 mg/dL on a routine test, or hepatic steatosis with hypocholesterolaemia in an asymptomatic adult and their relatives [3, 33, 70]. Oxford Desk Reference includes hypobetalipoproteinaemia and abetalipoproteinaemia among the inborn errors to be excluded in the ataxic child, recommending measurement of vitamin E, cholesterol and apoB and a search for retinopathy on fundoscopy [70]. Ataxia with isolated vitamin E deficiency (AVED) should be excluded by measuring vitamin E when testing for Friedreich ataxia is negative [70, 71]. In the adult without adequate treatment, the French protocol describes as modes of presentation the progressive onset of ataxia, dysarthria, muscle weakness or visual loss, first at night and then during the day, usually already with areflexia and reduced vibration sense, and the discovery of hepatomegaly with or without splenomegaly, of cytolysis with cholestasis or of cirrhosis [23]. The discovery of abetalipoproteinaemia or chylomicron retention disease in a previously asymptomatic adult is rare, and the history often reveals diarrhoea or neurological signs neglected since childhood [23].

In Refsum disease, the main warning sign is retinitis pigmentosa, especially when accompanied by anosmia, hearing loss, polyneuropathy, ataxia, ichthyosis or short metacarpals and metatarsals [7, 25]. Oxford Desk Reference recommends measuring phytanate in all simplex and recessively inherited cases of retinal dystrophy and looking for skeletal anomalies, because the ocular signs precede the neurological ones and early dietary advice changes the prognosis [61]. A sporadic demyelinating neuropathy with pigmentary retinopathy or night blindness, an acute Guillain-Barré-like polyneuropathy, unexplained cardiomyopathy or conduction block in an adult with visual loss and deafness, or ichthyosis of adolescent onset with neurological signs, should also raise suspicion [59, 66, 67, 69].

4.3. Emergency signs

In the class I hypobetalipoproteinaemias, bleeding due to vitamin K deficiency (including neonatal intracranial haemorrhage and postpartum haemorrhage) and severe malnutrition in the infant constitute emergencies [11]. In Refsum disease, the emergency is acute decompensation: rapidly progressive weakness, acute ataxia, arrhythmias, heart failure or tubulopathy with hypokalaemia, especially after fasting, weight loss, surgery or intercurrent illness; in these cases it is necessary to measure phytanate, monitor the cardiac rhythm, ensure caloric intake and consider plasmapheresis [7, 25].

4.4. Newborn screening and screening in founder populations

None of these diseases is included in newborn screening panels, including the French panel [23]. The Global DARE guide does not recommend routine biochemical newborn screening for Refsum disease, because phytanate, being of exogenous origin, is not raised at birth in a newborn breastfed by an unaffected mother (high quality of evidence; very strong recommendation), but recommends genetic testing of at-risk newborns (siblings of patients or a suggestive family history) and of any child with compatible brachymetatarsia or brachymetacarpia (low quality; very strong recommendation) [25]. In the French-Canadian population of Saguenay-Lac-Saint-Jean, with a carrier frequency of the MTTP c.419dup variant estimated at 1/203, the authors propose considering carrier screening or newborn screening for abetalipoproteinaemia [21]. The entry criterion of the Japanese criteria (LDL cholesterol and/or apoB below 15 mg/dL) has been proposed as an opportunistic screening tool on routine tests [33].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Lipid profile and biomarkers of the hypobetalipoproteinaemias

Hypobetalipoproteinaemia is defined by apoB, total cholesterol and LDL cholesterol persistently below the 5th centile for sex and age; before attributing it to a genetic cause, secondary causes should be excluded, such as a strict vegetarian diet, intestinal malabsorption, chronic pancreatitis, severe liver disease, malnutrition and hyperthyroidism [29, 33]. The following table summarises the typical values for each entity.

The ABLRDF values are means or medians from published studies; to convert cholesterol from mmol/L to mg/dL multiply by 38.67, and triglycerides by 88.57 [11]. Plasma vitamin E is so low in abetalipoproteinaemia (less than 1/100 of normal before treatment) that it serves mainly to assess adherence and not to adjust doses [2, 11].

The French protocol sets the 5th centile of LDL cholesterol using French paediatric data and Dutch adult data. The clearest values in its table are as follows (to convert to g/L multiply by 0.387).

Source: [23]. In the remaining adult age groups, the 5th centile lies between 1.6 and 2.5 mmol/L and rises with age; the original table has overlapping rows in the bands from 50 to 74 years.

The same protocol gives practical thresholds: in the forms with intestinal symptoms, total cholesterol below 2 mmol/L, LDL cholesterol and triglycerides below 0.1 mmol/L and apoB below 0.1 g/L in more than 90% of patients with abetalipoproteinaemia or biallelic FHBL-SD2; in chylomicron retention disease, total cholesterol below 2 mmol/L in only 60%, with reduced LDL and HDL and normal triglycerides; and a normal lipid profile in both parents points to abetalipoproteinaemia or chylomicron retention disease [23]. The reference values for each entity differ between the protocol and the ABLRDF, because they come from different series: in chylomicron retention disease the protocol gives total cholesterol 1.81 mmol/L (1.11–2.82), LDL 0.88, HDL 0.50, triglycerides 0.92 mmol/L and apoB 0.49 g/L; in biallelic FHBL-EC1, total cholesterol 1.9 ± 0.5, LDL 1.1 ± 0.4, HDL 0.6 ± 0.2 and triglycerides 0.4 ± 0.2 mmol/L, with apoB 0.6 ± 0.2 g/L; and in FHBL-EC2, total cholesterol 3.63 ± 0.62, LDL 1.63 ± 0.6, HDL 1.55 ± 0.54 and triglycerides 0.93 ± 0.45 mmol/L, values lower than those of the ABLRDF [11, 23].

The first-line investigations proposed by the French protocol are the lipid profile with apoB of the proband and parents, 3-day quantification of steatorrhoea, a search for acanthocytes, vitamins A, D, E and K, electrolytes with calcium–phosphate studies, prothrombin time and, possibly, the fat load test [23]. Steatorrhoea is defined as more than 3 g/day of faecal fat in children and more than 5 g/day in adults, but depends on the fat ingested; a fat absorption coefficient below 85%, measured on a normal diet, indicates malabsorption, present in more than 80% of patients with abetalipoproteinaemia or chylomicron retention disease and in biallelic patients with apoB less than 30% of normal length, and absent in APOB heterozygotes [23]. ApoB48 can be measured by ELISA, and a value below the limit of quantification points to abetalipoproteinaemia or chylomicron retention disease; vitamin E below the limit of quantification points to these two diseases or to biallelic FHBL-SD2 with a short apoB [23]. Acanthocytosis is defined as more than 5% acanthocytes; it is frequent in abetalipoproteinaemia, where it may exceed 50% of red cells, and rarer in biallelic FHBL-SD2 and chylomicron retention disease, with moderate haemolysis and reticulocytosis [23].

5.2. Diagnostic criteria for abetalipoproteinaemia

GeneReviews recognises no formal clinical criteria and establishes the diagnosis by the biochemical profile with biallelic variants in MTTP [2]. The ABLRDF lists five criteria: extremely low plasma lipids, absence of apoB-containing lipoproteins, low vitamins E, A, K, D and carotenoids, acanthocytosis and biallelic variants in MTTP [11]. The Japanese research group proposed operational criteria, used for access to public financial support in Japan [33].

Source: [33].

5.3. Diagnosis of chylomicron retention disease

The guideline by Peretti and colleagues, based on a literature review and the experience of two paediatric centres, summarises the diagnosis in four steps: chronic diarrhoea in an infant under 6 months with normal triglycerides and reduced total, LDL and HDL cholesterol; faltering growth; white duodenal mucosa on endoscopy, which suggests genetic hypocholesterolaemia; and a variant in SAR1B, which confirms the diagnosis [24]. Low HDL cholesterol and normal triglycerides are the most discriminating features; raised CK is discriminating but inconstant (60% in the cohort); absence of acanthocytosis is more frequent than in abetalipoproteinaemia; hepatic cytolysis (1.5–3 times normal) is accompanied by normal GGT, bilirubin and alkaline phosphatase; and the fatty acid profile shows linoleic acid (omega-6) deficiency with normal omega-3 and a raised 20:3n-9/20:4n-6 ratio [24]. The oral fat load test (12-hour fast, 50 g of fat per 1.73 m² of body surface area, in the form of cream, with measurements at 2, 3 and 5 hours) shows no rise in triglycerides or chylomicrons, but does not distinguish the disease from the other genetic hypocholesterolaemias [24]. Steatorrhoea may be falsely negative on a restricted diet, so the percentage of fat absorption should be measured on a normal diet [24]. A triglyceride-rich diet in the 3 preceding days increases the sensitivity of endoscopy, but the latter is not mandatory; histology shows multivacuolated enterocytes in the upper third of villi of normal architecture, sometimes with mild atrophy that can be confused with coeliac disease [5, 24]. The French protocol describes the load test with 50 g of fat per m² of body surface area after a 12-hour fast (Peretti: 50 g per 1.73 m²), considers it practically abandoned in favour of genetic testing and reserves it for atypical forms; it notes that endoscopy, once indispensable for the diagnosis of the intestinal forms, shows a "snow-like" or "white frost" mucosa, and that a high-fat diet in the 3 preceding days should be avoided in the most sensitive patients, in whom it may cause significant diarrhoea [23, 24].

5.4. Diagnosis of adult Refsum disease

The biochemical diagnosis rests on plasma phytanic acid, measured by gas chromatography: values above 20 times the upper limit are highly suggestive, with concentrations usually above 200 µmol/L (normal below 10 µmol/L) and sometimes above 1000 µmol/L, low pristanic acid (below 2 µmol/L) and a raised phytanic/pristanic ratio [7, 39]. Very long-chain fatty acids (VLCFA) and di- and trihydroxycholestanoic acids are normal; erythrocyte plasmalogens are normal in the PHYH form and reduced to normal in the PEX7 form [7].

Source: [7].

Saudubray considers phytanate a robust biomarker, with no false negatives described [39], but GeneReviews warns that the value depends on the local diet and may be misleadingly low in populations with lower intake of saturated fats [7], and the Global DARE guide describes genetically confirmed patients with normal or only mildly raised phytanate: two patients with retinitis pigmentosa for more than 10 years had phytanate below 20 µmol/L (reference below 15 µmol/L), which normalised rapidly with diet [25]. In the Daich Varela series, two of four patients with the hypomorphic variant c.678+5G>T had normal phytanate [56]. For this reason, the guide recommends genetic testing as first line: all patients with retinitis pigmentosa, or in whom Refsum disease is in the differential, should be tested for PHYH and PEX7, in a panel that includes the other causes of raised phytanate and the phenocopies (moderate quality; very strong recommendation) [25]. Phytanic and pristanic acids should be measured when there are suggestive ocular or extraocular signs, especially if genetic testing is declined or unavailable or if the panel does not include PHYH and PEX7 (moderate; very strong) [25]. In the presence of a variant of uncertain significance in PHYH without clear biochemistry, functional assays in fibroblasts (peroxisomal α-oxidation and β-oxidation) can confirm or exclude the diagnosis (low quality; strong recommendation) [25]; GeneReviews notes, however, that measurement of phytanoyl-CoA hydroxylase activity in fibroblasts is no longer clinically available and that cellular α-oxidation does not distinguish PHYH from PEX7 [7]. Heterozygotes have almost normal phytanate, so biochemical testing cannot be used to identify carriers [7].

The recommended initial assessment includes ophthalmological examination with perimetry, ERG, autofluorescence and optical coherence tomography, a standardised olfactory test (University of Pennsylvania Smell Identification Test, UPSIT), neurological assessment with electrophysiology and baseline brain magnetic resonance imaging, pure-tone audiometry with otoacoustic emissions and auditory brainstem responses, radiographs of the hands, feet and knees, echocardiogram and 24-hour Holter monitoring, renal function with urinary electrolytes and a urinary protein panel, and genetic counselling [7, 25].

5.5. Molecular testing, limitations and report

These figures are proportions of variants detectable by each method in patients already diagnosed, not clinical sensitivities of a panel in unselected patients [2, 7]. A negative result does not exclude the diagnosis: sequencing may miss deletions of one or more exons, deep intronic variants and regulatory regions; apparent homozygosity may correspond to an undetected deletion on the other allele or to uniparental disomy, so testing of the parents is recommended [3, 5, 33]. The identification of two variants of uncertain significance, or of one pathogenic variant and one of uncertain significance, neither establishes nor excludes the diagnosis [2, 7]. The report should state the gene, the transcript with version (preferably MANE Select), the HGVS nomenclature, the zygosity, the phase of the variants when known and the pathogenicity class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [2, 10]. In chylomicron retention disease and in the hypomorphic PHYH variants, family segregation and, when necessary, RNA studies (as in the demonstration of in-frame skipping caused by NM_006214.4:c.678+5G>T) help to reclassify variants [56]. The French protocol requires the technique to detect single-nucleotide variants and copy number variations, because large rearrangements have been described in APOB, MTTP and SAR1B; testing is done after genetic counselling and informed consent, signed by the legal representatives in the case of minors or adults under guardianship, and the list of reference laboratories is available on Orphanet [23]. A single deleterious variant in APOB, ANGPTL3 or PCSK9 confirms the corresponding heterozygous form, and two variants in ANGPTL3, inherited one from each parent, confirm the biallelic form of FHBL-EC1 [23].

5.6. Practical algorithm

In the presence of suspected hypobetalipoproteinaemia, the pathway proposed by the sources is: (1) fasting lipid profile with apoB and apoA-I, blood film for acanthocytes, vitamins A, D, E, 25-hydroxyvitamin D, INR, CK and aminotransferases, excluding secondary causes; (2) lipid profile of the parents — normal in abetalipoproteinaemia and chylomicron retention disease, with about half the values in FHBL-SD2; (3) pattern in the proband — very low triglycerides and almost absent apoB (abetalipoproteinaemia or biallelic FHBL-SD2) versus normal triglycerides with low HDL and raised CK (chylomicron retention disease) versus moderate reduction without symptoms (monoallelic FHBL-SD2 or class II); (4) hypocholesterolaemia panel with MTTP, APOB, SAR1B, ANGPTL3 and PCSK9 [3, 5, 11, 24]. In the presence of retinitis pigmentosa with or without extraocular signs, the pathway is a retinal dystrophy panel or genome including PHYH and PEX7, followed by phytanic and pristanic acids and, if necessary, erythrocyte plasmalogens and fibroblast studies [7, 25].

The French protocol organises the pathway for the hypobetalipoproteinaemias into two algorithms [23]:

• Child with chronic diarrhoea and hypocholesterolaemia, after secondary causes have been excluded: with collapsed LDL cholesterol (below 0.4 mmol/L, or 0.15 g/L), parents with a normal lipid profile suggest abetalipoproteinaemia, one parent with hypobetalipoproteinaemia suggests FHBL-SD2 and both parents with hypobetalipoproteinaemia suggest biallelic FHBL-SD2; with LDL cholesterol only reduced, parents with hypobetalipoproteinaemia point in the same way, and normal parents suggest chylomicron retention disease or atypical abetalipoproteinaemia. In parallel, malabsorption (steatorrhoea, vitamins) and hepatic, neurological, ophthalmological, cardiac, muscular (CK) and haematological (acanthocytes) involvement are assessed.
• Hypobetalipoproteinaemia discovered incidentally or with steatosis, without digestive signs: confirm persistence on a second lipid profile after 1 to 3 months when the deficit is moderate (immediate full assessment if severe) and exclude malnutrition, inflammatory syndrome, hepatocellular insufficiency and Smith-Lemli-Opitz syndrome; then, HDL cholesterol below 1 mmol/L (0.39 g/L) suggests the biallelic form of ANGPTL3, normal HDL with normal triglycerides suggests the heterozygous form of ANGPTL3 or loss of function of PCSK9, and normal HDL with reduced triglycerides suggests heterozygous FHBL-SD2.

The protocol's figures assign the low-HDL branch to "FHBL-EC2", in contradiction with its own list of abbreviations (FHBL-EC1 = ANGPTL3; FHBL-EC2 = PCSK9) and with the lipid values it presents (HDL reduced only in the biallelic form of ANGPTL3); the assignment consistent with the biology is that of the ABLRDF [11, 23].

5.7. Prenatal and preimplantation diagnosis

Once the familial pathogenic variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible for all the autosomal recessive entities in this article [2, 3, 5, 7]. There are no useful prenatal biochemical markers: in Refsum disease, phytanate at birth is normal or only mildly raised (below 30 µmol/L in two affected newborns of an affected mother, probably due to placental transfer) [25].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential within the hypobetalipoproteinaemias

The distinction between abetalipoproteinaemia and biallelic FHBL-SD2 is not possible on the clinical picture or the laboratory findings of the proband: the only distinguishing feature is the lipid profile of the obligate heterozygous parents, normal in abetalipoproteinaemia and with LDL cholesterol and apoB below 50% of normal in FHBL, and confirmation requires sequencing of MTTP and APOB [2, 11, 33]. Chylomicron retention disease is distinguished by normal triglycerides, a reduction of about 50% (rather than absence) of total, LDL and HDL cholesterol, raised CK and the rarity of acanthocytosis and pigmentary retinopathy; hepatic VLDL secretion is preserved [24, 33]. The degree of CK elevation differs between the two GeneReviews chapters by the same authors: 1.5 to 4 times the upper limit in the chapter on chylomicron retention disease and 1.5 to 5 times in that on abetalipoproteinaemia, with values up to 10 times described in the Peretti cohort [2, 5, 24]. The class II forms cause neither malabsorption nor symptoms, and recognising them avoids unnecessary dietary restrictions and supplements [5, 11]. Acanthocytosis also occurs in advanced liver disease, AVED, McLeod syndrome, pantothenate kinase-associated neurodegeneration (HARP variant), cobalamin C deficiency and Wolman disease [24, 59]. The HARP variant (hypoprebetalipoproteinaemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration) combines three features of abetalipoproteinaemia, but is distinguished by dystonia of childhood onset and by the "eye-of-the-tiger" sign in the globus pallidus on magnetic resonance imaging [74].

6.3. Differential diagnosis of adult Refsum disease

The main differential diagnosis is that of the syndromic forms of retinitis pigmentosa, and its practical consequence is that phytanate, or testing of PHYH and PEX7, should be part of the assessment of any retinitis pigmentosa, especially with anosmia, hearing loss, polyneuropathy or short digits [7, 25, 61]. Among the diseases with raised phytanate, AMACR deficiency is distinguished by raised pristanate and bile acid intermediates, the Zellweger spectrum by multiple abnormalities (VLCFA, plasmalogens, pipecolic acid, bile acids) and early onset, and mild rhizomelic chondrodysplasia punctata by the marked reduction in plasmalogens [7, 18, 25, 73]. PHARC syndrome is the main phenocopy with normal phytanate [25]. As regards the neuropathy, the disease may resemble other hereditary demyelinating neuropathies and, during decompensations, Guillain-Barré syndrome [25, 66]. The Saudubray tables of adult metabolic diseases place Refsum disease among the treatable causes of peripheral neuropathy, chronic cerebellar ataxia, deafness with retinitis and ichthyosis, alongside cerebrotendinous xanthomatosis, Niemann-Pick disease type C and AVED [59, 67].

7. Treatments and Risk Management Strategies

7.1. Class I hypobetalipoproteinaemias: principles

There are no randomised trials or meta-analyses to guide the treatment of the class I hypobetalipoproteinaemias; the recommendations are based on case series, small pharmacokinetic studies and the experience of expert panels, and their strength should be read in that context [11, 24, 78]. Treatment has three components: restriction of dietary fat to reduce enterocyte steatosis and steatorrhoea; fat-soluble vitamins in therapeutic doses, especially vitamin E at a very high dose; and adequate intake of energy, essential fatty acids (EFA) and micronutrients, with the support of a dietitian experienced in these diseases [11]. The aim is preventive: the neurological and retinal complications can be halted, but not reversed, and are preventable with early diagnosis and treatment [3, 5]. Monoallelic FHBL-SD2 requires neither treatment nor dietary restriction, and the class II forms require neither treatment nor surveillance [3, 11]. For the ABLRDF, fat-soluble vitamins should be regarded as therapy and not as supplements, because patients without adequate coverage progress to irreversible morbidity [11].

7.2. Diet

Sources: [2, 3, 5, 11, 23, 24, 33].

The divergence on the percentage of fat reflects different populations and eras: the more restrictive ABLRDF values apply mainly to abetalipoproteinaemia and biallelic FHBL-SD2, whereas the 30% limit comes from chylomicron retention disease and FHBL, in which VLDL secretion is preserved or partial [11, 24]. In all sources the principle is the same: the amount of fat is adjusted to digestive tolerance and growth, distributed throughout the day, with nutrient-dense foods, and breast milk and formulas rich in long-chain triglycerides are not recommended in the infant with abetalipoproteinaemia, MCT formula or skimmed and fortified breast milk being preferred [11]. Overly strict fat restriction aggravates EFA deficiency, which is particularly marked early in life and which neither oral nor intravenous supplementation normalised in the Peretti cohort; in that series, the Canadian cohort, with less supplementation and poorer plasma levels, had fewer complications [24]. Steatorrhoea may favour oxalate stones, preventable with sufficient dietary calcium, hydration and oxalate reduction [33]. Psychosocial support should address the risk of eating disorders [11]. In the infant with abetalipoproteinaemia, the ABLRDF estimates that MCT oil provides 8.3 kcal/g (one tablespoon, 14.25 g, corresponds to about 115 kcal) [11].

The French protocol has an internal divergence: the text sets fat at less than 30% of calories, with disappearance of digestive symptoms within a few days and their reappearance, with renewed slowing of growth, when the diet is not followed, and the treatment table sets it at less than 15% of energy intake, with 5–20 g/day in children; the table value is close to that of the ABLRDF and the text value to those of Peretti and Takahashi [11, 23, 24, 33]. The same document justifies MCT because they are absorbed directly into the portal circulation, without passing through the lymphatics, which allows the caloric density to be increased in infants and young children without digestive symptoms; it calls for monitoring of EFA, especially the omega-3 precursors of DHA, and monitoring and, if necessary, supplementation of iron, calcium, copper, zinc and selenium [23]. It also acknowledges that studies are lacking on the long-term impact of EFA deficiencies and on the optimal supplementation doses [23].

7.3. Fat-soluble vitamins: reference doses and comparison with the label

The reference doses are those of the guidelines and expert chapters; none of these vitamins has a specific approved indication for these diseases in the United States or the European Union, so their use at these doses is off-label prescription of the available products.

Sources: [2, 3, 5, 11, 23, 24, 33, 79, 80].

The guidelines set no absolute maximum daily dose for these vitamins: the upper limit of each range (vitamin E 300 IU/kg/day, vitamin A 400 IU/kg/day, vitamin D 1200 IU/day, vitamin K 35 mg/week) acts as the ceiling of the recommendation, the only total daily dose published for adults is that of Takahashi for vitamin E (up to 10,000 mg/day), and for vitamin A the practical limit is plasma retinol, which should remain at the lower limit of normal [2, 11, 33].

The vitamin E dose of 100–300 IU/kg/day, far higher than the recommended intake of 5–30 IU/day in healthy people, is based on the observation, over more than four decades, that high daily doses prevent retinal and neurological complications [11]; early treatment can delay or prevent neurological dysfunction, ophthalmoplegia and ptosis, and vitamin A can prevent corneal ulcers and halt visual progression [2]. Even at these doses, plasma vitamin E does not exceed about 30% of the lower limit in abetalipoproteinaemia and 50–67% of normal in chylomicron retention disease, regardless of dose (20, 40 or 100 IU/kg/day), and does not correlate with tissue content; adipose tissue reaches normal levels even with low plasma levels [24, 33]. For this reason, the ABLRDF advises against serial monitoring of plasma vitamin E and prefers erythrocyte tocopherol (a reproducible spectrophotometric method in abetalipoproteinaemia) or adipose tissue tocopherol, when available, and adjustment according to the ophthalmological and neurological course [11]. Vitamins A, D and K are adjusted to retinol and β-carotene, 25-hydroxyvitamin D and INR [11]. Vitamin A toxicity has been described in a patient with normal retinol who started supplementation, and the target should be the lower limit of normal to avoid hepatotoxicity [2, 33]. High-dose vitamin E may induce or worsen vitamin K deficiency and increase the bleeding tendency, so INR is monitored [33, 79]. The oral route is preferred to the intravenous and intramuscular routes because it is feasible lifelong, is not inferior in tissue levels and has no apparent toxicity; other routes have been associated with steatosis [33]. Vitamin E doses of 2000–3200 IU/day were well tolerated in the short term in double-blind studies [24].

The formulation of vitamin E differs between sources. The GeneReviews chapter on chylomicron retention disease, following Peretti, recommends the water-soluble form, and GeneGuidance cites the Cuerq crossover study as its basis [5, 81]. In that study, with three patients with abetalipoproteinaemia and four with chylomicron retention disease, the bioavailability of a single load was 2.8% for tocofersolan and 3.1% for α-tocopherol acetate in abetalipoproteinaemia, and 24.7% and 11.4% in chylomicron retention disease, but plasma α-tocopherol at 4 months did not differ between formulations in either disease [82]. The ABLRDF therefore concludes that there is no evidence to prefer one formulation [11]. Tocofersolan (d-α-tocopheryl polyethylene glycol succinate) inhibits P-glycoprotein and may increase the absorption of other fat-soluble vitamins and of lipophilic drugs such as ciclosporin and tacrolimus; it is contraindicated in preterm infants, contains parabens and sodium, and the most frequent adverse effect is diarrhoea [79]. The daily tablet burden is large in adults and the cost, not reimbursed in many systems, has reached USD 800 per month in the United States, which leads patients to adopt different regimens according to their financial capacity [11].

The French protocol converges with the other guidelines in principle and diverges on four points. First, it expresses vitamin E in children in mg/kg/day of the water-soluble form and not in IU/kg/day; as tocofersolan is dosed in mg of d-α-tocopherol, which corresponds to about 1.49 IU per mg, 100–200 mg/kg/day is equivalent to about 150–300 IU/kg/day, within the range of GeneReviews and the ABLRDF, but the document itself gives 100–300 mg/kg/day in the text and 100–200 mg/kg/day in the table [11, 23, 79]. Second, for adults it gives tocopherol acetate at 100–400 IU/kg/day, above the ceiling of 300 IU/kg/day of the other sources, and acknowledges that adherence is difficult because of the number of capsules [23]. Third, it prefers the water-soluble form in children because it is liquid and, in chylomicron retention disease, because of its better absorption (25% versus 11% for the acetate; 3% for both in abetalipoproteinaemia), whereas the ABLRDF finds no evidence to prefer one formulation, because levels at 4 months did not differ [11, 23, 82]. Fourth, it provides for intramuscular and monthly intravenous routes in defined situations, which the other sources generally consider unnecessary [2, 23]. According to the protocol, overdose is a real risk only with vitamins A and D, which require plasma measurements, and the intravenous route is justified only in the rare patients with late diagnosis and neurological complications, in whom the aim is to reach maximum plasma and tissue levels quickly [23]. The formulations cited in France are A 313® (vitamin A), Uvedose® 100,000 IU ampoule (colecalciferol), Toco 500® (500 mg per capsule) and Vedrop® 50 mg/mL (vitamin E) and Vitamine K1 Roche® 10 mg/mL in a 1-mL ampoule (vitamin K) [23]. The reference doses are those of the ABLRDF, GeneReviews and Peretti, which agree with each other in units; those of the French protocol are the alternative of a national guideline, with the unit inconsistencies noted in the table.

7.4. Other measures in the class I hypobetalipoproteinaemias

Mild anaemia generally requires no treatment, but may justify iron, folate or vitamin B12 when there is an associated deficiency; in biallelic FHBL iron does not improve the anaemia inherent to the disease [2, 3, 33]. Ataxia benefits from coordination rehabilitation, walking aids, home adaptation, weighted utensils and weight control; dysarthria, from speech therapy (rare with early vitamin E); visual loss, from low-vision aids; and hypothyroidism is treated with levothyroxine [2, 3]. Steatosis without fibrosis is treated with fat restriction, without anti-inflammatory drugs; fibrosis and cirrhosis, rare with early diagnosis, may justify liver transplantation [2, 3]. The cardiomyopathy of chylomicron retention disease is treated according to cardiological standards and reduced bone mineral density with vitamin D [5]. Fatty foods should be avoided, especially those rich in long-chain fatty acids [2, 5]. MTP inhibitors, such as lomitapide, pharmacologically reproduce abetalipoproteinaemia and have no role in these diseases [19, 83]. For heterozygous FHBL-SD2, the French protocol provides for neither diet nor vitamins, because there is no clinically relevant malabsorption; if vitamin E deficiency is detected, supplementation may be offered, of uncertain long-term benefit in patients without steatohepatitis [23]. In all forms with hepatic risk, including asymptomatic heterozygotes, it recommends weight control, physical activity, good glycaemic control in diabetes and limitation of alcohol, as these are factors that aggravate steatosis and fibrosis [23]. There are no contraindications to treatment, but it should be confirmed that caloric intake allows optimal growth [23].

7.5. Pregnancy, lactation and the peripartum period in the hypobetalipoproteinaemias

Men and women with abetalipoproteinaemia may be fertile and successful pregnancies have been described [11, 33]. The four GeneReviews chapters and Takahashi recommend reducing the vitamin A dose by 50% during pregnancy or when pregnancy is planned, monitoring retinol and β-carotene and not stopping vitamin A, whose deficiency causes maternal morbidity; the ABLRDF presents the 50% reduction as an option to be considered and recalls that low maternal vitamin A has been associated with bilateral ocular colobomas in the infant [2, 3, 5, 11, 33]. The ABLRDF further recommends normalising vitamin K and INR before conception and monitoring them during pregnancy, because postpartum haemorrhage due to vitamin K deficiency is a significant cause of maternal morbidity and fetal deficiency may cause neonatal and intracranial haemorrhage; maintaining vitamin E, whose deficiency increases miscarriages; correcting vitamin D (fetal hypocalcaemia, deficient mineralisation, enamel defects); monitoring progesterone, which is subnormal in the luteal phase and whose placental synthesis may be insufficient, and considering exogenous progesterone; giving folic acid 400–800 µg/day; and using MCT (4–6 tablespoons per day, 385–765 kcal, tolerated in other diseases) and DHA 1–3 g/day to cover caloric and omega-3 needs [11]. Follow-up should bring together a lipidologist and a dietitian [11]. The French protocol adds that the menstrual cycle is normal in women with abetalipoproteinaemia, that preconception assessment and counselling serve to obtain optimal plasma vitamin levels, and that the doses are maintained during pregnancy, except that of vitamin A, to be reduced by half or more, with plasma retinol every 3 months [23]. It associates maternal vitamin A deficiency with prematurity, intrauterine growth restriction, congenital visual loss and coloboma, and excess with neural tube defects, cardiac and urological malformations and dysmorphism, stressing that the teratogenic risk is real only with high doses, a very rare situation in this population with malabsorption; vitamin K deficiency with delivery haemorrhage and neonatal haemorrhage; and vitamin D deficiency with neonatal hypocalcaemia, bone demineralisation and dental enamel abnormalities in the child [23]. Progesterone requirements before and during pregnancy in women with severe hypocholesterolaemia remain to be defined [23].

7.6. Adult Refsum disease: chronic treatment

The aim is to keep circulating phytanic acid low, and diet is the mainstay of treatment [7, 25, 39]. The ClinGen actionability working group classified Refsum disease as of moderate actionability, by consensus, in the adult and paediatric contexts [84]. The Global DARE guide recommends restricting phytanate intake to less than 10 mg/day and avoiding nutritional supplements containing it during any oral, enteral or parenteral nutritional support (moderate quality; very strong recommendation) [25]. Dairy products, ruminant meat (beef, lamb, goat), some fish and shellfish (including cod) and walnuts, which contain phytanate and phytol, should be avoided; the almonds, coconut and peanuts tested did not contain these compounds [7, 25]. Green vegetables do not need to be restricted, because the phytol of chlorophyll is not released in humans [39]. When dietary support is limited, a vegetarian diet without dairy products, with egg, chicken and turkey, is an acceptable option; the Global DARE food guide is updated with new food analyses [25, 85]. Sources of omega-3 (oily fish, fish oils, algae) have a high phytanate content, which makes it necessary to monitor EFA and supplement them when necessary [58].

The efficacy of the diet is documented in case series. In 13 patients followed at a British centre for 11 to 28 years (237 patient-years), median phytanate fell from 1631 µmol/L (370–2911) to 85 µmol/L (10–1325), a mean reduction of 89% ± 11%; it normalised (below 30 µmol/L) in 30%, partially normalised (30–300 µmol/L) in 50% and remained above 300 µmol/L in 15%; the time to halve was 44.2 ± 15.9 months in adherent patients and none required admission or apheresis, despite peaks associated with intercurrent illness, surgery, sudden weight loss or psychological illness [86]. With updated dietary recommendations, the fall may be faster: two newly diagnosed patients reduced phytanate by 65% in 27 and 5 months [58]. GeneReviews and Saudubray indicate that the fall resolves the ichthyosis, sensory neuropathy and ataxia, approximately in that order, and stabilises the cardiac abnormalities, whereas retinitis pigmentosa, deafness and anosmia are more refractory and the retinopathy progresses slowly even with a strict diet [7, 39]. Neurological and skin improvement is clearer when phytanate falls below 500 µmol/L [25].

The diet must be hypercaloric, or at least isocaloric, because an energy deficit mobilises stored phytanate [7, 25]. In the Firman series, four patients on the diet for more than 10 years had rapid rises in phytanate — from 200–300 to 557 µmol/L after a 5-kg weight loss due to pain, from 340 to 1078 µmol/L after a 3.7-kg loss with exercise and a low-carbohydrate diet, up to 1363 µmol/L with a 4-kg loss, and from 124 to 891 µmol/L solely through carbohydrate reduction to control blood glucose — and reductions of 47–84% in 1.6–5 months on re-establishing regular meals with carbohydrates and stabilising weight, without admission or plasmapheresis [58]. The guide recommends minimising weight loss (moderate; very strong), avoiding intentional weight loss with phytanate above 200 µmol/L, limiting postpartum weight loss to 0.5 kg per week and avoiding prolonged fasting (moderate; very strong); phytanate doubles in about 29 hours of fasting, but overnight fasting is acceptable if daytime intake is adequate [25]. It also recommends a carbohydrate-containing meal or snack before moderate or vigorous exercise and during exercise lasting more than 45 minutes (low; strong), and avoiding excess caffeine and adrenergic stimulants (low; weak) [25].

The low-phytanate diet is considered adequate in micronutrients, but in a study of 11 patients all had a high sodium intake (1873–4828 mg/day), there were non-coinciding insufficiencies of vitamin A (2), D (6), E (3) and K (10) and suspected metabolic insufficiency of vitamin B12 in 4, with low intakes of copper and selenium but adequate plasma levels; the authors concluded that the diet is safe without routine supplementation, with periodic screening [87]. The guide recommends monitoring vitamins K, D, E, A and B12 and micronutrients (low; strong) [25].

7.7. Adult Refsum disease: intercurrent illness, surgery and acute decompensation

In the event of intercurrent illness with inability to eat or drink normally, the patient should start an oral emergency regimen with glucose polymers, extrapolated from the fatty acid oxidation disorders; if it is not tolerated or there is no improvement within 24–48 hours, the patient should attend the emergency department and contact the metabolic team for intravenous glucose, cardiac monitoring and possible plasmapheresis (low quality; very strong recommendation) [25]. Diabetic patients need frequent glucose monitoring and an adapted regimen [25].

Before any procedure involving fasting, the surgical team should contact the metabolic team in advance. In adults, the guide recommends intravenous glucose at 200 mg/kg/h — 10% glucose at 2 mL/kg/h or, with fluid restriction, 20% glucose at 1 mL/kg/h or 50% at 0.4 mL/kg/h — from the start of fasting until feeding resumes; in children, the rate follows the intravenous regimens for long-chain fatty acid disorders; if blood glucose remains above 10 mmol/L (180 mg/dL), insulin is added rather than reducing the glucose, which also inhibits lipolysis; and, if intake is inadequate for more than 48 hours, complete low-phytanate enteral or parenteral nutrition should be started (low; very strong) [25]. GeneReviews adds that lipid emulsions of soya oil and egg yolk phospholipids (Intralipid® 10, 20 or 30%) contain no phytanate and can be used [7].

Acute decompensation is treated with therapeutic plasmapheresis (plasma exchange), a low-phytanate diet and sufficient energy to prevent or reverse catabolism (moderate quality; very strong recommendation) [25]. Plasma exchange is preferred in non-specialist centres because it is more widely available; lipoprotein apheresis is an alternative of equivalent efficacy in centres that have it, with less loss of immunoglobulins and clotting factors and without the allergic risk of plasma, because about 35% of phytanate circulates in LDL [25]. Each session reduces phytanate by 50–70%, typically to 100–300 µmol/L, but there is a rebound within 24–48 hours due to redistribution, so the panel uses 3–4 sessions at 24–48-hour intervals, with removal of 1–1.5 L of plasma volume and replacement with albumin or fresh frozen plasma; according to one model, three to four sessions remove as much phytanate as is ingested on a restricted diet over more than one year [7, 25]. The thresholds proposed for considering apheresis in patients with acute symptoms lie between 900 and 1500 µmol/L, without robust evidence; with neurological deterioration, arrhythmias or tubulopathy, apheresis may be started and continued until clinical improvement, and acute complications are rare below 200 µmol/L [25]. The patient should not fast before the session [25]. The American Society for Apheresis (ASFA) guidelines classify apheresis in Refsum disease as category II (second line), grade 2C, based on fewer than 100 patients; the most widely described practice is 1–2 sessions per week for weeks to months [25, 88]. Regular maintenance apheresis outside decompensation and with phytanate below 1000 µmol/L is not recommended (low; strong) [25]. Monthly plasmapheresis as a way of liberalising the diet was used in previous decades and its maintenance efficacy rests on series of few patients [8, 25, 89].

7.8. Adult Refsum disease: drugs, target organs and pregnancy

There is no targeted pharmacological therapy with demonstrated benefit; orlistat reduced phytanate by 55% and improved the neuropathy and skin in two patients, possibly through better adherence to a low-fat diet, but had no effect in six already adherent patients, and the guide does not recommend its routine use (low; very strong) [25]. The drugs to be avoided or used with caution differ between sources: GeneReviews advises avoiding ibuprofen, because it may interfere with phytanate metabolism, and amiodarone, because of the risk of hyperthyroidism and catabolism [7]; the Global DARE guide recommends caution with drugs racemised by AMACR, such as naproxen (no cases of worsening described), and with those that promote lipolysis, such as glucocorticoids and amiodarone (low; weak) [25]. The two recommendations on anti-inflammatory drugs have the same basis: AMACR, which converts the (2R)-pristanoyl-CoA produced by α-oxidation into the S isomer, is also involved in the metabolism of ibuprofen and related drugs [73]. In practice, amiodarone is advised against by both sources, and propionic-type non-steroidal anti-inflammatory drugs call for caution.

Cataracts are operated on with iris hooks, because the pupil dilates poorly or not at all; zonular fragility may require an iris-fixated anterior chamber lens or capsular tension rings, and the surgeon should anticipate more posterior capsular opacification and cystoid macular oedema [7, 25]. Ichthyosis is treated with emollients, deafness with hearing aids or a cochlear implant (good results in two patients; caution with amplification if auditory evoked potentials are absent), and visual loss with low-vision aids and rehabilitation [7, 25]. Arrhythmias and cardiomyopathy require cardiological follow-up, antiarrhythmic drugs and support; arrhythmias improve with plasmapheresis, and heart transplantation can be life-saving in refractory cardiomyopathy, with hypercaloric nutritional support during and after surgery (at least two transplanted patients, one with survival of more than 10 years) [7, 25]. Chronic hypokalaemia required potassium in two of 25 patients [25].

Pregnancy tends to induce catabolism, especially in the third trimester, with increased insulin resistance; rapid reduction of the visual fields has been observed in the third trimester, but in another family there were no clinical events despite the rise in phytanate [7, 25]. The guide recommends informing the metabolic team as soon as the pregnancy is known, drawing up a metabolic delivery plan, maintaining the diet with vitamins and omega-3, monitoring caloric intake to avoid weight loss, having a low threshold for antiemetics and admission in the event of hyperemesis, minimising fasting during induction of labour with oral caloric supplements, using intravenous glucose during labour, resorting to apheresis if there is decompensation and limiting postpartum weight loss to 0.5 kg per week (low; very strong) [25]. GeneReviews advises against breastfeeding, to avoid phytanate intake by the infant and maternal catabolism in the postpartum period [7]. Unaffected children of mothers with the disease have no related problems [7].

7.9. Regulatory status

In France, fat-soluble vitamins are reimbursed, but omega-3 supplementation is prescribed outside the marketing authorisation, is not reimbursed, must be stated on the prescription and justified in the clinical record; non-reimbursed products may be covered on a derogatory and temporary basis, after an opinion from the HAS and consultation of the medicines agency (ANSM), when there is no alternative and they are indispensable, and the protocol serves as the basis for the application for exemption from co-payment as an off-list long-term condition (ALD "hors liste") [23].

7.10. Studies supporting treatment

None of these studies is randomised or has an untreated control group, and the numbers of patients are very small; bioavailability results do not translate directly into clinical outcomes, the Refsum series measure a surrogate marker (phytanate), and comparison between cohorts from different eras and centres does not allow superiority of one regimen to be inferred [25, 82, 86]. The absence of trials reflects the rarity of the diseases and the preventive nature of the treatment, whose withdrawal for comparison purposes would not be acceptable.

7.11. Developments in the last 12 months and research

In May 2026 the first guide dedicated to adult Refsum disease, from the Global DARE Foundation, was published, with 20 recommendations graded by the GRADE system (publication; consensus guideline level) [25]. In the same month, a British case series showed faster falls in phytanate than previously described with the updated dietary recommendations and with correction of caloric and carbohydrate deficit (publication; case series) [58]. New PHYH variants with macular dystrophy (case report) and an abetalipoproteinaemia with the in-frame deletion MTTP p.(Ser615del) without malabsorption (case report) were described [48, 65]. In the search of 31 October 2026, ClinicalTrials.gov had no active interventional trials for these diseases; the observational study CAROCHOL (carotenoids and macular pigment in hypocholesterolaemias, Lyon, 10 patients) ended in November 2024 without results located, and the CoRDS registry includes patients with Refsum disease [92]. The strategies under investigation for Refsum disease — alternative substrates for the 2-oxoglutarate binding site of PHYH, pharmacological induction of hepatic ω-oxidation (with urinary 3-methyladipate as a possible biomarker) and gene therapies using mRNA, AAV vectors or editing of PHYH and PEX7 — remain at the preclinical or hypothesis stage [25]. For abetalipoproteinaemia, gene therapy correcting MTP in the liver and intestine is mentioned as a candidate, with no ongoing trials identified [33, 92]; reversal of the cellular phenotype by CRISPR/Cas9 editing in hepatocytes and cardiomyocytes derived from a patient's iPSCs (section 2.2) is a preclinical proof of concept [46]. No marketing applications, opinions or regulatory decisions for these diseases were identified in the period; a negative search does not prove the absence of unregistered programmes.

7.12. Transition and organisation of care

All the entities require lifelong follow-up by a multidisciplinary team — lipidology or metabolic diseases, dietetics, neurology, ophthalmology, gastroenterology and hepatology in the hypobetalipoproteinaemias; ophthalmology, neurology, cardiology, otorhinolaryngology and audiology, dietetics, dermatology and clinical genetics in Refsum disease — and the transition to adult care should preserve dietetic follow-up, which is the main determinant of prognosis [7, 11, 25]. The ABLRDF identifies as gaps the absence of directories of experts, the scarcity of dietary guidance and the lack of recognition, by insurers and regulators, of the need for high-dose vitamins [11].

In France, the national protocol assigns the follow-up of the class I hypobetalipoproteinaemias to a reference centre for rare digestive diseases or complex dyslipidaemias, in coordination with the attending physician and the competence centres [23]. The coordinator is usually a physician nutritionist — in children, a paediatric gastroenterologist, nutritionist or metabolic disease specialist; in adults, an endocrinologist or lipidologist — with a dietitian, a neurologist, an ophthalmologist, a hepatologist in the event of liver complications and, possibly, a cardiologist; the biologist or lipidologist guides the diagnosis and the molecular geneticist confirms it [23]. The proposed schedule is one consultation every 3 months in the first year, then follow-up every 6 months alternating consultation and day hospital, and annual follow-up after 10 years of age; the coordinating physician sees the child every 6 months and the adult annually, and the dietitian every 6 to 12 months in children and every 1 to 3 years in adults, depending on dietary balance [23]. Each consultation assesses adherence to treatment and diet, digestive symptoms (pain, distension, diarrhoea as a sign of dietary transgression), day and night vision, paraesthesiae, gait, balance and speech, dyspnoea and chest pain, the growth curve, abdominal palpation (hepatomegaly, splenomegaly), neurological examination with reflexes and sensation, and cardiac auscultation [23].

The diagnosis should be disclosed unhurriedly, in a quiet place, ideally with both parents and with the involvement of a psychologist during the consultation or shortly afterwards, and this is a process that may need to be repeated at subsequent consultations; psychological follow-up of the patient, parents and siblings is offered from disclosure and throughout the care pathway, with particular attention to the parent–infant bond when the diagnosis is perinatal [23]. In children, the protocol provides for developmental assessments (speech therapy, psychomotor therapy, neuropsychology, occupational therapy, physiotherapy) and support from the French early medico-social action services (CAMPS), special education and home care services (SESSAD), school support assistants (AESH) and an individualised reception plan (PAI) at school; when one of the parents has to interrupt their professional activity, the paediatrician liaises with the social services, bearing in mind that applications for support may take 6 to 12 months [23].

The transition to adult care generally occurs at the end of growth, but the process begins in early adolescence; the transition consultation is organised by the reference centre team, preferably multidisciplinary, reassesses the complications of the disease and treatments and discusses continuation of the diet and high-dose vitamins; autonomy is built through therapeutic education sessions, consultations without the parents and progressive self-management of medication, also addressing sexuality and lifestyle [23].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Abetalipoproteinaemia, chylomicron retention disease and adult Refsum disease are autosomal recessive: the parents of a patient are obligate heterozygotes, asymptomatic and, in abetalipoproteinaemia and chylomicron retention disease, with a normal lipid profile; each sibling has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of inheriting neither variant; the children of a patient are obligate carriers, unless the partner is a carrier or affected; and aunts and uncles have a 50% chance of being carriers [2, 5, 7]. Molecular confirmation of the parents' status is recommended because, if only one is a carrier, a de novo variant in the proband, parental post-zygotic mosaicism or uniparental disomy (already documented in abetalipoproteinaemia) should be considered and, in the presence of apparent homozygosity, a large deletion on the other allele [5, 7, 33]. In Refsum disease, expression may vary greatly between siblings with the same variants [7].

In FHBL-SD2, the scenario is different because heterozygotes have a biochemical phenotype: a couple of heterozygotes has a 25% risk of a child with biallelic disease, 50% of a heterozygous child (with hypocholesterolaemia, occasional steatosis and cardiovascular protection) and 25% of a child without variants; a heterozygote with a partner without variants has 50% heterozygous children, and the children of a biallelic patient are all heterozygous [3]. Identified heterozygotes should have lipid and liver surveillance [3].

8.2. Cascade and sibling screening

The siblings of a patient should be assessed as early as possible, including older asymptomatic siblings, because early treatment prevents complications: in the hypobetalipoproteinaemias, with a full lipid profile with apoB (and apoA-I in chylomicron retention disease) or with testing for the familial variants; in classic abetalipoproteinaemia, affected siblings present soon after birth [2, 3, 5]. In Refsum disease, the Global DARE guide recommends counselling and screening all at-risk relatives — usually all siblings and, where there is consanguinity, other biological relatives — and genetic testing of at-risk newborns, because phytanate at birth does not exclude the disease (moderate and low quality; very strong recommendations) [25]. When the familial variants are not known, plasma phytanate serves to assess siblings who already have a diversified diet [7]. Biochemical testing does not identify carriers of Refsum disease, because phytanate is almost normal in heterozygotes [7]. In the case in section 10, the sister's diagnosis was made on cord blood at 3 weeks, allowing treatment from the fourth month with normal development [47].

8.3. Carriers in the population and consanguinity

Outside founder populations, an unrelated partner is rarely a carrier; in isolated populations the probability is higher, as shown by the MTTP carrier frequencies of 1/131 in Ashkenazi Jews and 1/203 in Saguenay-Lac-Saint-Jean, and the SAR1B founder variants in French Canadians [5, 20, 21]. In consanguineous couples with an affected child, testing of at-risk relatives should be offered before further pregnancies [25].

8.4. Prenatal diagnosis, preimplantation testing and family planning

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss these options is before pregnancy, and it is appropriate to offer genetic counselling to young adults who are affected, carriers or at risk of being carriers [2, 3, 5, 7]. As these diseases are treatable and the prognosis with early treatment is good, the decision on prenatal diagnosis is a personal one and the discussion should include the daily burden of treatment [2, 11]; the French protocol calls for an ethical discussion with the family on the practical consequences of such testing, given the good outcome when the diagnosis is made early [23]. DNA banking should be considered for probands without a confirmed molecular diagnosis [5, 7].

8.5. Pregnancy in an affected woman and testing of minors

Pregnancy in a woman with abetalipoproteinaemia requires adjustment of vitamins A and K, continuation of vitamin E and possibly progesterone (section 7.5), and that in a woman with Refsum disease requires prevention of catabolism, a metabolic delivery plan and avoidance of breastfeeding (section 7.8) [7, 11, 25]. In a patient with Refsum disease married to a cousin carrying a PHYH variant, eight pregnancies resulted in six live births, two of them affected; the affected infants had only mildly raised phytanate at birth (below 30 µmol/L), which normalised with low-phytanate feeding [25]. Testing of at-risk minors is justified, because there is immediate medical benefit from early treatment in all the entities in this article [2, 25].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

None of these values is a national prevalence measured by population screening of patients, except the frequency of apoB truncations in the Framingham cohort; counts of published cases underestimate the true frequency, and the concentration of Refsum patients in the United Kingdom and Norway reflects, according to GeneReviews, greater awareness in those countries and suggests that worldwide prevalence is higher than estimated [7]. The relatively high frequency of c.678+5G>T and the existence of forms with normal phytanate suggest that some patients with hypomorphic PHYH variants remain undiagnosed among cases of "isolated" retinitis pigmentosa [25, 56].

9.2. Geography, ancestry and founder effect

MTTP variants are distributed throughout the gene and are not concentrated in any ethnic group, but founder effects have been documented in Ashkenazi Jews and in French Canadians from Quebec; about one third of patients are born of consanguineous unions [2, 20, 21, 33]. In chylomicron retention disease, consanguinity is frequent and the SAR1B variant p.(Asp137Asn) is a founder variant in French Canadians [5, 19]. Japanese patients with abetalipoproteinaemia and five private variants have been described [33]. In Refsum disease, the patients described come mainly from the United Kingdom and Norway, and the series include patients of British, Greek, British Indian, Ukrainian, Arab and Moroccan origin [7, 55, 58, 69]; the PEX7 variant p.(His285Arg) is proposed as a Dutch founder variant [18]. The sources consulted describe no Portuguese or Brazilian cases or frequencies of these diseases; this absence in the sources does not demonstrate the absence of patients in those countries.

9.3. Special populations

Infants with abetalipoproteinaemia require MCT formula and more marked fat restriction (5–10% of calories), with attention to growth and EFA [11]. Adolescents and adults with Refsum disease face specific risks of decompensation associated with weight-loss diets, intense exercise without carbohydrates, intercurrent illness, surgery, pregnancy and diabetes treated with carbohydrate restriction [25, 58]. In pregnant women of both groups, caloric and vitamin requirements change (sections 7.5 and 7.8). The cost of the vitamins and the lack of reimbursement affect adherence, especially in health systems with limited coverage [11]. Depression is very frequent in patients with Refsum disease who responded to the registry survey [64].

9.4. Reference networks and patient organisations

In Europe, these diseases fall within the European Reference Network for Hereditary Metabolic Disorders (MetabERN), in the subnetwork for peroxisomal and lipid-related disorders (https://metab.ern-net.eu/) [26]. The Abetalipoproteinemia and Related Disorders Foundation (ABLRDF), founded in 2019, brings together patients with class I hypobetalipoproteinaemias, carers, researchers and professionals, and its panel published the 2022 guide [11]. The Global DARE Foundation (Defeat Adult Refsum Everywhere) maintains a food guide and an emergency regimen for Refsum disease (https://www.defeatadultrefsumeverywhere.org/diet-guide) and a patient registry on the Coordination of Rare Diseases at Sanford (CoRDS) platform [7, 85]. GeneReviews also lists Metabolic Support UK, the Foundation for Ichthyosis and Related Skin Types (FIRST), the United Leukodystrophy Foundation and, for abetalipoproteinaemia, the Genetic and Rare Diseases Information Center (GARD) and the National Organization for Rare Disorders (NORD) [2, 7].

In France, the class I hypobetalipoproteinaemias come under the reference centre for rare digestive diseases (MaRDi), based at the Hôpital Femme Mère Enfant of the Hospices Civils de Lyon, which coordinated the 2021 national protocol, and the health network for rare abdominothoracic diseases (FIMATHO), with the regional competence centres [23]. The protocol records that there is no patient organisation for these diseases in France, and lists as research support the F-CRIN paediatric network PEDSTART and the participation of children and parents through the EYPAGnet/KIDS France network [23].

10. Illustrative Clinical Case

Vlasschaert and colleagues described, in 2021, three Canadian siblings of Filipino and Chinese ancestry, born to non-consanguineous parents, with abetalipoproteinaemia [47]. Two identical twins had faltering growth and steatorrhoea from shortly after birth; the clinical diagnosis was made at 18 months at another centre, and total parenteral nutrition was instituted without restriction of oral feeding [47]. At 3 years, at the lipid clinic, they had severe underweight, poor appetite, low energy, easy fatigue, muscle weakness, delay in most developmental milestones, persistent abdominal distension and abundant daily steatorrhoea, without visual symptoms or bleeding; vitamins A and E were undetectable, vitamin D was at the lower limit and the INR was 1.1 [47]. Parenteral nutrition was stopped and replaced by a varied diet with fat limited to 20% of calories and high-dose oral vitamins — vitamin A 20,000 IU/day, vitamin D 10,000 IU five days a week, vitamin E 2400 U/day and vitamin K 5 mg/week — to which an EPA and DHA supplement in a 1:2 ratio (50 mg of DHA per day) was added at 9 years [47]. Within 2 months the parents reported that the children were more alert and active, with less distension and fewer stools; within a year they were attending pre-school and later primary school at the level for their age [47]. After 8 years of treatment their weight remained below the 3rd centile, but they had recovered strength, dexterity and developmental milestones; vitamins A and E became detectable, with vitamin E low but stable (3 µmol/L; reference 18–29 µmol/L), measured every 6 months [47].

A sister was born when the twins were 7 years old and was diagnosed by molecular analysis of cord blood at 3 weeks. She was exclusively breastfed for the first month and transitioned by 4 months to a fat-restricted diet with high-dose medium-chain fatty acids and fat-soluble vitamins; at 4 years she had normal development, weight at or above the 3rd centile, normal vitamins A and D and vitamin E of 3 µmol/L, on vitamin A 10,000 IU/day, vitamin D 1000 IU five days a week, vitamin E 1600 IU/day and vitamin K 2.5 mg/week [47]. The three siblings undergo annual neurological examination, ophthalmological examination and abdominal ultrasound, all normal up to publication [47]. A next-generation sequencing dyslipidaemia panel, confirmed by Sanger sequencing, showed in all three homozygosity for an intron 13 splice acceptor variant of MTTP, NM_001386140.1:c.1990-2A>G (MANE Select; same numbering in NM_000253.4), absent from population databases; the asymptomatic parents were heterozygous [10, 47].

The figures of the article, consulted in the full text on PubMed Central, show the role of MTP in lipoprotein assembly (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC8182224/figure/fig1-23247096211022484/), the family pedigree and the growth curves of the three siblings (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC8182224/figure/fig2-23247096211022484/) and the synopsis of the MTTP variants described by domain (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC8182224/figure/fig3-23247096211022484/) [47].

The case illustrates three points. First, the contrast between the partial reversal in the twins, treated from 3 years of age, and the complete prevention in the sister, treated from the first month, reflects the principle that early treatment prevents more than it repairs [2, 47]. Second, plasma vitamin E remained at about one sixth of the lower limit despite a favourable clinical course, which confirms that the plasma value cannot serve as a therapeutic target [11, 47]. Third, management differed from the guidelines in details that should not be taken as routine: fat at 20% of calories is at the upper limit of GeneReviews and above the 10–15% of the ABLRDF; vitamin E was prescribed at a fixed dose and not per kilogram; erythrocyte vitamin E, preferred by the ABLRDF, was not used; and exclusive breastfeeding in the first month does not correspond to the recommendation to avoid non-skimmed breast milk [2, 11].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without treatment, abetalipoproteinaemia and biallelic FHBL-SD2 progress to severe neuromyopathy, blindness at around 40 years and death usually before the end of the third decade; with high-dose vitamins maintained throughout life, survival into the seventh and eighth decades with relatively minimal symptoms has been described, but growth may fall short of potential and established retinal and neurological lesions only stabilise [2, 3, 11, 33]. Monoallelic FHBL-SD2 has a normal life expectancy, with reduced cardiovascular risk and a small risk of progressive liver disease, especially with cofactors [3, 50]; cardiovascular protection is not absolute, because ischaemic events have been described in patients with FHBL-SD2 and other risk factors [23]. Very long-term follow-up data in adults are lacking, and the most severe complications have been described in abetalipoproteinaemia and biallelic FHBL-SD2 [23]. Chylomicron retention disease has a favourable prognosis with early diagnosis: in the Canadian cohort, nine patients treated orally from an early age remained free of neurological complications, two of them at 22 years, and early vitamin D prevented osteopenia; patients with late diagnosis did not reach their growth potential [5, 24]. In adult Refsum disease, early onset does not imply poorer survival; arrhythmias and heart failure are frequent causes of death, and sudden death occurs mainly during decompensations with very high phytanate [7, 25]. With the diet maintained, admissions decrease and, in a series of 12 patients, repeated electrocardiograms after more than 5 years on the diet showed no significant changes [25, 86]. The Global DARE guide concludes that a diet started before further target-organ damage offers the best prognosis [25].

11.2. Surveillance table

The French protocol's schedule is more intensive than those of GeneReviews and the ABLRDF: vitamins, full blood count, liver function tests, coagulation and CK every 6 months in children, versus an annual assessment; an annual lipid profile, whereas the ABLRDF advises against repeating it; annual densitometry from 10 years, versus every 3 to 5 years; and specialist ophthalmological and neurological examinations every 3 years from 10 years, whereas GeneReviews proposes examination every 6 to 12 months [2, 3, 11, 23, 33]. The protocol accepts that clinical surveillance may suffice for the peripheral nervous system, with further tests only in the presence of abnormalities, and that liver function tests are not enough to detect progression to fibrosis, whose non-invasive diagnosis (serum tests, elastography) has not been validated in these diseases [23]. In the presence of liver abnormalities, other causes of chronic liver disease (viral, autoimmune, metabolic or genetic) and cofactors such as alcohol, excess weight and the metabolic syndrome should be sought [23].

12. Summary and Final Considerations

Abetalipoproteinaemia, APOB-related familial hypobetalipoproteinaemia and chylomicron retention disease form class I of the hypobetalipoproteinaemias, defined by a defect in the assembly or secretion of apoB-containing lipoproteins that prevents the absorption of fat-soluble vitamins. All three present in infancy with steatorrhoea and faltering growth, are distinguished by the lipid profile of the patient and the parents, by CK and by the presence or absence of acanthocytosis and retinopathy, and are confirmed by sequencing of MTTP, APOB and SAR1B. Very high-dose vitamin E, with vitamins A, D and K, a diet low in long-chain fat and the provision of essential fatty acids, prevents the ataxia and retinopathy that previously killed patients in the third decade; the divergences between sources on the percentage of fat and the formulation of vitamin E reflect the lack of trials and do not alter the principle. The monoallelic form of APOB-related hypobetalipoproteinaemia and the class II forms due to ANGPTL3 and PCSK9 require no treatment and protect against cardiovascular disease.

Adult Refsum disease, due to variants in PHYH or, in a minority, in PEX7, should be sought in any retinitis pigmentosa, especially with anosmia, hearing loss, polyneuropathy or short digits, using a genetic panel that includes these genes and measurement of phytanic and pristanic acids, bearing in mind that hypomorphic forms may have normal phytanate. Treatment — less than 10 mg/day of phytanate, sufficient caloric and carbohydrate intake, avoidance of fasting and rapid weight loss, intravenous glucose protocols for surgery and intercurrent illness, and plasmapheresis in decompensations — resolves the ichthyosis, neuropathy and ataxia and reduces arrhythmias, but has little effect on established retinopathy, deafness and anosmia. In all the entities in this article, the main determinant of prognosis is the time that elapses between the first signs and the start of treatment.

13. References

1. OMIM — Online Mendelian Inheritance in Man. MIM 200100: Abetalipoproteinemia; ABL. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/200100
2. Burnett JR, Hooper AJ, Hegele RA. Abetalipoproteinemia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 25 Oct 2018; revised 19 May 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532447/
3. Burnett JR, Hooper AJ, Hegele RA. APOB-Related Familial Hypobetalipoproteinemia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 13 May 2021; revised 9 Sep 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570370/
4. OMIM — Online Mendelian Inheritance in Man. MIM 615558: Hypobetalipoproteinemia, familial, 1; FHBL1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/615558
5. Burnett JR, Hooper AJ, Hegele RA. Chylomicron Retention Disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 24 Mar 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK578949/
6. OMIM — Online Mendelian Inheritance in Man. MIM 246700: Chylomicron retention disease; CMRD. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/246700
7. Waterham HR, Wanders RJA, Leroy BP. Adult Refsum Disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 20 Mar 2006; updated 30 Sep 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1353/
8. OMIM — Online Mendelian Inheritance in Man. MIM 266500: Refsum disease, classic. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/266500
9. OMIM — Online Mendelian Inheritance in Man. MIM 614879: Peroxisome biogenesis disorder 9B; PBD9B. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/614879
10. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. doi:10.1002/humu.23348. Accessed at https://rest.variantvalidator.org (GRCh38, MANE Select)
11. Bredefeld C, Hussain MM, Averna M, Black DD, Brin MF, Burnett JR, et al. Guidance for the diagnosis and treatment of hypolipidemia disorders. J Clin Lipidol. 2022;16(6):797-812. doi:10.1016/j.jacl.2022.08.009
12. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37(3):333-9. doi:10.1007/s10545-013-9665-4
13. Orphanet. Abetalipoproteinemia (ORPHA:14). Available from: https://www.orpha.net/en/disease/detail/14
14. Orphanet. APOB-related familial hypobetalipoproteinemia (ORPHA:727915). Available from: https://www.orpha.net/en/disease/detail/727915
15. Orphanet. Familial hypobetalipoproteinemia (ORPHA:426). Available from: https://www.orpha.net/en/disease/detail/426
16. Orphanet. Chylomicron retention disease (ORPHA:71). Available from: https://www.orpha.net/en/disease/detail/71
17. Orphanet. Adult Refsum disease (ORPHA:773). Available from: https://www.orpha.net/en/disease/detail/773
18. Braverman NE, Carroll R, Muss C, Fallatah W, Jain M. PEX7-Related Rhizomelic Chondrodysplasia Punctata. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 16 Nov 2001; updated 7 Aug 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1270/
19. Ramaswami U, Humphries SE. Inborn Errors of Lipoprotein Metabolism Presenting in Childhood. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 36, section 36.1 (Tables 36.1 and 36.2). doi:10.1007/978-3-662-63123-2_36
20. OMIM — Online Mendelian Inheritance in Man. MIM 157147: Microsomal triglyceride transfer protein; MTTP. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/157147
21. Guay SP, Paquette M, Girard L, Desgagné V, Gosse G, Poulin V, et al. High carrier frequency for abetalipoproteinemia and evidence of a founder variant in a French-Canadian population. J Clin Lipidol. 2024;18(4):e625-e630. doi:10.1016/j.jacl.2024.04.132
22. Welty FK, Lahoz C, Tucker KL, Ordovas JM, Wilson PW, Schaefer EJ. Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the framingham offspring population. Arterioscler Thromb Vasc Biol. 1998;18(11):1745-51. doi:10.1161/01.atv.18.11.1745
23. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Hypocholestérolémies génétiques intestinales. Centre de référence des maladies rares digestives (MaRDi), filière FIMATHO. Saint-Denis La Plaine: HAS; 2021 Oct 20. Available from: https://www.has-sante.fr/jcms/p_3272488
24. Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J, et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis. 2010;5:24. doi:10.1186/1750-1172-5-24
25. Ramachandran R, Buttigieg R, Eichler F, Leroy BP, Mahroo O, Huckfeldt RM, et al. Diagnosis and Metabolic Management of Adult Refsum Disease: Guidance From the Medical and Scientific Committee of Global DARE (Defeat Adult Refsum Everywhere). J Inherit Metab Dis. 2026;49(3):e70201. doi:10.1002/jimd.70201
26. MetabERN — European Reference Network for Hereditary Metabolic Disorders. Subnetwork Peroxisomal and lipid-related disorders. Available from: https://metab.ern-net.eu/
27. OMIM — Online Mendelian Inheritance in Man. MIM 603776: Hypercholesterolemia, familial, 3; FHCL3 (includes LDL cholesterol level QTL 1). Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/603776
28. OMIM — Online Mendelian Inheritance in Man. MIM 607786: Proprotein convertase, subtilisin/kexin-type, 9; PCSK9. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/607786
29. OMIM — Online Mendelian Inheritance in Man. MIM 605019: Hypobetalipoproteinemia, familial, 2; FHBL2. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/605019
30. Orphanet. Hypocholesterolemia due to PCSK9 deficiency (ORPHA:727932). Available from: https://www.orpha.net/en/disease/detail/727932
31. Orphanet. Familial combined hypolipidemia (ORPHA:727925). Available from: https://www.orpha.net/en/disease/detail/727925
32. Bassen FA, Kornzweig AL. Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood. 1950;5(4):381-87. PMID: 15411425
33. Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, et al. Current Diagnosis and Management of Abetalipoproteinemia. J Atheroscler Thromb. 2021;28(10):1009-1019. doi:10.5551/jat.RV17056
34. Salt HB, Wolff OH, Lloyd JK, Fosbrooke AS, Cameron AH, Hubble DV. On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea. Lancet. 1960;2(7146):325-9. doi:10.1016/s0140-6736(60)91478-1
35. Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258(5084):999-1001. doi:10.1126/science.1439810
36. Sharp D, Blinderman L, Combs KA, Kienzle B, Ricci B, Wager-Smith K, et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature. 1993;365(6441):65-9. doi:10.1038/365065a0
37. Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S, et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet. 2003;34(1):29-31. doi:10.1038/ng1145
38. Bredefeld C, Peretti N, Hussain MM, Medical Advisory Panel. New Classification and Management of Abetalipoproteinemia and Related Disorders. Gastroenterology. 2021;160(6):1912-1916. doi:10.1053/j.gastro.2020.11.040
39. Wanders RJA, Engelen M, Vaz FM. Inborn Errors of Non-Mitochondrial Fatty Acid Metabolism Including Peroxisomal Disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 42, sections 42.1 and 42.3. doi:10.1007/978-3-662-63123-2_42
40. Jansen GA, Ofman R, Ferdinandusse S, Ijlst L, Muijsers AO, Skjeldal OH, et al. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet. 1997;17(2):190-3. doi:10.1038/ng1097-190
41. Mihalik SJ, Morrell JC, Kim D, Sacksteder KA, Watkins PA, Gould SJ. Identification of PAHX, a Refsum disease gene. Nat Genet. 1997;17(2):185-9. doi:10.1038/ng1097-185
42. van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, et al. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003;72(2):471-7. doi:10.1086/346093
43. Jansen GA, Waterham HR, Wanders RJ. Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat. 2004;23(3):209-18. doi:10.1002/humu.10315
44. Cupido AJ, Stoekenbroek RM, Kastelein JJP. Genetic Disorders of Lipoprotein Metabolism: Diagnosis and Management. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 387–411. doi:10.1007/978-3-030-45457-9_23
45. OMIM — Online Mendelian Inheritance in Man. MIM 176790: Prolyl 4-hydroxylase, subunit beta; P4HB. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/176790
46. van Mil A, Neef K, Balk GM, Buikema JW, Sluijter JPG, Doevendans PAFM. Induced Pluripotent Stem Cells. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 439–55 (section 26.3, p. 449). doi:10.1007/978-3-030-45457-9_26
47. Vlasschaert C, McIntyre AD, Thomson LA, Kennedy BA, Ratko S, Prasad C, et al. Abetalipoproteinemia Due to a Novel Splicing Variant in MTTP in 3 Siblings. J Investig Med High Impact Case Rep. 2021;9:23247096211022484. doi:10.1177/23247096211022484
48. Hamasaki M, Hara K, Kotani K. Abetalipoproteinemia With a Novel Microsomal Triglyceride Transfer Protein Gene Mutation and Unique Oxidized Lipoprotein Levels. J Med Cases. 2026;17(10):554-557. doi:10.14740/jmc5341
49. Firth HV, Hurst JA. Hyperlipidaemia. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 458–9.
50. Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol. 2020;31(2):49-55. doi:10.1097/MOL.0000000000000663
51. García-Cazorla Á, Dionisi-Vici C, Saudubray JM. Disorders of Cellular Trafficking. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 44, section 44.1.3.
52. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72. doi:10.1056/NEJMoa054013
53. Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69(16):2054-63. doi:10.1016/j.jacc.2017.02.030
54. Wierzbicki AS, Lloyd MD, Schofield CJ, Feher MD, Gibberd FB. Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem. 2002;80(5):727-35. doi:10.1046/j.0022-3042.2002.00766.x
55. OMIM — Online Mendelian Inheritance in Man. MIM 602026: Phytanoyl-CoA hydroxylase; PHYH. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/602026
56. Daich Varela M, Schiff E, Malka S, Wright G, Mahroo OA, Webster AR, et al. PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease. Invest Ophthalmol Vis Sci. 2024;65(2):38. doi:10.1167/iovs.65.2.38
57. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Chondrodysplasia punctata, rhizomelic type. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 360.
58. Firman SJ, Cook J, Hall I, Yeung K, Buttigieg R, Vaz F, et al. Adult Refsum Disease: Case Series of Reducing Circulating Phytanic Acid Levels With Dietary Interventions. JIMD Rep. 2026;67(3):e70048. doi:10.1002/jmd2.70048
59. Saudubray JM, García-Cazorla Á. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1.
60. Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;3:19. doi:10.1186/1750-1172-3-19
61. Firth HV, Hurst JA. Retinal receptor dystrophies. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 302–5.
62. Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. Eye (Lond). 2001;15(Pt 4):525-30. doi:10.1038/eye.2001.167
63. Mouzaki M, Shah A, Arce-Clachar AC, Hardy J, Bramlage K, Xanthakos SA. Extremely low levels of low-density lipoprotein potentially suggestive of familial hypobetalipoproteinemia: a separate phenotype of NAFLD? J Clin Lipidol. 2019;13(3):425-31. doi:10.1016/j.jacl.2019.02.002. PMID: 30879942
64. Li JJ, Kim JJ, Nausheen F. Phytanic Acid Intake and Lifestyle Modifications on Quality of Life in Individuals with Adult Refsum Disease: A Retrospective Survey Analysis. Nutrients. 2023;15(11):2551. doi:10.3390/nu15112551
65. Gregory-Evans CY, Lehman A, Mattman A, Kirby M, Gregory-Evans K. Identification of novel pathogenic variants in the PHYH gene and extending the phenotypic range in Refsum disease. Ophthalmic Genet. 2026;47(3):283-286. doi:10.1080/13816810.2025.2591819
66. Firth HV, Hurst JA. Charcot–Marie–Tooth disease (CMT). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 362–5.
67. Mochel F, Sedel F. Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 2.
68. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary Neuromuscular Diseases and Cardiac Involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 371–86. doi:10.1007/978-3-030-45457-9_22
69. Arous S, Atlas I, Arous A, Zahidi H, Benouna EGM, Habbal R. Dilated cardiomyopathy revealing Refsum disease: a case report. J Med Case Rep. 2024;18(1):470. doi:10.1186/s13256-024-04789-5
70. Firth HV, Hurst JA. Ataxic child. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 74–7.
71. Firth HV, Hurst JA. Ataxic adult. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 70–3.
72. OMIM — Online Mendelian Inheritance in Man. MIM 614307: Alpha-methylacyl-CoA racemase deficiency; AMACRD. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/614307
73. Clayton PT. Disorders of Bile Acid Synthesis. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 38, section 38.8.2 (α-methylacyl-CoA racemase deficiency). doi:10.1007/978-3-662-63123-2_38
74. Firth HV, Hurst JA. Developmental regression. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 128–31.
75. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Neonatal adrenoleukodystrophy/disorders of peroxisomal biogenesis. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 481–90.
76. Firth HV, Hurst JA. Retinitis pigmentosa (RP). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 518–9.
77. OMIM — Online Mendelian Inheritance in Man. MIM 612674: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract; PHARC. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/612674
78. GeneGuidance. MTTP — clinical curation of the gene and the condition abetalipoproteinaemia. GeneGuidance database (extraction of 2026-10-31).
79. European Medicines Agency. Vedrop (tocofersolan) 50 mg/ml oral solution: EPAR — Summary of Product Characteristics. Recordati Rare Diseases; first authorisation 24 Jul 2009, renewal 23 Apr 2014. Available from: https://www.ema.europa.eu/en/documents/product-information/vedrop-epar-product-information_en.pdf
80. Morris AAM, Jones S. Medications Used in the Treatment of Inborn Errors of Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 45 (Table 45.1). doi:10.1007/978-3-662-63123-2_45
81. GeneGuidance. SAR1B — clinical curation of the gene. Local GeneGuidance database (extraction 2026-10-31).
82. Cuerq C, Henin E, Restier L, Blond E, Drai J, Marçais C, et al. Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease. J Lipid Res. 2018;59(9):1640-1648. doi:10.1194/jlr.M085043
83. U.S. Food and Drug Administration. Drugs@FDA (openFDA drugsfda endpoint): search for tocofersolan and lomitapide (NDA203858, Juxtapid, original approval 21 Dec 2012). Available from: https://api.fda.gov/drug/drugsfda.json
84. GeneGuidance. PHYH — clinical curation of the gene. Local GeneGuidance database (extraction 2026-10-31).
85. Global DARE Foundation (Defeat Adult Refsum Everywhere). Refsum diet guide and emergency regimen. Available from: https://www.defeatadultrefsumeverywhere.org/diet-guide
86. Baldwin EJ, Gibberd FB, Harley C, Sidey MC, Feher MD, Wierzbicki AS. The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiatry. 2010;81(9):954-7. doi:10.1136/jnnp.2008.161059
87. Baldwin EJ, Harrington DJ, Sampson B, Feher MD, Wierzbicki AS. Safety of long-term restrictive diets for peroxisomal disorders: vitamin and trace element status of patients treated for Adult Refsum Disease. Int J Clin Pract. 2016;70(3):229-35. doi:10.1111/ijcp.12770
88. Connelly-Smith L, Alquist CR, Aqui NA, Hofmann JC, Klingel R, Onwuemene OA, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue. J Clin Apher. 2023;38(2):77-278. doi:10.1002/jca.22043
89. Weinstein R. Phytanic acid storage disease (Refsum's disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. J Clin Apher. 1999;14(4):181-4. doi:10.1002/(sici)1098-1101(1999)14:4<181::aid-jca5>3.0.co;2-z
90. Agência Nacional de Vigilância Sanitária (ANVISA). Open data — registered medicines (DADOS_ABERTOS_MEDICAMENTOS.csv). Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
91. European Medicines Agency. Lojuxta (lomitapide): EPAR — Summary of Product Characteristics. First authorisation 31 Jul 2013; renewal 26 May 2023. Available from: https://www.ema.europa.eu/en/documents/product-information/lojuxta-epar-product-information_en.pdf
92. ClinicalTrials.gov. Search by condition: abetalipoproteinemia, hypobetalipoproteinemia, chylomicron retention, Refsum disease, phytanic acid (API v2). Available from: https://clinicaltrials.gov/