Congenital Disorders of Glycosylation (CDG)

PMM2-CDG as the central disorder within the group, with MPI-CDG, ALG6-CDG, ALG1-CDG, SRD5A3-CDG, PGM1-CDG, defects of O-glycosylation, the glycosylphosphatidylinositol anchor and multiple pathways, and NGLY1 deficiency.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Glycosylation is the most extensive post-translational modification of human proteins. Most secreted proteins, such as transferrin, coagulation factors and glycoprotein hormones, most membrane proteins and several intracellular proteins, such as lysosomal enzymes, carry sugar chains (glycans) that determine folding, stability, targeting and function. When a step in the synthesis, transfer or processing of these glycans fails, the defect manifests simultaneously in many organs. This is why CDG present as multisystem diseases, with neurological involvement in almost all forms, and why the same laboratory marker, serum transferrin, reveals very different enzyme defects [1, 12].

The group originated from a clinical observation in Leuven. In 1980, Jaak Jaeken and colleagues described twin girls with psychomotor delay and strabismus, fluctuating prolactin, follicle-stimulating hormone and growth hormone concentrations, partial thyroxine-binding globulin (TBG) deficiency and increased serum arylsulphatase A activity. Abnormalities in two functionally unrelated glycoproteins led to the hypothesis of a common defect in the carbohydrate moiety. In 1984, the same group demonstrated sialic acid-deficient serum and cerebrospinal fluid transferrin; subsequent demonstration of sialic acid, galactose and N-acetylglucosamine deficiency in several glycoproteins consolidated the interpretation [12, 27]. Phosphomannomutase deficiency was described in 1995 by Van Schaftingen and Jaeken, and the PMM2 gene was identified in 1997 by Matthijs and colleagues, who designated the entity Jaeken syndrome [28, 29]. In 1998, Niehues and colleagues identified phosphomannose isomerase deficiency (CDG-Ib, now MPI-CDG) and showed correction with oral mannose, making this the first CDG with targeted therapy [30]. Patients with the same picture had been described before the cause was known: Pedersen and Tygstrup reported congenital hepatic fibrosis with protein-losing enteropathy and recurrent thrombosis in 1980, and Pelletier and colleagues published in 1986 four infants from the Lac-Saint-Jean region (Quebec) with secretory diarrhoea, protein-losing enteropathy, intestinal lymphangiectasia and congenital hepatic fibrosis; the first of these patients, carrying p.(Arg295His), was confirmed as having MPI-CDG in 2002. Saudubray dates the Quebec description to 1985 (section 3.3); the primary publication is from January 1986 [1, 24].

Alphanumeric nomenclature (CDG-Ia, -Ib, -IIa…) reflected the transferrin pattern and order of discovery, but became inadequate as the group grew. In 2009 the gene symbol followed by “-CDG” was adopted [2]. Discovery continues: between the 6th and 7th editions of Saudubray the number of CDG increased by approximately 50% (from 91 to 137), and 2025–2026 reviews report approximately 190 defects and new entities such as RPN1-CDG, UGGT1-CDG and DHRSX-CDG [1, 4, 21]. As at least 1% of the genome participates in glycosylation, the Saudubray authors predict that most CDG remain undescribed [1].

From the clinical geneticist’s perspective, the group presents three problems. The first is recognition: some CDG have almost specific signs (fat pads in PMM2-CDG, coloboma in SRD5A3-CDG, cleft palate and rhabdomyolysis in PGM1-CDG, alacrima in NGLY1 deficiency), but many present only as developmental delay. The second is laboratory-based: transferrin screening detects only some CDG and has false positives and negatives requiring interpretation. The third is therapeutic: few forms have targeted treatment, and MPI-CDG, potentially fatal and treatable with an oral sugar, must not be missed. This article organises the group around PMM2-CDG, describes forms for which treatment or surveillance differs, and identifies where sources diverge [1, 17, 18].

2. Molecular Genetics and Pathophysiology

2.1. Glycosylation pathways

Glycans are classified by their attachment atom. N-glycans attach to the amide group of asparagine; O-glycans attach to the hydroxyl group of serine or threonine and form distinct families (O-xylosylglycans, O-N-acetylgalactosaminyl or mucin-type glycans, O-mannosylglycans, O-fucosylglycans and O-glucosylglycans). There is also lipid glycosylation, for example of ceramide in ganglioside synthesis, and the GPI anchor, a glycolipid with a core of one glucosamine and three mannoses that attaches more than 150 proteins to the outer plasma membrane surface [1, 31].

N-glycan synthesis proceeds in three phases. First, nucleotide-activated sugars are formed in the cytosol, mainly guanosine diphosphate-mannose (GDP-mannose), uridine diphosphate-glucose (UDP-glucose) and UDP-N-acetylglucosamine (UDP-GlcNAc); on the cytosolic face of the endoplasmic reticulum (ER), GlcNAc and mannose units are added to dolichol phosphate and the nascent structure is translocated (flipped) into the lumen. Second, the 14-sugar precursor, dolichol-pyrophosphate-GlcNAc₂-mannose₉-glucose₃, is completed in the ER. Third, the oligosaccharyltransferase (OST) complex transfers the precursor en bloc to the nascent polypeptide chain, and the glycan is trimmed and remodelled in the ER and Golgi. O-glycosylation involves assembly but not processing and occurs mainly in the Golgi [1].

These phases explain the laboratory pattern. Assembly and transfer defects (up to OST) cause loss of entire N-glycan chains and the type 1 transferrin pattern; Golgi processing defects produce present but incomplete chains and the type 2 pattern [1, 3].

2.2. Classification by pathway and clinical examples

The table summarises Tables 43.1 to 43.4 of Saudubray; the complete updated list is available in the 2025–2026 reviews, which count approximately 190 genes [1, 4, 21]. Some of these entities retain descriptive names still in use, such as hereditary multiple osteochondromas (EXT1/EXT2-CDG), hyperphosphataemic familial tumoral calcinosis (GALNT3-CDG), Peters-plus syndrome (B3GLCT-CDG) or autosomal recessive cutis laxa type 2A (ATP6V0A2-CDG). The hereditary cutis laxa disorders include ATP6V0A2-CDG. For COG6, ATP6V0A2 and other proteins with functions beyond glycosylation, the authors propose the term “CDG-plus” [1].

2.3. PMM2-CDG and MPI-CDG: mannose metabolism

Phosphomannose isomerase (MPI) catalyses the first committed step of GDP-mannose synthesis, converting fructose-6-phosphate to mannose-6-phosphate; phosphomannomutase 2 (PMM2), the main PMM isoenzyme, catalyses the second, converting mannose-6-phosphate to mannose-1-phosphate, which yields GDP-mannose and dolichol-phosphate-mannose. These mannose donors supply assembly of the dolichol-linked precursor as well as O-mannosylation and GPI anchor synthesis [1, 7, 12]. PMM2 deficiency reduces the mannose-1-phosphate and GDP-mannose pools; fibroblasts accumulate shortened dolichol-linked oligosaccharides, such as Man₃GlcNAc₂ and Man₅GlcNAc₂, which are poor OST substrates, leaving glycosylation sites empty. The result is hypoglycosylation of serum proteins (TBG, haptoglobin, factor XI, antithrombin, cholinesterase, among others), lysosomal enzymes and membrane glycoproteins, with probable activation of the unfolded protein response [1, 12]. The mechanism is loss of function [3].

As MPI acts immediately upstream, blood biochemical abnormalities in MPI-CDG are indistinguishable from those in PMM2-CDG. Fructose-6-phosphate does not accumulate because it is channelled into glycolysis. Exogenous mannose is phosphorylated by hexokinases to mannose-6-phosphate and bypasses the block, providing the rationale for treatment [1]. In MPI-CDG intracellular mannose falls below 10 µmol/L, versus 50–100 µmol/L in healthy individuals; excess mannose-6-phosphate, conversely, inhibits hexokinase, phosphoglucose isomerase and glucose-6-phosphate dehydrogenase, defining a therapeutic window [7, 18]. In PMM2-CDG, mannose corrects glycosylation in fibroblasts but has not demonstrated benefit in patients because the mannose-6-phosphate formed still requires PMM2 [1, 32].

The same reasoning explains a secondary cause of a type 1 pattern: in hereditary fructose intolerance, accumulated fructose-1-phosphate inhibits phosphomannose isomerase [7, 33].

Mannose-6-phosphate has two sources: conversion from glucose, which depends on MPI, and phosphorylation of free mannose, which comes mainly from the diet (orange, apple, peach, carob). With a usual diet, the exogenous pathway is insufficient to compensate for the block. The plasma membrane mannose transporter works under basal conditions at about half its capacity, so the rise in blood mannose with supplementation increases cellular entry and the fraction available for N-glycosylation. Oral mannose is well absorbed; its half-life is about 4 hours, the normal serum concentration lies between 46 and 65 µmol/L, blood mannose rises in proportion to the dose and peaks 1–2 hours after a dose of 0.07–0.2 g/kg, which supports division into several daily doses. The absence of neurological involvement is attributed to the ability of neurons to produce GDP-mannose, albeit in small amounts, a hypothesis supported by a zebrafish model; the disease does not accumulate toxic substrates, because fructose-6-phosphate is a glycolytic intermediate [24].

The MPI gene lies at 15q24.1–q24.2; the reference transcript is NM_002435.3 (ENST00000352410.9, MANE Select), with 8 coding exons, and the genomic organisation is conserved between mouse and human. More than 20 pathogenic variants have been described, and the proportion of homozygotes is high owing to frequent consanguinity in the published families. Three missense variants account for about half of the reported alleles: NM_002435.3:c.656G>A p.(Arg219Gln), the first identified and the most frequent, classified as pathogenic in ClinVar (VCV000014345); NM_002435.3:c.455G>A p.(Arg152Gln) (VCV002503985); and NM_002435.3:c.884G>A p.(Arg295His), the variant of the first Lac-Saint-Jean patient (VCV000014349); the last two have conflicting classifications in ClinVar. The French PNDS (National Diagnosis and Care Protocol) writes the second as c.457G>A; VariantValidator rejects that description, because the reference nucleotide at position c.457 is C, and confirms c.455G>A as the change producing p.(Arg152Gln). p.(Arg219Gln) was found in six compound heterozygotes and, in the homozygous state, in two asymptomatic adults, suggesting incomplete penetrance of mild alleles or unknown modifier genes. Neither enzyme activity nor the transferrin profile predicts the phenotype, because these adults had markedly reduced activity and markedly abnormal transferrin [8, 24, 34, 35].

2.4. The PMM2 gene, variants and correlations

The PMM2 gene is located at 16p13.2, has eight exons across approximately 51.5 kb and encodes a 246-amino-acid protein; a processed pseudogene, PMM2P1, exists on chromosome 18 and should be considered when designing molecular assays [3, 12]. At least 139 pathogenic or likely pathogenic variants have been described, mainly missense; intragenic deletions are rare (fewer than 1% of variants), including a 28 kb deletion spanning exon 8 and complete loss of exon 8 through Alu retrotransposition [1, 3]. The table uses MANE Select transcript NM_000303.3; GeneReviews uses the earlier version NM_000303.2, with identical c. numbering for the listed variants [3, 8, 35].

Genotype–phenotype correlations exist, but variability with the same genotype is considerable, and siblings tend to have similar presentations [3]. In the 137-patient cohort, dimerisation and folding variants and p.Val231Met were associated with greater severity and p.Cys241Ser with lower severity [36]. A relatively common mild ALG6 variant, p.Phe304Ser, may worsen PMM2-CDG as a modifier, without individual predictive value [3]. Enzyme activity in heterozygotes is approximately 50% of normal, but biochemical carrier detection is unreliable [12, 40].

2.5. Other genes with clinically relevant mechanisms

In ALG6-CDG, addition of the first of three glucoses to the Man₉GlcNAc₂-PP-dolichol intermediate fails; the unglucosylated oligosaccharide is transferred less efficiently. As GDP-mannose synthesis is preserved, GDP-fucose and GPI-anchored proteins are unaffected, which may explain a less severe phenotype than PMM2-CDG; blood glycoproteins, particularly factor XI, antithrombin and protein C, are nevertheless especially low. Variants p.(Ala333Val) (c.998C>T, VCV000005497) and p.(Ile299del) (c.894AAT[1], VCV000030420; NM_013339.4) are the most common [1, 35]. In ALG1-CDG, addition of the first of nine mannoses to GlcNAc₂-PP-dolichol fails; GlcNAc₂-PP-dolichol accumulates and transferrin carries a xeno-tetrasaccharide that acts as a biomarker; the most frequent variant is c.773C>T p.(Ser258Leu) (NM_019109.5, VCV000004724) [1, 7, 35]. In DPAGT1-CDG addition of the second GlcNAc fails; in MAN1B1-CDG, involving a Golgi mannosidase, the pattern is type 2 with hybrid N-glycans on mass spectrometry [1].

SRD5A3, a polyprenol reductase, participates in dolichol synthesis; its deficiency reduces dolichol phosphate available for all dependent pathways [1]. PGM1 interconverts glucose-1-phosphate and glucose-6-phosphate; its deficiency simultaneously causes a muscle glycogenosis (formerly GSD XIV) and the only primary defect with both N-glycan assembly and processing abnormalities, through UDP-glucose and UDP-galactose depletion; galactose replenishes galactose-1-phosphate and these nucleotide sugars [1, 41]. In SLC39A8-CDG, the manganese transporter ZIP8 fails; manganese deficiency compromises manganese-dependent galactosyltransferases and mitochondrial superoxide dismutase, resulting in combined glycosylation and mitochondrial disease [20, 42]. SLC35C1 transports GDP-fucose into the Golgi; SLC35A2 transports UDP-galactose and is X-linked, with female predominance, postzygotic mosaicism and brain-restricted somatic variants in mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) [7].

The GPI anchor is synthesised in the ER by approximately 27 genes; PIGA is one of seven proteins involved in the first step, transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol. The defect reduces cell-surface GPI-anchored proteins, such as CD16 and CD24, and alkaline phosphatase, normally anchored, is released into plasma, explaining hyperphosphatasaemia [1, 31]. NGLY1 is a cytoplasmic N-glycanase in the ER-associated degradation (ERAD) pathway, removing glycans from misfolded glycoproteins before proteasomal degradation; its deficiency is a deglycosylation disorder and does not alter transferrin [1, 23].

GMPPA is the regulatory subunit, without catalytic activity, of the GMPPA–GMPPB complex, which forms GDP-mannose from mannose-1-phosphate and guanosine triphosphate; it binds GDP-mannose and mediates allosteric feedback inhibition of GMPPB, thereby regulating the cellular amount of this donor [7, 43]. In patient lymphoblasts, GDP-mannose pyrophosphorylase activity is normal and GDP-mannose is strongly increased, so GMPPA-CDG is a defect of regulation rather than of enzyme deficiency [43]. In two sisters homozygous for the splice variant NM_013335.4:c.853+1G>A, lymphoblasts showed complete loss of GMPPA protein and increased GDP-mannose [34, 44]. In total, 17 different GMPPA variants of all types have been described, without genotype–phenotype correlation [9]. TRAPPC11 is a subunit of the TRAPP (transport protein particle) tethering complex, which localises proteins to the Golgi and takes part in anterograde ER-to-Golgi transport; pathogenic variants reduce binding to the other components of the complex, disorganise Golgi architecture and delay the exit of cargo from the Golgi to the cell surface, with abnormal lysosomal glycoproteins LAMP1 and LAMP2 [45]. The splice variant NM_021942.6:c.1893+3A>G, homozygous in two Turkish families with a triple A phenotype, causes incomplete exon skipping and a marked reduction of the protein, with LAMP1 hypoglycosylation and delayed arrival and exit of proteins at the Golgi [7, 10, 34]. Downstream, the disease behaves as a dystroglycanopathy: muscle biopsy shows hypoglycosylation of α-dystroglycan, which is also reduced in Purkinje cells and dentate nucleus neurons, and the cerebellar involvement resembles the neuropathology of N-glycosylation CDG such as PMM2-CDG, suggesting defects in several glycosylation pathways [46, 47]. TRAPPC11 and GOSR2 were the first membrane trafficking proteins associated with dystroglycanopathies [47].

2.6. Inheritance and special genetic mechanisms

Most CDG are autosomal recessive. PIGA-CDG, SLC35A2-CDG, ALG13-CDG and SSR4-CDG are X-linked; multiple osteochondromas (EXT1/EXT2) are autosomal dominant; DHDDS causes recessive retinitis pigmentosa (RP59, Ashkenazi founder variant c.124A>G p.Lys42Glu) and, through monoallelic de novo variants, a neurodevelopmental disorder with myoclonus [1, 7]. In PMM2-CDG, uniparental isodisomy of chromosome 16 and de novo variants have been described, altering counselling [3]. The 2025 ACMG standard lists, among genes with at least “moderate” evidence in GenCC, 120 with autosomal recessive inheritance, 14 autosomal dominant (several, such as COG4, DHDDS, EXT2, GNE, NUS1, POGLUT1 and SEC23B, also with recessive inheritance) and 11 X-linked (ALG13 and SLC35A2 also de novo), and notes that CDG have been described with every inheritance mode except mitochondrial [22]. Somatic variants are relevant in two genes: PIGA variants in haematopoietic cells cause paroxysmal nocturnal haemoglobinuria, an acquired disease that should not be confused with germline PIGA-CDG; brain-restricted SLC35A2 variants cause focal epilepsy with MOGHE [1, 7].

3. Clinical Spectrum and Manifestations by System

3.1. Main phenotypes of the group

Most CDG are multisystem diseases with prominent neurological manifestations: variable degrees of cognitive impairment, from severe encephalopathies to mild intellectual disability, and associated neurological signs, particularly cerebellar or pontocerebellar. Dysmorphism, thrombosis, retinopathy and cardiac and hepatic involvement are other frequent components. Some epileptic encephalopathies improve with specific treatment, such as vitamin B6 in PIGO-CDG and galactose in a transporter defect [1].

3.2. PMM2-CDG

PMM2-CDG is the most frequent CDG, with at least 900 known patients according to Saudubray and more than 1,000 according to the Atlas; it was described in Belgium and recognised in Spain, Taiwan and the United States, including patients of African ancestry [1, 12]. The nervous system is always involved and almost every other organ may be affected. The spectrum ranges from fatal fetal hydrops to adults with a mild neurological phenotype and normal cognition, diagnosed through cerebellar ataxia [3, 12]. The historical Hagberg and Jaeken classification distinguishes four stages: infantile multisystem, childhood ataxia and intellectual disability, adolescent lower-limb atrophy and adult hypogonadism; GeneReviews groups them into infantile multisystem, late-childhood ataxia–intellectual disability and adult stable disability [3, 12].

Fetal and neonatal period. Non-immune fetal hydrops was described in 12 individuals, with hydropic placenta and polyhydramnios; all presenting with antenatal or neonatal hydrops died by 3 months [3]. Most patients are born at term following an uncomplicated pregnancy, with appropriate weight. Inverted nipples and esotropia are almost universal at birth; lipoatrophy may be generalised or band-like, and the most characteristic sign is subcutaneous fat pads in unusual locations, typically above or over the buttocks, in the suprapubic region and, in girls, the labia majora, with thickened “tallow-like” or peau d’orange skin. These signs may be absent in the first months and disappear with age [3, 12].

Infantile multisystem stage. Feeding difficulties, with projectile vomiting, lack of interest in feeding and need for tube feeding during the first year, dominate the first three months; by one year, most have only doubled their birthweight, although there are exceptions with macrosomia [12]. Axial hypotonia, hyporeflexia and developmental delay are early features; head control may be absent at 12 months. Ataxia is recognisable from 7 months, and nerve conduction velocity may decrease at 6–8 months [12]. Dysmorphic features include bitemporal narrowing, prominent forehead, long face, almond-shaped palpebral fissures, short nose, long philtrum, thin upper lip and large dysplastic ears; approximately half develop microcephaly [3, 12]. Two courses are observed: non-fatal neurological, with growth delay, strabismus, developmental delay, cerebellar hypoplasia and liver disease, followed by neuropathy and retinitis pigmentosa; and severe neurological–multivisceral, with approximately 20% first-year mortality from severe infection or hepatic, cardiac or renal failure [1, 3]. Severe forms may include intractable hypoalbuminaemia, anasarca, pericardial effusion, hyperechogenic or cystic kidneys, nephrotic syndrome, hepatic fibrosis and multiorgan failure [3].

Cardiac involvement merits specific attention. Pericardial effusions are frequent in infancy, usually without consequence and resolving within 1–2 years, but may persist and prove fatal through tamponade; hypertrophic cardiomyopathy and cardiac malformations are rare [3, 12]. In a series of 222 patients from eight European centres, 57 (45 children) had cardiac involvement and 24 of these died (median age 21 months); pericardial effusion was the most frequent manifestation (55.4%), mainly in the first 6 months, and variant p.(Val231Met) was present in 36% of patients with cardiac involvement, 3.5 times more than in the remainder (21 of 36 carriers with cardiac involvement, 15 of whom died) [37]. In a French series of 96 patients, 20 had cardiac manifestations (pericarditis in 14, malformation in 9, cardiomyopathy in 2) and 12 died, at a mean age of 3.8 years, mainly from pericarditis and other cardiac causes [49].

Liver and gastrointestinal tract. Hepatomegaly is frequent; transaminases rise in the first year and may reach 1,000–1,500 U/L without clinical consequence, usually normalising between 3 and 5 years, with mild rises during intercurrent illnesses. Histology shows steatosis, fibrosis and lamellar lysosomal inclusions in hepatocytes and macrophages, but not Kupffer cells; liver biopsy is unnecessary for diagnosis [1, 3, 12]. Hypoalbuminaemia and gastrointestinal bleeding may occur [12].

Haemostasis. Procoagulant factors (IX, XI, prothrombin) and anticoagulants (antithrombin, protein C, protein S, heparin cofactor II) are reduced; intermittent thrombocytosis may reach 800,000/mm³ [3, 12]. Antithrombin was below normal in 79.5% (93 of 117) of patients in the international natural history study [36]. These imbalances rarely cause everyday problems, but explain both bleeding and thrombosis, including deep venous thrombosis in children and adults, more likely in sedentary patients, and occasional intracranial haemorrhage [3].

Childhood (3 to 10–12 years): ataxia and intellectual disability. Hypotonia and ataxia dominate; few patients acquire independent walking; most sit unsupported after 2 years and use a wheelchair. Intelligence quotient (IQ) is usually between 40 and 70, with cases of borderline or normal function; comprehension exceeds expression, with scanning speech, and patients are typically outgoing and cheerful. There is no intellectual regression except after stroke-like episodes [1, 3, 12]. These episodes (SLE) occur mainly in childhood, often triggered by fever, seizures, dehydration or trauma; they manifest as stupor or coma, seizures and hemiplegia, with recovery over hours to months; permanent deficits are rare and associated with infarction; two patients were blind for months [3, 12]. In the US cohort of 51 patients, SLE occurred in 15.7%, all in patients with previous seizures, and febrile seizures were the most common trigger [50]. Seizures occur in approximately half of patients, with the first at a mean age of 17 months (3–53 months) in a series of 23 patients, and usually respond to antiepileptics [3, 12]. In the same 51-patient cohort, ataxia was present in 90.2%, myopathy in 82.4%, seizures in 56.9%, neuropathy in 52.9%, extrapyramidal signs in 27.5%, microcephaly in 19.1% and spasticity in 13.7% [50].

Eye. Esotropia and other abnormal eye movements occur early; retinitis pigmentosa from progressive photoreceptor degeneration arises after early childhood, with myopia and, in adults, cataract [3, 12].

Adolescence and adulthood. Progressive lower-limb muscle atrophy and weakness from lower motor neuron dysfunction, axonal and demyelinating peripheral neuropathy and skeletal deformities (kyphosis, scoliosis, pectus carinatum, shortened and broadened thorax) dominate adolescence. Fat pads disappear; liver disease may stabilise. Osteopenia and osteoporosis are common, without a clear increase in fractures [3, 12]. Hypogonadism is frequent, particularly in women, with absent pubertal development and ovarian failure, sometimes with absent ovaries on laparoscopy; in men, virilisation is usually normal, with reduced testicular volume. The 2019 guideline describes 29 adult women with hypergonadotrophic hypogonadism or ovarian failure, and at least 27 received oestrogens; the Atlas also classifies it as hypergonadotrophic, whereas GeneReviews and one section of the guideline itself use “hypogonadotrophic”. Pathophysiological interpretation favours primary ovarian failure, but the divergence reinforces individual hormonal assessment [3, 12, 17]. Hyperprolactinaemia, insulin resistance and, rarely, hyperinsulinaemic hypoglycaemia may coexist; hypoglycosylation of IGFBP3 and the acid-labile subunit contributes to short stature [3]. Intellectual disability is stable; most adults are non-ambulatory but participate socially with support [3].

Childhood endocrinology. TBG is low in 75% of patients; the partial TBG deficiency pattern (low total T4, normal free T4 and TSH) is usual and requires no treatment unless TSH is elevated with low free T4, ideally measured by equilibrium dialysis [3, 12]. Infantile hypoglycaemia is hyperinsulinaemic in 40% of cases [3].

Kidney and immunity. Kidneys may be large and hyperechogenic owing to microcysts, with function usually preserved into adulthood; nephrotic syndrome and tubulopathy are rare [3, 12, 49]. Recurrent infections and poor vaccine response warrant baseline immunological assessment [3].

Allelic presentation without neurological involvement. Promoter variant c.-167G>T, homozygous or in trans with a coding variant, causes congenital hyperinsulinaemic hypoglycaemia with polycystic kidney disease, without typical PMM2-CDG signs or laboratory pattern; a child with genotype c.-167G>T/c.422G>A had normal growth and development at 6 years [1, 3, 39].

3.3. MPI-CDG

MPI-CDG presents as gastrohepatic disease, without dysmorphism and with no or little neurological involvement. Of 35 patients from 30 families reviewed in the international consensus, onset was in childhood in 93%, at a mean age of 1.2 years; two had adolescent onset and two adult siblings remained asymptomatic until their forties [7, 18]. The presentation combines gastrointestinal disease (cyclical vomiting, abdominal pain, protein-losing enteropathy and growth delay, in 26 patients), hypoglycaemia (15; hyperinsulinaemic in more than two-thirds), hepatic involvement (14; hepatomegaly, fibrosis) and coagulation abnormalities (7; laboratory coagulopathy, thrombosis, gastrointestinal bleeding); nine had isolated gastrointestinal disease [7, 18]. The main adult complication is portal hypertension with oesophageal varices; transaminases are normal or slightly elevated, potentially rising 30–40-fold during decompensation. Seizures are secondary to hypoglycaemia, thrombosis or intravenous mannose; absence of intellectual disability distinguishes MPI-CDG from PMM2-CDG. Diagnostic delay ranged from 0 to 30 years (median 2.15), and diagnosis was made post mortem in six of 35 [7]. In 1985, four Quebec infants described with “Saguenay–Lac-Saint-Jean syndrome” were retrospectively recognised as MPI-CDG [1]. One patient had recurrent vomiting and liver disease that disappeared with introduction of solid food at 3 months [1]. Cerebral venous thrombosis may be the first and only manifestation, as in the case in section 10 [51].

Organ involvement according to the 2022 PNDS. The French protocol (PNDS, French National Diagnosis and Care Protocol), drawn up from 79 articles and the national series of nine patients, describes the disease system by system; symptoms begin before 2 years of age in the great majority, rarely in adolescence or adulthood, and several patients died early before diagnosis and treatment [24, 52].

Gastrointestinal tract. Diarrhoea is the most frequent symptom and is often associated with vomiting; both may be intermittent. It results from protein-losing enteropathy, due to increased permeability of the intestinal barrier or to lymphangiectasia, demonstrated by faecal alpha-1-antitrypsin clearance calculated from serum and faecal concentrations. Enteropathy should be suspected in a child with oedema and hypoalbuminaemia without proteinuria or impaired hepatic synthesis; in severe forms it causes an oedema–ascites syndrome, and protein loss increases thrombotic risk. Duodenal biopsies may show villous atrophy or lymphangiectasia, but are normal in some patients with proven protein-losing enteropathy; steatorrhoea has been described. Malnutrition and growth failure may require enteral or parenteral nutrition [24].

Liver. Firm hepatomegaly is the most frequent and earliest hepatic sign; splenomegaly may appear later. Transaminases are usually 1.5–5 times the upper limit of normal (up to 30–40 times at diagnosis) and may be normal despite liver damage; GGT and bilirubin are usually normal. The hypoglycaemia, coagulopathy and hypoalbuminaemia present at diagnosis result from systemic hypoglycosylation and enteropathy, not from hepatocellular failure, and normalise with mannose. Biopsy shows congenital hepatic fibrosis, with an excess of dilated and dystrophic biliary structures of the ductal plate malformation type, sometimes with minimal steatosis not visible on ultrasound; these lesions are developmental and do not regress with mannose, so portal hypertension may progress on treatment. Portal hypertension is recognised by clinical signs (splenomegaly, abdominal collateral circulation, telangiectasia or presenting upper gastrointestinal bleeding), ultrasound signs (reversed portal flow, thickening of the lesser omentum and gastric wall, spontaneous portosystemic anastomoses) and laboratory signs (progressive fall in platelets due to hypersplenism). Its onset warrants referral to hepatology for endoscopy (oesophagogastric varices, gastric antral vascular ectasia, ulcer, rectal varices) and screening for hepatopulmonary syndrome and portopulmonary hypertension, the latter not yet described in MPI-CDG [24].

Endocrinology. Hypoglycaemia predominates in the first years; it may be asymptomatic, cause seizures or malaise, and be the only manifestation. It is mainly due to hyperinsulinism, of poorly understood mechanism (hypoglycosylation of receptors such as SUR1 is one hypothesis), but has been described without hyperinsulinism. Short stature is associated with low IGF-1, IGFBP-3 and acid-labile subunit, which track the glycosylation profile and respond to mannose. There was a single case of peripheral hypothyroidism (TSH, T4 and TBG usually normal), and delayed puberty in rare female patients, with spontaneous onset at 14 and 15 years and gonadotrophins normal for age, suggesting a central origin; GH, cortisol, LH, FSH, oestradiol and testosterone were normal when measured [24].

Haemostasis. Laboratory coagulation abnormalities are almost constant: mainly antithrombin deficiency, with frequent factor XI deficiency and sometimes protein C and S deficiency, aggravated by enteropathy or consumption. Disseminated intravascular coagulation has been described, with decreased factors II, V, VII, VIII and IX and fibrinogen and raised D-dimers. Thromboses occur mainly during acute infections and dehydration, may be presenting and recurrent, and have been described in the deep veins of the lower and upper limbs, in the cerebral parenchyma and venous sinuses, in the lung (embolism) and in the right atrium. Bleeding is mainly gastrointestinal, linked to ulcers or portal hypertensive varices, and the same patient may have both thromboses and bleeding. A combined deficiency of procoagulant and anticoagulant factors, or unexplained disseminated intravascular coagulation, should raise the possibility of CDG [24].

Other organs. There is no intellectual disability: the developmental delay described was mild and transient, except in one child with very severe gastrointestinal disease who died at 2 years; hypotonia was rare and transient; seizures resulted from severe hypoglycaemia or cerebral thrombosis and did not require long-term antiepileptic treatment; brain imaging was normal, without cerebellar hypoplasia. In the kidney, hyperechogenicity, nephromegaly, cysts and tubular acidosis have been described, with slightly reduced clearance in one adult woman and glomerular hyperfiltration in another patient. The only severe heart disease was hypertrophic cardiomyopathy with atrial septal defect in the same child who died at 2 years of heart failure; two other patients had an atrial septal defect of uncertain relationship to the disease. Unusual and severe infections (herpes encephalitis, bronchiolitis obliterans, cryptosporidiosis, Candida urinary tract infection) have been described with normal immune studies, and IgG hypogammaglobulinaemia (with normal IgA and IgM) due to intestinal loss in six patients. There are no prenatal manifestations or characteristic dysmorphism: one patient had strabismus, another inverted nipples, and none had abnormal fat distribution or skeletal deformities [24].

3.4. Other N-glycosylation CDG

ALG6-CDG is the second most frequent N-glycosylation CDG, with at least 89 patients. It shares developmental delay, hypotonia, ataxia, seizures, strabismus, nystagmus and growth delay with PMM2-CDG, but usually lacks retinitis pigmentosa or cerebellar hypoplasia. Skeletal anomalies (brachydactyly, arachnodactyly, short arms, scoliosis), behavioural abnormalities and non-specific dysmorphism are frequent; some patients have protein-losing enteropathy. The oldest known patient was 38 years old [1]. In a cohort of 41 patients from Euroglycan, hypotonia and delay were present in all; nine developed intractable epilepsy; seven had absent phalanges with brachydactyly; cyclical behavioural abnormalities with autistic traits and depressive episodes were prominent complaints; eleven children died before 4 years from protein-losing enteropathy, sepsis or seizures [7, 53].

ALG1-CDG is predominantly neurological, with usually severe intellectual disability and constant hypotonia; most have dysmorphism (including inverted nipples and fat pads), microcephaly from the neonatal period, intractable epilepsy, visual abnormalities, tremor, ataxia, severe infections or unexplained fever and brain lesions (infarction, atrophy, periventricular white matter abnormalities). Laboratory findings include low LDL cholesterol, factor XI, antithrombin, proteins C and S, variable hypoalbuminaemia, elevated transaminases, low cholinesterase and immunoglobulins, and low IGF1/IGFBP3. Fifty-seven patients from 47 families have been described, with survival from 2 days to over 20 years [1]. In a series of 39 patients, specific genotypes were associated with death within the first two years [7, 54].

DPAGT1-CDG presents in two forms: severe multisystem encephalopathy (moderate to severe psychomotor delay, microcephaly, hypotonia, epilepsy, cataracts, contractures; 23 patients died between 6 weeks and 5 years) or limb-girdle congenital myasthenic syndrome, with proximal weakness and minimal craniobulbar involvement, onset between birth and 17 years and slow progression. Fifty-two patients from 25 families have been described; creatine kinase is elevated in the multisystem form and normal in the myasthenic form; transferrin shows a type 1 pattern in all multisystem patients, but only approximately half the myasthenic patients [1]. Tubular aggregates on muscle biopsy are characteristic but absent in early biopsies [7, 55].

MAN1B1-CDG, described in 34 patients from 21 families, causes mild to severe intellectual disability, language delay, hypotonia, facial dysmorphism and truncal obesity; half have behavioural abnormalities (verbal and physical aggression, autism, inappropriate sexual behaviour, hyperphagia). It was initially described as non-syndromic autosomal recessive intellectual disability (MRT15); transferrin shows a type 2 pattern [1, 7].

3.5. O-glycosylation defects

The most frequently described forms involve synthesis of glycosaminoglycans, mucins, O-mannosylglycans and O-fucosylglycans [1]. B4GALT7-CDG (progeroid Ehlers–Danlos variant, at least 52 patients) combines short stature, forearm and elbow anomalies, bowed limbs, joint laxity, skin hyperextensibility and poor healing; Reunion Island Larsen syndrome results from a homozygous founder variant, with multiple dislocations and no progeroid appearance; perinatal lethal skeletal dysplasia with cleft palate and radial defects was described in one family. GALNT3-CDG (at least 66 patients, mainly from the Middle East or Africa) prevents the O-glycosylation protecting FGF23 from inactivation, causing hyperphosphataemic familial tumoral calcinosis, with painful calcified subcutaneous masses, or hyperphosphataemic hyperostosis with diaphysitis, sometimes within the same family. Hereditary multiple osteochondromas (EXT1/EXT2, autosomal dominant, prevalence 1 in 50,000) result from a defect in the heparan sulphate-synthesising complex, with variants identified in more than 70% of cases and risk of chondrosarcoma and osteosarcoma [1]. Dystroglycanopathies due to POMT1/POMT2 (cerebro-ocular dysplasia with muscular dystrophy, including Walker–Warburg) cause cobblestone lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, hydrocephalus, ocular defects and congenital muscular dystrophy, with a usually fatal course before 1 year; POMT1/2 account for approximately 20% of these patients; muscle–eye–brain disease (POMGNT1/POMGNT2) is less severe, and POMGNT1 may cause non-syndromic retinitis pigmentosa [1, 31, 56]. B3GLCT-CDG causes Peters-plus syndrome, in at least 50 patients: anterior chamber anomalies, growth delay and brachydactyly, frequent intellectual disability, cleft lip and/or palate, heart disease and dysmorphism in approximately half; no variants were found in patients with an incomplete phenotype [1].

3.6. Lipid glycosylation and GPI anchor defects

X-linked PIGA-CDG has been described in at least 76 patients, with severe (multiple congenital anomalies–hypotonia–seizures syndrome type 2, MCAHS2) and less severe forms. Severe forms combine poorly responsive epilepsy (sometimes vitamin B6-responsive), hypotonia, multiple brain anomalies, dysmorphism and, in a minority, skin, cardiac, hepatic and renal involvement, with a high frequency of sudden death in childhood; some have systemic iron overload (ferro-cerebro-cutaneous syndrome). Most have hyperphosphatasaemia and reduced CD16 and CD24 on blood cells [1, 7, 57]. GPI deficiency syndromes, involving at least 27 genes, cause multisystem presentations with a severe neurological component, with or without seizures and congenital anomalies; PIGG and PIGT cause cerebellar hypoplasia, and PIGT may associate macrocephaly with cerebellar hypoplasia; plasma alkaline phosphatase may be high or low [31, 56]. Hyperphosphatasia with intellectual disability syndrome (HPMRS, Mabry syndrome) combines facial dysmorphism, brachytelephalangy, nail hypoplasia, sometimes anorectal anomalies, and seizures beginning neonatally or in childhood, with mildly to moderately elevated serum alkaline phosphatase; it is caused mainly by biallelic PIGV variants and less frequently by PIGO or PGAP2; whether seizures respond to pyridoxine is unclear [1, 58, 59]. ST3GAL5-CDG (GM3 synthase deficiency) and B4GALNT1-CDG (GM2 synthase deficiency, spastic paraplegia 26) are addressed with sphingolipidoses [1].

3.7. Multiple pathway and dolichol defects

SRD5A3-CDG (at least 38 patients) is the CDG in which the eye guides diagnosis: visual impairment, nystagmus, coloboma and optic atrophy, with intellectual disability, hypotonia, spasticity, cerebellar ataxia and vermian atrophy; a minority have ichthyosiform lesions, kyphosis, contractures, heart disease, coagulopathy and elevated transaminases. Transferrin shows a type 1 pattern in the vast majority; the oldest patient was 45 years old [1, 7].

PGM1-CDG has two phenotypes: myopathic glycogenosis (formerly GSD XIV) and multisystem disease with growth delay, hypoglycaemia, malformations (bifid uvula, cleft palate) and hepatic, cardiac and endocrine involvement, with little or no neurological involvement [1, 41]. In 57 confirmed patients, cleft palate was the most common anomaly (28), followed by bifid uvula (25) and Pierre Robin sequence (15); dilated cardiomyopathy and conduction abnormalities are the principal threat to life; rhabdomyolysis with exercise intolerance, hypothyroidism, hypogonadotrophic hypogonadism, coagulopathy and vascular complications occur; malignant hyperthermia was described in 2 of 22 surgical patients [7, 19]. Serum caeruloplasmin and copper may be low [42].

COG6-CDG (at least 28 patients) combines liver disease, microcephaly, intellectual disability, recurrent infections, early lethality and ectodermal signs (hypohidrosis with hyperthermia risk, hyperkeratosis); splice variant c.1167-24A>G is associated with a mild phenotype without liver disease or glycosylation deficiency, and loss-of-function variants c.511C>T and c.1238_1239insA with death between 1 and 15 months. COG7-CDG adds malignant hyperthermia, adducted thumbs and heart disease [1]. ATP6V0A2-CDG (autosomal recessive cutis laxa type 2) causes generalised cutis laxa at birth attenuating with age, microcephaly, joint laxity and ophthalmological abnormalities, with usually normal mental development; transferrin has a type 2 pattern and apoC-III is abnormal [1]. TMEM199-CDG (7 patients) causes non-progressive chronic liver disease; CCDC115-CDG (11 patients) causes a storage disease-like phenotype with regressive hepatosplenomegaly, markedly elevated bone alkaline phosphatase, altered copper metabolism and neurological symptoms; two died of liver failure and one underwent successful transplantation [1]. GNE-CDG (GNE myopathy; hereditary inclusion body myopathy, allelic to Nonaka myopathy) usually begins after 20 years and progresses over 10–20 years, sparing the quadriceps; GFPT1-CDG causes limb-girdle congenital myasthenic syndrome, sometimes with leukoencephalopathy, and responds partially to cholinergic agents [1].

SLC39A8-CDG (15 described patients, approximately 20 known) causes developmental delay and intellectual disability, hypotonia and movement disorder in all, feeding difficulties and ophthalmological involvement in 14 of 15, spasticity and epilepsy in 9, growth delay and hearing loss in 3; magnetic resonance imaging (MRI) may show Leigh syndrome-like basal ganglia lesions, craniosynostosis and lacunar skull; blood manganese is low and urinary xanthine elevated [20, 42]. SLC35A2-CDG, predominantly affecting females, is a developmental and epileptic encephalopathy with infantile spasms, severe intellectual disability, dysmorphism, skeletal and cardiac anomalies and cortical visual impairment [7, 60]. SLC35C1-CDG (leukocyte adhesion deficiency type II) combines recurrent bacterial infections with marked neutrophilia, Bombay phenotype and growth and developmental delay [7, 48].

3.8. Congenital disorders of deglycosylation: NGLY1 deficiency

NGLY1 deficiency (NGLY1-CDDG) is characterised by a tetrad: developmental delay or intellectual disability (mild to profound), hypolacrima or alacrima, elevated transaminases in early childhood with spontaneous normalisation, and a complex hyperkinetic movement disorder (choreiform, athetoid, dystonic, myoclonic, action tremor, dysmetric) [23]. Approximately half have seizures, beginning between 2 months and 10 years. Other findings include intrauterine growth restriction (birthweight below the 10th percentile in approximately half), weight faltering despite preserved appetite, acquired microcephaly, sleep apnoea, auditory and peripheral neuropathy, constipation, scoliosis, hypohidrosis and low cerebrospinal fluid protein [1, 23]. Most are non-verbal but use augmentative communication; adaptive strengths lie in socialisation, with weaknesses in fine motor function [23]. Dry eyes may cause corneal neovascularisation, pannus and scarring [7]. Most survive into early adulthood with a stable course; childhood deaths have been described [1, 23]. Lysosomal glycoconjugate degradation diseases (sphingolipidoses, mucopolysaccharidoses, oligosaccharidoses) are formally lysosomal deglycosylation disorders and are not developed here [1].

3.9. Triple A phenocopies: GMPPA-CDG and TRAPPC11-related disorders

Triple A syndrome (Allgrove syndrome, due to biallelic AAAS variants), which combines adrenal insufficiency due to adrenocorticotrophic hormone (ACTH) resistance, achalasia of the cardia and alacrima, enters the differential diagnosis. Orphanet links two CDG genes, GMPPA and TRAPPC11, to its entry (ORPHA:869); they reproduce achalasia and alacrima without the same relationship to adrenal insufficiency [10, 11, 43]. The authors who described the TRAPPC11-associated phenotype estimated that about 30% of undiagnosed patients with triple A symptoms do not have AAAS variants [10].

GMPPA-CDG (alacrima–achalasia–intellectual disability syndrome, AAMR) was described in 2013 in families with a triple A phenotype without AAAS variants [43]. In the 2025 review of 26 patients (23 published and 3 new, the latter from the North American CDG natural history study), alacrima, achalasia and developmental delay were present in all, intellectual disability in 22 with data, most without speech or with few words, and growth failure in 11 of 12 with data [9]. Less frequent were hypotonia (10/21), gait abnormalities (7/17), hypohidrosis (8/24), hearing loss (6/17), postural hypotension (5/17), hyperkeratosis (4/17), microcephaly (3/10), anodontia (2/5) and ocular abnormalities (nystagmus, anisocoria, esotropia) [9]. The digestive symptoms of achalasia were the first manifestation in almost all, sometimes mistaken for food intolerance. No patient had reported adrenal insufficiency, although the publications reviewed did not record ACTH or cortisol values, and none had reported transferrin profile abnormalities [9, 61]. Two sisters homozygous for c.853+1G>A had intellectual disability, epilepsy, dysmorphism and autonomic dysfunction [44]. In a 28-month-old Indian boy born to consanguineous parents, with vomiting since the end of the first year, absent tears since early infancy, global delay, delayed tooth eruption and a “rat-tail” oesophagogram, morning cortisol and ACTH were normal and exome sequencing identified homozygous GMPPA NM_013335.4:c.895del p.(Ala299LeufsTer13); Heller myotomy with Dor fundoplication led to a weight gain of 1 kg in 3 months [62]. Denominators vary by sign, because the figures come from published reports and series rather than from a natural history cohort with uniform assessment.

Disorders related to TRAPPC11 form a spectrum ranging from limb-girdle muscular dystrophy to syndromic congenital muscular dystrophy [45, 47]. In a consanguineous Syrian family, three patients homozygous for NM_021942.6:c.2938G>A p.(Gly980Arg), in the gryzun domain, had limb-girdle muscular dystrophy (LGMD R18, formerly LGMD2S); in five patients of Hutterite descent, the homozygous splice variant c.1287+5G>A, which causes an in-frame deletion of 58 amino acids (p.Ala372_Ser429del) in the foie gras domain, was associated with myopathy, hyperkinetic movements with onset in infancy, ataxia and intellectual disability [34, 45]. In five patients with early-onset muscular dystrophy, all with muscle weakness, motor delay and raised creatine kinase (CK) from the first year of life, cataract, liver disease, intellectual disability, cardiomyopathy, movement disorder and structural brain anomalies also occurred; the neuropathology of one patient showed cerebellar atrophy, granular layer hypoplasia and loss and degeneration of Purkinje cells, without neuronal migration defects [46]. A girl with severe seizures and developmental deterioration, brain, ocular and liver anomalies and raised aminotransferases and CK was compound heterozygous for c.851A>C and c.965+5G>T (nomenclature of the publication), with a severely dystrophic muscle biopsy [47]. The “triple A-like” phenotype was described in four patients from two Turkish families homozygous for c.1893+3A>G (NM_021942.6), with achalasia, alacrima, myopathy with mild dystrophic changes and focal absence of β-sarcoglycan, cerebral atrophy, global delay and scoliosis, LAMP1 hypoglycosylation and delayed trafficking through the Golgi; the abstract of the publication does not mention adrenal insufficiency [10]. Orphanet records three cases for LGMD R18 (ORPHA:369840) and a prevalence below 1 per 1,000,000, a count predating several of the published series [7].

4. Clinical Recognition and Warning Signs

Saudubray recommends considering a CDG in any unexplained clinical presentation, particularly multiorgan disease with neurological involvement, but also when the only sign is non-specific developmental delay; ALG6-CDG illustrates that even mild psychomotor delay without dysmorphism warrants transferrin testing [1].

4.1. Clinical situations warranting glycosylation testing

4.2. Characteristic signs of selected entities

Saudubray lists signs present in at least 50% of patients, in a syndromic context, that guide the gene hypothesis [1].

4.3. Warning signs in PMM2-CDG and emergencies

In infants, the combination of hypotonia, esotropia, inverted nipples and abnormal fat distribution should trigger transferrin testing. In children with delay and hypotonia, GeneReviews adds growth delay, hypothyroidism or hypogonadism, pericardial effusion, seizures, SLE, recurrent infections with poor vaccine response, osteopenia and scoliosis, cerebellar hypoplasia or atrophy with a small brainstem, elevated transaminases, coagulopathy with low factors IX, XI, antithrombin and proteins C and S, and hypoglycaemia; in adolescents or adults, cerebellar dysfunction, non-progressive cognitive impairment, neuropathy, absent sexual development in women or small testes in men, retinitis pigmentosa and myopia, and progressive scoliosis with truncal shortening [3].

Situations requiring urgent assessment include prolonged fever, vomiting or diarrhoea in infants because of reduced physiological reserve; acute neurological deficit, which may be an SLE or a true stroke; dyspnoea or deterioration with feeding in an infant with pericardial effusion because of tamponade risk; asymmetric limb pain or swelling in a patient with limited communication because of deep venous thrombosis risk; and hypoglycaemia [3, 12, 40]. In MPI-CDG, emergencies are hypoglycaemia, gastrointestinal bleeding, thrombosis and enteropathy-related decompensation [7, 18].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal clinical criteria for the group. In PMM2-CDG, diagnosis is established in a proband with suggestive findings and, in most cases, a type 1 transferrin pattern, together with biallelic pathogenic or likely pathogenic PMM2 variants or, if molecular results are uncertain, low PMM2 activity. Two variants of uncertain significance, or one pathogenic and one of uncertain significance, neither establish nor exclude diagnosis [3]. In MPI-CDG, confirmation relies on MPI activity in leukocytes and/or fibroblasts and gene analysis, used together wherever possible because glycosylation tests do not distinguish MPI from PMM2 or other type 1 CDG [7, 18]. The French PNDS (National Diagnosis and Care Protocol) ranks them differently: analysis of MPI in the patient and parents is mandatory, and enzyme activity is reserved for situations of diagnostic difficulty [24]. In most other CDG, diagnosis is molecular, supported by glycosylation biomarkers; in NGLY1 deficiency, diagnosis is exclusively molecular [1, 23].

5.2. Serum transferrin screening

Normal transferrin has two biantennary N-glycans with four terminal sialic acids (tetrasialotransferrin) and small quantities of mono-, di-, tri-, penta- and hexasialo forms. Loss of negatively charged sialic acid causes a cathodal shift on isoelectric focusing (IEF), followed by immunofixation [1, 3, 12].

IEF is qualitative. Carbohydrate-deficient transferrin (CDT) quantification measures total sialic acid-deficient transferrin; it has a non-negligible number of false positives. Whole-serum capillary zone electrophoresis is a rapid screen whose abnormal result should be confirmed by IEF. High-performance liquid chromatography (HPLC) and capillary electrophoresis automate quantification, and tandem mass spectrometry (including ESI-TOF and MALDI-MS) characterises glycan structure and detects subtle processing differences [1, 3, 12]. In PMM2-CDG, quantitative CDT showed an approximately tenfold increase in cathodal forms; half of transferrin loses two or four terminal sialic acids. Abnormal transferrin also exists in the liver and cerebrospinal fluid, and electrophoresis shows low-molecular-weight isoforms of many glycoproteins, including alpha-1-antitrypsin; combining IEF of several glycoproteins (alpha-1-antitrypsin, alpha-1-antichymotrypsin) improves accuracy [12].

The 2025 ACMG technical standard describes current US laboratory practice. IEF was the initial method, but most laboratories now use tandem mass spectrometry, by liquid chromatography with electrospray ionisation (LC-ESI) or MALDI-TOF, after transferrin enrichment on an anti-human transferrin antibody affinity column and matrix clean-up by solid-phase extraction. Because of differences in mass resolution, MALDI-TOF does not detect the small mass differences of some type 2 defects, although its sensitivity for the type 1 pattern is very high. Interpretation relies on species ratios (predominance of the form with two oligosaccharides, or tetrasialo, and a small or absent amount of the form with one oligosaccharide, or disialo), rather than absolute transferrin quantity, which varies considerably; common transferrin sequence variations (formerly “polymorphisms”) alter the profile and should be distinguished from true abnormalities by an experienced interpreter; galactosylation defects, such as TMEM165-CDG and PGM1-CDG, can also be identified through isoform analysis [22].

IEF of apolipoprotein C-III, which has only core 1 mucin-type O-glycans, detects some O-glycosylation defects and combined N/O defects (for example ATP6V0A2-CDG and COG6-CDG) [1, 40]. In the ACMG standard, relative quantification of glycoforms with 0, 1 or 2 sialic acids (apoC-III-0, -1 and -2), expressed as a ratio to apoC-III-2, clarifies the subtype when transferrin shows a type 2 pattern and identifies mixed profiles; it may be multiplexed with transferrin in LC-MS/MS. ApoC-III abnormalities mainly reflect disturbed Golgi homeostasis and trafficking, also affecting N-glycosylation, and therefore detect combined N/O defects; GALNT2-CDG, a mucin-type defect with childhood epilepsy and developmental delay, is specifically detected because apoC-III is a direct GALNT2 target, with a distinct signature (absence of whole O-glycans). Dystroglycanopathies due to O-mannosylation defects, frequently with elevated creatine kinase, may require muscle biopsy to identify the defect [22].

Glycan profiles examine all plasma or serum glycoproteins rather than one protein: N-glycans are released with PNGase F and O-glycans by β-elimination (16 to 24 hours’ incubation), purified, permethylated and analysed by MALDI-TOF (reliable from approximately m/z 600, sufficient for N-glycans); O-glycans require LC-MS/MS quantification (T antigen and apoC-III have clinical use). Low overall intensity of MALDI profiles may miss low-abundance glycans, so the laboratory should define acceptance criteria and, if necessary, repeat plate spotting or analyse replicates. N-glycan profiling qualitatively identifies a tetrasaccharide present in PMM2-CDG, MPI-CDG and ALG1-CDG, useful for suggesting these entities. These profiles are qualitative, have no reference intervals and should be reviewed by a qualified laboratory director [22].

5.3. Screening limitations

Coverage. Transferrin detects only N-glycosylation defects with sialic acid deficiency; normal results do not exclude O-glycosylation CDG, lipid/GPI defects, several multiple pathway disorders or CDDG [1]. The proportion of CDG detectable through transferrin should not be confused with test sensitivity for a specific entity: in PMM2-CDG and MPI-CDG the type 1 pattern is present in almost all symptomatic patients, with the exceptions below, whereas in NGLY1 deficiency transferrin and N- and O-glycan profiles do not detect disease [3, 18, 23]. The 2025 ACMG standard stresses that negative biochemical testing does not exclude CDG: because of defect location and, in some cases, tissue-restricted expression, clinically available tests are often normal even with causal variants. In a small 2016 study cited by the standard, only 7 of 15 patients with confirmed CDG had clearly abnormal clinically available tests and 5 of 15 had all tests normal. The standard states that precise sensitivity and specificity data do not exist, would vary greatly between entities, and that transferrin probably has high sensitivity for entities formerly classified as type 1 CDG [22]. In GMPPA-CDG, a regulatory defect with normal enzyme activity, the transferrin profile showed no abnormalities in the patients reviewed and GeneGuidance considers standard CDG screening unreliable, so a normal result does not rule out the disease and diagnosis is molecular [7, 9, 62].

False negatives. Patients with the PMM2-CDG phenotype and enzyme deficiency but normal transferrin have been described; in adults with mild forms the pattern may be slightly abnormal or almost normal; transferrin spontaneously improves with age in some PMM2-CDG patients, as shown by the US natural history study [3, 32]. In myasthenic DPAGT1-CDG, a type 1 pattern occurs in approximately half of patients; in SLC35A2-CDG, IEF may normalise after the first year [1, 60]. In SLC39A8-CDG, abnormal glycans were found by MALDI-TOF with normal transferrin [20]. In treated MPI-CDG, mannose improves but rarely normalises the profile [7]; the ACMG standard acknowledges that dietary treatment, such as mannose in MPI-CDG, may normalise transferrin and N-glycan profiles, so the laboratory should know whether the patient is treated [22]. The same standard describes PMM2-CDG patients with normal transferrin as uncommon and associated with a small number of causal variants [22].

Age. The 2019 guideline notes that newborns and infants may initially have a normal profile that later becomes abnormal, and that the profile may normalise with age. GeneReviews considers validity before 3 weeks of life questionable; the Atlas cites false positives in the first three months and a recommendation not to test before 3 months, although paradoxically justifying this through prevention of false negatives. The ACMG standard records false-positive and false-negative transferrin results shortly after birth and includes prematurity among false-negative causes [22]. A prudent approach is cautious interpretation of neonatal results, repeat testing after the neonatal period and no delay in molecular testing when clinical findings are suggestive [3, 12].

Sample. Guthrie cards with whole blood are unsuitable; serum applied to a card yields correct results [3]. Contamination with neuraminidase-producing microorganisms and transferrin polymorphisms produce false positives; these are resolved by neuraminidase preincubation, another glycoprotein study or parental transferrin analysis [1, 12, 18]. Fetal serum is unreliable, and fetal glycosylation may be normal [1, 3]. According to the ACMG standard, testing requires no fasting and is unaffected by recent diet; serum, plasma and urine should be frozen immediately after collection and shipped on dry ice, and whole blood for enzyme testing should reach the laboratory as quickly as possible (or isolated frozen leukocytes should be sent). Transfusions, particularly fresh frozen plasma, introduce normal glycans or dilute abnormal ones; as circulating transferrin has an 8 to 10 day half-life, the diagnostic sample should be collected before transfusion or, in transfusion-dependent patients, immediately before the scheduled transfusion, always informing the laboratory. Screening methods using dried blood spots (transferrin and apoC-III) and dried serum spots (transferrin only) have been published but were not clinically available in the United States in 2025 [22].

Specificity. A type 1 pattern also occurs in chronic alcoholism (more than 70 g daily, according to the guideline), untreated galactosaemia and hereditary fructose intolerance, liver disease, severe infections and chronic inflammatory diseases (section 6) [1, 3]. The ACMG standard adds peroxisomal disorders (type 1 pattern and immature glycans resembling PMM2-CDG and MPI-CDG) and haemolytic uraemic syndrome, and summarises each test’s limitations in the following table [22].

The table reproduces Table 2 of the 2025 ACMG standard, describing known limitations without estimating error rates [22].

5.4. Second-line tests

Type 1 pattern. First consider PMM2-CDG or MPI-CDG according to presentation: measure leukocyte PMM and MPI activity. In severe PMM2-CDG, leukocyte and fibroblast activity is typically 0–10% of normal; in a 16-patient series, leukocyte activity was 0.02–0.08 mU/mg protein, versus 1.6–2.3 in controls, and fibroblast activity 0.1–1.4 versus 2.2–6.4. Fibroblasts may yield intermediate or normal values, making leukocytes preferable; with a type 1 pattern and only moderately reduced activity, PMM2 should be sequenced [1, 3, 12]. In MPI-CDG, activity is usually below 10% in leukocytes and fibroblasts, but residual values of 14–21% have been described in severely affected patients; leukocytes should reach the laboratory within 24 hours at room temperature [7, 18]. According to the ACMG standard, confirmatory enzyme analysis is clinically available only for these two entities: both are colorimetric assays in leukocytes or fibroblasts measuring generated NADPH (mannose-1-phosphate as substrate for phosphomannomutase; mannose-6-phosphate for phosphomannose isomerase) and cannot be multiplexed because the measured product is identical. Activity overlaps between heterozygotes and affected individuals for both enzymes, requiring clinical and laboratory correlation, and each laboratory should define affected and heterozygote intervals; running both activities simultaneously helps exclude reductions due to sample handling. Bone marrow transplantation may cause false negatives [22]. Once PMM2 and MPI are excluded, options include fibroblast dolichol-linked oligosaccharide analysis (GlcNAc₂-PP-dolichol accumulation in ALG1-CDG), a CDG gene panel or exome/genome sequencing [1]. In ALG1-CDG, transferrin-linked xeno-tetrasaccharide NeuAc-Gal-GlcNAc₂ was found in all 27 tested patients in one series [54].

Type 2 pattern. Protein-linked glycan analysis (N-glycan mass spectrometry profile), intact transferrin mass spectrometry (for example, hybrid N-glycans in MAN1B1-CDG, hypogalactosylation in PGM1-CDG and SLC39A8-CDG), apoC-III IEF, panel or exome/genome [1, 20]. In SLC39A8-CDG, whole-blood manganese is low and urinary xanthine elevated [20].

MPI-CDG in the French PNDS. Screening is performed on serum, which can be stored at −20 °C after centrifugation, avoiding contamination by neuraminidase-producing microorganisms (pneumococcus, Escherichia coli); an abnormal profile should be repeated on a new sample in an experienced laboratory. Western blot can use blood on a Guthrie card, whereas the PMM2-CDG GeneReviews considers whole blood on a card unsuitable for isoelectric focusing (only serum applied to a card), a difference that depends on the technique (section 5.3). The PNDS (French National Diagnosis and Care Protocol) attributes an analytical sensitivity of 100% in MPI-CDG to the screening techniques; on mannose the profile improves but usually does not normalise, which must be taken into account when interpreting an already treated patient. On isoelectric focusing, the sum of the disialo and asialo fractions gives the CDT percentage, useful for monitoring on mannose: in non-drinkers it ranges from 0.5% to 1.7% and exceeds 1.7% with excessive alcohol intake; in MPI-CDG it is 7–20% in mildly symptomatic or asymptomatic adults and 38–50% in severe forms, and one asymptomatic patient was taken for an alcoholic on the basis of this value. Western blot of transferrin, orosomucoid, alpha-1-antitrypsin and haptoglobin shows additional lower-mass bands, typical of type 1. MPI activity is measured spectrophotometrically, coupling the reaction to the reduction of NADP to NADPH, in nmol/h/mg or mU/mg protein, under standardised conditions (substrate, buffers, temperature) and in a specialised laboratory; parents have intermediate values. In France, enzyme testing and MPI sequencing (Sanger or next-generation sequencing by panel, exome or genome, with informed consent and clinical information) are performed in the reference laboratories for glycosylation disorders of the Hôpital Bichat–Claude Bernard (Paris), the Hospices Civils de Lyon (Bron) and the CHU de Lille [3, 24].

Triple A phenocopies. In GMPPA-CDG, transferrin is normal and the first-line test is molecular; GDP-mannose concentration in lymphoblasts, increased in patients, is a research test with no routine diagnostic use [9, 43, 44]. In TRAPPC11-related disorders, creatine kinase and muscle biopsy, with study of α-dystroglycan and the sarcoglycans, are the supporting investigations before or after the molecular result [7, 10, 46].

Other biomarkers. Elevated alkaline phosphatase and GPI-anchored protein flow cytometry (CD16, CD24) in GPI defects (the ACMG standard notes that cytometry may require a specific request and that neutropenia and transfusions cause false negatives [22]); urinary tetrasaccharide in MOGS-CDG; Bombay phenotype, leukocytosis and neutrophil sialyl-Lewis X (CD15s) expression in SLC35C1 deficiency; plasma and urinary GlcNAc-Asn as a candidate pharmacodynamic marker in NGLY1 deficiency; urinary sorbitol as a PMM2-CDG severity marker [1, 7, 31, 71]. The ACMG standard recommends considering high-resolution urinary oligosaccharide screening (mass spectrometry, developed for lysosomal diseases) as early CDG screening because urine is easy to obtain and characteristic metabolites have been described for some CDG; testing may also help when molecular results are equivocal in an entity with a characteristic profile. In NGLY1 deficiency, previously thought to lack a distinctive biochemical profile, an abnormal urinary oligosaccharide has been discovered, qualifying the 2018 GeneReviews statement that diagnosis is exclusively molecular [22, 23]. The standard considers sorbitol a proposed severity biomarker and potential therapeutic trial marker, and coagulation and liver function tests non-diagnostic but critical for management [22].

5.5. Molecular testing and reporting

In patients with distinctive PMM2-CDG findings, PMM2 sequencing detects more than 99% of known variants in patients with abnormal transferrin or confirmed enzyme deficiency; intragenic deletions/duplications account for less than 1% and require targeted methods (quantitative PCR, MLPA, gene-targeted array) if only one or no variant is found. This value is the proportion of variants detectable by the method, not the clinical sensitivity of the test [3]. When the phenotype is non-specific, exome (or genome) sequencing is preferred; panels vary between laboratories in included genes and copy-number variation detection [3, 20]. The PMM2P1 pseudogene should be considered in assay design [3]. Promoter variant c.-167G>T lies outside coding regions and may escape exomes lacking regulatory region coverage; it should be sought in hyperinsulinaemic hypoglycaemia with polycystic kidneys or when only one coding variant is found [3, 39]. Deep intronic or splice variants may require RNA studies, as in the case in section 10 [40]. In X-linked or mosaic forms (SLC35A2), low-level blood mosaicism may be undetected, and somatic brain variants are absent from blood DNA [7]. Fucose-unresponsive SLC35C1-CDG warrants reopening the genetic investigation [7].

Reports should indicate gene, versioned transcript (for example, NM_000303.3 for PMM2, NM_002435.3 for MPI, NM_013339.4 for ALG6, NM_019109.5 for ALG1, NM_002633.3 for PGM1, NM_018297.4 for NGLY1, NM_001135146.2 for SLC39A8), c. and p. HGVS nomenclature, zygosity, classification under the five-class ACMG/AMP rules and technical limitations; variant phase should be confirmed in parents. Literature uses historical names (R141H, F119L) and sometimes older transcripts (NM_000303.2); both should be indicated when used by the source [3, 8, 35]. A variant of uncertain significance does not become pathogenic through treatment response or partial segregation; functional confirmation (enzyme activity, glycomics, RNA) is a reclassification tool interpreted under ACMG/AMP rules [3]. The 2025 ACMG standard observes that enzyme and metabolic findings are increasingly used to confirm uncertain or equivocal sequencing results and requests that available molecular results be sent to the biochemical laboratory for integrated interpretation. Biochemical reports should be interpreted by a certified biochemical geneticist or equivalent, compare quantitative values with age- and sample-appropriate reference intervals, describe qualitative abnormalities using standardised language, use gene-based nomenclature (allowing common names for frequent CDG or when citing older literature), indicate next steps (molecular testing, family studies, further biochemical investigations or consultations) and state assay limitations [22].

5.6. Practical algorithm

The algorithm summarises local sources, GeneReviews and the guideline; the guideline also recommends collecting outside acute illness, fever, infection or malnutrition, storing serum or heparinised plasma at −20 °C and repeating an abnormal profile in another sample at an experienced laboratory (grade D) [1, 3, 12, 17]. The 2025 ACMG technical standard does not propose a fixed algorithm: it considers that testing timing and order are changing, with molecular and biochemical testing used first- or second-line according to clinical findings, urgency and insurance coverage, and that many glycosylation defects identified by exome or genome are biochemically undetectable. It nevertheless maintains that in an infant with classical PMM2-CDG, transferrin isoform analysis is a good first step, that most N-glycosylation CDG are identified by this analysis, that CDG should be excluded in any unexplained presentation, particularly multisystem disease, and that biochemical testing is necessary both to establish diagnosis alongside molecular testing and to monitor therapies improving glycosylation, adjust doses and avoid dose-dependent adverse effects. For laboratories, all CDG screening assays are laboratory-developed tests requiring validation; each run should include two quality controls (normal and abnormal), unavailable commercially; laboratories should participate in external quality assessment where available (a qualitative European carbohydrate-deficient transferrin programme exists) or maintain internal programmes through sample exchange; and establish their own age-appropriate reference intervals. The document is a voluntary laboratory technical standard, developed through literature review and expert opinion without formal evidence grades [22].

6. Differential Diagnosis

Differential diagnosis has three levels: other causes of abnormal transferrin patterns (secondary glycosylation abnormalities), diseases with overlapping phenotypes before testing, and differentials of isolated signs. The first task with an abnormal pattern is to exclude secondary causes, because a type 1 pattern is not specific to CDG [1, 3, 12].

6.1. Secondary glycosylation abnormalities and false positives

6.2. Clinical differential of PMM2-CDG

Before MRI, the differential in an infant with hypotonia, delay and growth faltering includes other CDG and CDDG (more than 175 genes), sometimes indistinguishable, but only PMM2-CDG has reduced PMM2 activity; mitochondrial disorders (more than 300 genes), sharing multisystem involvement, pigmentary retinopathy and movement disorder, but usually with metabolic decompensation and acidaemia, absent in PMM2-CDG; peroxisome biogenesis defects (more than 20 genes), with abnormal very-long-chain fatty acids; and urea cycle disorders and organic acidurias, with decompensation and hyperammonaemia [3].

For congenital cerebellar hypoplasia, Oxford adds Joubert syndrome (molar tooth sign), cerebro-oculo-renal syndromes, Leber congenital amaurosis, lissencephaly with cerebellar hypoplasia (tubulinopathies, RELN), dystroglycanopathies (Walker–Warburg, muscle–eye–brain disease), pontocerebellar hypoplasias (for example VRK1), CASK-related microcephaly with pontocerebellar hypoplasia in females, non-progressive ataxia with disequilibrium (VLDLR), SNX14 and PIGT with macrocephaly, Gillespie syndrome (ITPR1, partial aniridia) and respiratory chain disorders [31].

6.3. Differential of isolated signs

6.4. Achalasia and alacrima: triple A syndrome and CDG phenocopies

In a child with achalasia and alacrima, assessment of adrenal function separates triple A syndrome from the CDG phenocopies; normal adrenal function avoids unnecessary lifelong corticosteroid therapy, and GeneGuidance recommends assessing it at least once in all patients with GMPPA-CDG [7, 9, 62]. Intellectual disability is present in almost all patients with GMPPA-CDG, and myopathy with raised CK points to TRAPPC11 [9, 10]. In GMPPA-CDG, intellectual disability begins in the first year, whereas in triple A syndrome cognitive impairment, when present, is mild and of later onset; GeneGuidance considers standard CDG screening unreliable in this entity, so clinical suspicion leads directly to molecular testing [7, 9, 72]. The X-linked form recorded in Orphanet (ORPHA:289483), with no gene identified, enters the differential diagnosis of a boy with severe intellectual disability, speech delay, alacrima and achalasia and a compatible pedigree [73].

6.5. Differential diagnosis of MPI-CDG by presenting feature

The French PNDS (National Diagnosis and Care Protocol) organises the differential diagnosis of MPI-CDG by the manifestation prompting consultation; in every row, MPI-CDG is the treatable hypothesis that the transferrin profile can screen for [24].

7. Treatments and Risk Management Strategies

7.1. General principles and evidence hierarchy

For most CDG there is no disease-modifying treatment; management is symptomatic, multidisciplinary and guided by organ surveillance. Exceptions with targeted therapy are few and rely on case series and grade D consensus recommendations (expert opinion, SIGN methodology), rather than randomised trials: D-mannose in MPI-CDG, D-galactose in PGM1-CDG, manganese with galactose in SLC39A8-CDG, L-fucose in some SLC35C1-CDG patients and acetylcholinesterase inhibitors in myasthenic syndromes [1, 7, 18–20]. In October 2026, no disease-modifying therapy was approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for any CDG, and most interventions were off-label, experimental or supported by limited observational evidence [21, 74]. The article therefore distinguishes five levels: guideline recommendation, peer-reviewed publication, company announcement or preliminary results, regulatory designation (orphan, rare paediatric disease, fast track) and marketing authorisation, which no product has obtained for CDG.

7.2. PMM2-CDG: management by system

The 2019 international guideline (54 authors, systematic review to December 2017, SIGN levels) and 2021 GeneReviews agree on essentials; GeneReviews summarises the guideline recommendations [3, 17]. The table integrates both and indicates divergences.

Publications after the guideline added haematological and cardiac management data. In a prospective 50-patient cohort, antithrombin was abnormal in 83.3% (40/48) and below 50% in 62.5%; spontaneous bleeding occurred in 16% and thrombosis in 10%, always with infection; authors advise caution when antithrombin is below 65% and prophylactic anticoagulation only with a thrombotic history or oestrogen exposure [75]. In a French series of 13 patients with 31 acute episodes (27 cerebral: 7 SLE, 4 venous thromboses, 4 haemorrhages and 15 “stroke mimics”), factor XI, antithrombin and protein C fell during episodes, and the authors propose that diffusion and perfusion MRI, electroencephalography and haemostasis guide choice between anticoagulation, antithrombin concentrate, plasma or antiepileptics [76]. For the heart, the guideline recommends annual or more frequent assessment; the FCDGC consortium, with 17 cardiomyopathy cases among 305 CDG patients (10 with PMM2-CDG, all hypertrophic), proposes echocardiography and electrocardiography at diagnosis, annually for the first 5 years, then every 2–3 years until adulthood and then every 5 years; the European 222-patient series, in which 10 of 44 patients with cardiac involvement developed it after diagnosis, proposes annual childhood and biennial adult assessment [17, 37, 77]. Given the divergence, the more protective option is annual assessment during childhood and reassessment of adult intervals, particularly in p.Val231Met carriers.

7.3. Targeted therapies by entity

The 2025 ACMG standard adds that fresh frozen plasma and/or protein C concentrate have been used in several CDG to prevent bleeding and improve capillary leakage and oedema, particularly during infections, that substantial mortality occurs in the first years from severe infection or vital organ failure, and that glycosylation-targeted therapies require reliable reproducible biochemical testing for monitoring, dose adjustment and prevention of dose-dependent adverse effects; it also recalls that mannose in MPI-CDG does not necessarily halt liver disease progression [22]. Mannose and galactose doses appear in no FDA or EMA label with a CDG indication; their use rests on the cited consensuses and involves preparations without authorisation for this indication, to be decided by specialist centres [18, 19, 21]. The MPI-CDG consensus states that mannose treatment “was approved in the United States and Europe”, citing a review; primary regulatory sources show only FDA designations (orphan drug in January 2019 and fast track in August 2019 for D-mannose CERC-802), so this sentence should not be read as marketing authorisation [18, 84].

In MPI-CDG, liver transplantation was undertaken in a patient with hepatopulmonary syndrome due to portal hypertension: clinical condition, pulmonary function, coagulation and transferrin pattern improved, but MPI activity and non-hepatic protein glycosylation remained deficient; transplantation may be necessary in selected cases and does not correct the underlying defect [7, 18]. In the French nine-patient series diagnosed at a median 3 months, the only death occurred in the untreated patient at 2 years; the eight treated patients, with median follow-up of 14 years 9 months, confirmed efficacy and safety, but also persistent fibrosis, portal hypertension, venous thrombosis and impaired renal function in adulthood [7, 52]. In CCDC115-CDG, one patient was successfully treated with liver transplantation [1].

7.4. PMM2-CDG: investigational therapies

Mannose. It corrects glycosylation in fibroblasts but has not demonstrated clinical benefit in patients; spontaneous age-related transferrin improvement documented in natural history argues against attributing biomarker normalisation to supplements without a control group [1, 32].

Acetazolamide. The AZATAX trial (Spain) included 24 patients with mean age 12.3 ± 4.5 years, with a 6-month open-label phase followed by 5-week randomised withdrawal. There were no serious adverse events; 13 patients required dose adjustment for low bicarbonate or asthenia. The International Cooperative Ataxia Rating Scale (ICARS) improved from 40.7 ± 24.8 to 34.9 ± 23.2 (p < 0.001), the Nijmegen Pediatric CDG Rating Scale (NPCRS) and syllable repetition test also improved, and withdrawal worsened ICARS; prothrombin time, factor X and antithrombin improved [85]. The US randomised, placebo-controlled, quadruple-blinded trial (NCT04679389, 25 patients, terminated for lack of funding) did not confirm the effect: change in mini-ICARS at 6 months was 1.64 (SD 3.20) with acetazolamide and 1.36 (SD 3.23) with placebo (11 patients per group; p = 0.84); NPCRS p = 0.09; serious adverse events in 1 of 13 acetazolamide patients and 3 of 12 placebo patients [86]. In the FCDGC cohort, off-label acetazolamide improved verbal fluency without statistically significant improvement in objective ataxia scales [50]. The 2019 guideline does not mention acetazolamide [17]. Acetazolamide is used off-label in PMM2-CDG; the AZATAX dose was not read in the full text and is not reproduced. In the absence of a labelled dose for ataxia and of a dose read from the guideline, the label for an analogous indication with the same drug is used: the Portuguese SmPC of Carbinib® (acetazolamide 250 mg) indicates, for epilepsy, 8–30 mg/kg/day in divided doses in children, not exceeding 750 mg/day, and 250–1,000 mg/day in adults; its application to PMM2-CDG is an extrapolation [87].

Epalrestat. An aldose reductase inhibitor authorised in Japan for diabetic neuropathy, proposed for repurposing after increased PMM2 activity in cellular and model-organism systems; urinary sorbitol was proposed as a severity biomarker [71, 88]. The single-centre randomised, placebo-controlled phase 3 trial (NCT04925960; 42 patients aged 2 to 17 years; primary outcomes: sorbitol, ICARS and antithrombin at 9 months) was terminated for futility, with primary completion in February 2025; no published results were found [89]. Epalrestat has no authorisation in the USA or EU.

GLM101 (liposomal mannose-1-phosphate). Substrate replacement therapy by weekly intravenous infusion, designed to deliver the deficient reaction’s product. In the open-label phase 2 study (NCT05549219; 27 patients aged 2 to 65 years, doses of 10, 20 or 30 mg/kg weekly for 24 weeks), 2026 data were published for three adults receiving 30 mg/kg: baseline ICARS 50.7 (SD 19.0), with changes of −14.0 (7.2) at 12 weeks and −17.7 (3.1) at 24 weeks, no serious adverse events and one infusion reaction; ICARS was an exploratory outcome assessed outside the protocol schedule, without a control group, and two authors are sponsor employees [74, 90]. The randomised, placebo-controlled phase 2b POLAR trial (NCT06892288) completed recruitment in April 2026 with 43 patients aged 4 to 47 years at 15 centres in the USA, United Kingdom and Europe; the primary outcome is ICARS at 24 weeks, and the sponsor announced top-line results for the fourth quarter of 2026 [91, 92].

7.5. Regulatory status

Orphan drug designation is not authorisation, and authorisation would not guarantee reimbursement or access in each country; no INFARMED, ANVISA or CONITEC decisions for CDG products were identified in the sources consulted.

7.6. Trials and developments in the last 12 months

Between October 2025 and October 2026, developments included publication of the first peer-reviewed GLM101 data (September 2026, three adults, open-label study) [74]; completion of recruitment to the controlled POLAR trial (April 2026, sponsor announcement) [92]; presentation of interim GS-100 data at the American Society of Gene and Cell Therapy meeting (May 2026): seven patients in four cohorts, dose-dependent adverse events (18%, 26% and 56%), thrombotic microangiopathy in two patients and grade 3 thrombocytopenia at the highest dose, which was abandoned, and reported motor and interaction improvements, still without peer-reviewed publication [95]; GS-100 RMAT designation (2026) [95]; update of the epalrestat trial registry as terminated for futility [89]; two MPI-CDG pregnancy reports [99, 100]; and the “state of the art 2026” review, adding RPN1-CDG, UGGT1-CDG and DHRSX-CDG and confirming absence of approved therapy [21]. Preclinically, AAV9-NGLY1 gene therapy suppressed non-epileptic seizures in Ngly1-deficient rats [101]. In ClinicalTrials.gov searches on 27 and 28 October 2026 (terms “GMPPA”, “TRAPPC11”, “LGMD R18”, “alacrima”, “triple A syndrome”, “Allgrove” and “AAAS”), no interventional trial appeared for GMPPA-CDG or for TRAPPC11-related disorders; the latter are included in two recruiting observational studies, the clinical trial readiness study in dystroglycanopathies (NCT00313677, since 2006) and the Cure CMD patient-reported outcome registry for congenital muscle disease (NCT01403402, since 2009) [102, 103]. The only treatment data for GMPPA-CDG are the open-label N-acetylglucosamine series in 3 patients (section 7.3) [9].

Interpretive limitations. GLM101 results come from three uncontrolled patients, with the outcome assessed outside the schedule and sponsor authors; ICARS improvement cannot be compared with AZATAX because populations, age, scale (ICARS versus mini-ICARS) and design differ. The randomised acetazolamide trial was negative, contrasting with open-label AZATAX with withdrawal and recalling that PMM2-CDG ataxia is largely non-progressive and subject to expectancy effects; the controlled trial was stopped for funding and has limited power. The epalrestat trial was terminated for futility without published results. GS-100 data are conference results from a single-arm study.

7.7. Special populations and circumstances

Fever, dehydration and anaesthesia. Fever worsens residual glycosylation and precipitates SLE and seizures; early antipyretics and hydration are recommended, particularly during anaesthesia and surgery [12, 20, 50]. Preanaesthetic assessment should include haemostasis and, in PGM1-CDG, malignant hyperthermia risk and pseudocholinesterase [17, 19]. Malignant hyperthermia has been described in COG7-CDG [1]. In NGLY1 deficiency and COG6-CDG, hypohidrosis requires avoidance of hot environments [1, 23]. In MPI-CDG, the PNDS (French National Diagnosis and Care Protocol) asks that mannose not be interrupted, or be interrupted for the shortest possible time, during perioperative fasting, gastroenteritis or other digestive illnesses, with a continuous glucose infusion to keep blood glucose above 4 mmol/L; full haemostasis testing (prothrombin time, fibrinogen, antithrombin, factor XI, proteins C and S) is performed before surgery and repeated postoperatively if abnormal, with fresh frozen plasma or antithrombin if indicated, and postoperative thromboprophylaxis follows the rules for the general population, ideally discussed with haematology. During fever, mannose is continued to limit coagulopathy; coagulation studies are requested only if there are signs of thrombosis, and hypogammaglobulinaemia due to enteropathy should be considered in the presence of fever. The vaccination schedule is the general one, with additional vaccination against hepatitis A and B and checking of the response in protein-losing enteropathy; alcohol abstinence is recommended for adolescents and adults, and hepatotoxic drugs or drugs increasing bleeding risk, such as acetylsalicylic acid and non-steroidal anti-inflammatory drugs, are avoided [24].

Children and off-label use. No targeted intervention has a CDG label; diazoxide and levothyroxine are labelled for hyperinsulinaemic hypoglycaemia and hypothyroidism, respectively, and their use in CDG follows those general indications; acetazolamide, mannose, galactose, manganese and fucose are used off-label or as preparations without authorisation for the indication [17–20].

Pregnancy. See section 8.4: in MPI-CDG, consensus recommends caution with mannose in pregnancy because of embryonic toxicity in mouse models, although no human embryonic lethality has been reported, and contraindicates diazoxide [18, 99, 100].

Transition. The PMM2-CDG guideline has no transition section; it recommends preparation for independent living, and GeneReviews adds functional and vocational education, independence and successor carer planning [3, 17]. For MPI-CDG, the PNDS applies the general transition recommendations of the G2M filière: explain the concept of transfer at around 12 years of age and progressively introduce consultations without the parents; a transition plan drawn up by the paediatric team; joint consultations of the paediatric and adult teams; transfer when the situation has been stable for one year (no rapidly evolving complication or major adherence problem); shared case review meetings and therapeutic education programmes [24].

Therapeutic education. In MPI-CDG, therapeutic education is addressed first to the parents and then to the patient, with age-appropriate tools and particular attention to adolescents, whose adherence may fail. It covers the course of the disease with and without treatment, its genetic nature and the need for lifelong follow-up, and the mechanism of the enzyme deficiency, and emphasises four points: the importance of mannose; liver disease and portal hypertension, which may progress despite treatment (contraindication of non-steroidal anti-inflammatory drugs, regular surveillance, risk of gastrointestinal bleeding); the risks of stopping treatment (thrombosis, recurrence of hypoglycaemia and digestive disease); and what to do in the event of pregnancy [24].

7.8. MPI-CDG: the 2022 French PNDS and its differences from the international consensus

The HAS PNDS (French National Diagnosis and Care Protocol) for MPI-CDG (August 2022, published on 9 September 2022) was written by the G2M and Filfoie filières, with the FIRENDO and MHEMO networks, general practitioners and patient associations, following the 2012 HAS method; it follows the lines of the 2020 international consensus, in which several of its authors took part, and differs mainly in the detail of liver management [18, 24].

Initial assessment and mannose. Before starting mannose, all organs are assessed with the surveillance investigations (section 11.3). The starting dose is 150–170 mg/kg per dose every 4–6 hours, which the PNDS equates to 0.5–0.75 g/kg/day; once a steady state is reached, 3–5 doses per day are sufficient. In adults, 12–20 g per day is probably sufficient, adjusted according to digestive tolerance. The dose is adjusted according to clinical status, haemostasis, the transferrin profile, which also informs on adherence, and, where possible, residual blood mannose, always measured in the same specialised laboratory. Efficacy has been described in more than 30 patients over more than 20 years: clinical response appears in about one week, biochemical correction takes weeks to months, the diarrhoea, vomiting and hypoalbuminaemia of the enteropathy are corrected, villous atrophy normalised in follow-up biopsies, and hepatic fibrosis does not regress. No thrombosis has been described in treated patients, but thromboses occurred after discontinuation, including, in unpublished data from the French group, death from pulmonary embolism in a patient who stopped treatment; the PNDS therefore maintains mannose for life, contrary to the earlier suggestion that it could be discontinued [24].

Adverse effects and adherence. Abdominal pain and diarrhoea occur with overdosage, but also with underdosage or poor adherence, and resolve with adjustment. Renal toxicity of mannose has been suggested; it is very rare with current experience and cannot be distinguished from the course of the disease. Raised plasma mannose may increase HbA1c, which has been proposed for detecting overdosage. Intravenous mannose, unavailable in France, may cause haemolysis and hepatic and neurological complications. Poor adherence is suspected in the presence of digestive symptoms with an abnormal transferrin profile and low residual mannose; without measurement, the return of abdominal pain or diarrhoea leads to an increase in dose [24].

Availability in France. On 20 July 2022 there was no mannose medicinal product in France (marketing authorisation, compassionate access or early access). Treatment is a magistral preparation made by the community pharmacy, or sometimes the hospital pharmacy, from pharmaceutical-grade raw material, and the prescription must state that it is a therapeutic prescription in the absence of an equivalent medicinal product, to be reimbursed under ALD 17. This is consistent with the absence of FDA or EMA authorisation (section 7.5) [24, 84].

Hypoglycaemia. Mannose is the preferred treatment and abolishes hypoglycaemia. During a crisis, oral or intravenous glucose targets 4–6 mmol/L. In hyperinsulinism, diazoxide is started only after echocardiography has excluded pulmonary arterial hypertension; the PNDS dose is 5–15 mg/kg/day in three doses in the text and 10–15 mg/kg/day in the summary table, versus 4–15 mg/kg/day in the 2020 consensus, which remains the reference dose of section 7.3; diazoxide is contraindicated in pregnancy. When necessary, frequent meals and complex carbohydrates are added [18, 24].

Thrombosis and bleeding. Mannose usually corrects haemostasis. In thrombosis, anticoagulation uses unfractionated or low-molecular-weight heparin, with transition to a vitamin K antagonist, according to the general venous thromboembolism guidelines, after confirming the absence of threatening oesophageal varices and with caution in portal hypertensive gastropathy. The PNDS gives no doses: in adults, the enoxaparin sodium label (Lovenox®, FDA label) indicates 1 mg/kg every 12 hours subcutaneously, or 1.5 mg/kg once daily in inpatients, an extrapolation from venous thromboembolism in general; the label does not establish safety or efficacy in paediatric patients, so in children the dose is decided by the haemostasis centre. In bleeding, local haemostatic measures are used and, if factors are very low, fresh frozen plasma; factor XI concentrate and recombinant activated factor VII are not recommended, because of thrombotic risk. In surgery, prophylactic plasma may be used if antithrombin and/or factor XI are very low, and antithrombin concentrate after haematology or haemostasis advice [24, 104].

Protein-losing enteropathy. Mannose is the most effective treatment. Portal hypertension may make the enteropathy resistant to mannose, a situation that may require a low-fat diet, bowel rest and parenteral nutrition. With albumin below 20 g/L (the same 2 g/dL threshold as in the consensus) and oedema, intravenous 20% albumin solution is indicated, also because hypoalbuminaemia increases thrombotic risk. Hypogammaglobulinaemia due to intestinal loss requires regular intravenous or subcutaneous immunoglobulin; the PNDS gives no dose, and the 10% intravenous immunoglobulin label (Privigen®, FDA label) indicates, in primary immunodeficiency, 200–800 mg/kg every 3–4 weeks, an extrapolation to secondary hypogammaglobulinaemia adjusted to the IgG level. Heparin, as experimental treatment of severe enteropathy in a patient who refused mannose, had a convincing effect on symptoms, but carries bleeding risk with coagulopathy, portal hypertension or varices [18, 24, 105].

Portal hypertension. Management is that of any portal hypertension, by a specialised team. Acetylsalicylic acid and non-steroidal anti-inflammatory drugs are contraindicated in all patients, because of the high risk of portal hypertension. In adults, endoscopic signs of portal hypertension lead to proposing a prophylactic non-selective beta-blocker, whose efficacy is not validated in children; the Portuguese SmPC of propranolol (Inderal®) indicates, in adults with portal hypertension or oesophageal varices, 80–320 mg/day in divided doses, an extrapolation from portal hypertension in general. Ulcers are treated with proton pump inhibitors, and testing for Helicobacter pylori is systematic. Bleeding risk is assessed at endoscopy by variceal grade, subcardial extension and red signs; with high risk, prophylaxis by band ligation is performed according to age, and without it annual endoscopy. Gastric varices and gastric antral vascular ectasia are rarely amenable to endoscopic prophylaxis. Acute bleeding is treated in a specialised intermediate or intensive care unit, without disease-specific features; in bleeding recurring despite well-conducted prophylaxis, surgical portosystemic shunting (mesocaval or splenorenal), transjugular intrahepatic portosystemic shunt (TIPS) or liver transplantation are discussed. Several patients have undergone transplantation for complications of portal hypertension, but only one case had been published [24, 106].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risk

PMM2-CDG and most CDG are autosomal recessive. Parents are usually asymptomatic heterozygotes; rigorous counselling requires testing both. If only one parent is a carrier and the child appears homozygous, an untested deletion on one allele or chromosome 16 uniparental isodisomy should be considered; if the child is compound heterozygous, one variant may be de novo [3]. The theoretical risk for each sibling is 25% affected, 50% carrier and 25% inheriting neither variant; however, in PMM2-CDG, prenatal diagnosis results in at-risk pregnancies show an affected fetal proportion closer to 1/3 because of transmission distortion, a confirmed finding [3]. Absence of R141H/R141H homozygotes, incompatible with life, also produces deviation from Hardy–Weinberg equilibrium in the population [12, 13]. The 2019 guideline mentions the hypothesis that the approximately 1/72 R141H allele frequency in the Netherlands and Denmark reflects heterozygote advantage, with possible resistance to hepatitis B and C viruses, an unproven hypothesis [17]. If the patient results from uniparental isodisomy with only one carrier parent, sibling risk does not exceed population risk [3]. Adults with PMM2-CDG are not known to reproduce; parental siblings have a 50% chance of being carriers [3].

In X-linked forms (PIGA-CDG, SLC35A2-CDG, ALG13-CDG, SSR4-CDG), counselling depends on the proband’s sex, maternal status and possible de novo variants and mosaicism; in SLC35A2-CDG, de novo variants in girls predominate [7, 60]. For multiple osteochondromas (EXT1/EXT2) and de novo DHDDS variants, the dominant model applies [1, 7]. In MPI-CDG, enzyme activity does not identify carriers: tested parents had values between 30% and 83% of normal (median 50%), overlapping normal values, so heterozygote detection should rely on familial variants [7, 18].

GMPPA-CDG and TRAPPC11-related disorders follow the autosomal recessive model, with a 25% risk for each sibling when both parents are heterozygous and a two-thirds probability of being a carrier for an unaffected sibling; in a consanguineous family or in a population with a founder variant, such as GMPPA c.265dup in the Maya-Mam community of Guatemala or TRAPPC11 c.1287+5G>A in the Hutterites, the probability that a partner is a carrier is higher than in the general population [9, 10, 45, 61]. In the X-linked form of ORPHA:289483 the risk follows X-linked recessive inheritance, but the absence of an identified gene precludes carrier testing and molecular prenatal diagnosis [73].

8.2. Carrier testing, prenatal diagnosis and preimplantation testing

Carrier testing in at-risk relatives requires prior identification of both familial variants; biochemical heterozygote detection is unreliable [3, 12]. Three common European variants (p.Arg141His, p.Phe119Leu, p.Val231Met, to which GeneReviews adds p.Pro113Leu) may be included in carrier screening panels [3]. In an empirical study of 23,453 individuals, CDG-Ia carrier frequency was 1 in 135.4 (95% CI 1/86–1/328) in the Hispanic population (1,625 tested); neither ACMG nor the American College of Obstetricians and Gynecologists then recommended offering such screening to this population [107, 108].

Prenatal diagnosis and preimplantation genetic testing are possible when both familial variants are identified; the ideal time to discuss risk and options is before pregnancy, and counselling should be offered to young adults at risk of being carriers [3]. The 2019 guideline prefers first-trimester molecular testing when parental variants are known; enzyme activity can be measured in cultured amniocytes, but not chorionic villi [17]. Prenatal diagnosis cannot rely on glycosylation tests: fetal glycosylation is normal or unreliable (normal in a 19-week fetus and in fetal studies), and PMM2 activity may be falsely low in poorly growing amniocytes or chorionic villi [1, 3, 12]. In non-immune fetal hydrops without a known family, molecular PMM2 testing should be considered [3]. In cerebellar hypoplasia, early ultrasound diagnosis is unreliable, and detailed ultrasound in a subsequent pregnancy should be offered with that limitation explained [31]. In probands without molecular diagnosis, DNA banking is recommended [3]. Considering prenatal and preimplantation diagnosis is a personal family decision that may benefit from discussion [3]. In MPI-CDG, the PNDS (French National Diagnosis and Care Protocol) makes prenatal diagnosis conditional on identification of both variants and confirmation that both parents are heterozygous, with genetic counselling; a request for termination of pregnancy requires discussion in a multidisciplinary prenatal diagnosis centre, and psychological support is important, especially when the diagnosis is disclosed. The PNDS describes no prenatal manifestations of the disease [24].

8.3. At-risk relatives and newborn screening

At-risk newborns should undergo molecular testing for familial PMM2 variants [3]. In SLC39A8-CDG, all at-risk siblings of any age should be tested so manganese and galactose can begin as early as possible [20]; the same reasoning applies even more strongly to treatable MPI-CDG [18]. PMM2-CDG newborn screening has not been implemented successfully: altered TBG could be detected by hypothyroidism screening, but this has not occurred consistently; transferrin can be studied in serum applied to a Guthrie card, but not whole blood [3, 12].

8.4. Pregnancy in a patient with CDG

Experience is limited to MPI-CDG. The 2020 consensus contraindicates diazoxide in pregnancy and recommends caution with mannose (and mannose-containing antibiotics), because prenatal mannose accelerated embryonic death in MPI-null mice and caused ocular defects in mice with residual activity, although human embryonic lethality has not been reported; two women had experienced normal pregnancies [7, 18]. In a French report, D-mannose was stopped at 6 weeks’ gestation because of potential toxicity observed mainly in animal models; severe digestive symptoms and hypoglycaemia recurred, and mannose was reintroduced at 10 weeks, with gradual increases guided by transferrin and coagulation; delivery occurred at 38 weeks following intrauterine growth restriction, with a 2,390 g newborn who rapidly caught up [99]. In a 2026 British report, a woman with MPI-CDG and irregular adherence in adulthood, with hepatic fibrosis, protein-losing enteropathy and osteoporosis, had two pregnancies without mannose: the first with anaemia, hypoalbuminaemia, intrahepatic cholestasis of pregnancy and emergency caesarean delivery, followed by progression to cirrhosis; the second with fewer complications [100]. These two reports show that pregnancy is possible but do not establish fetal mannose safety; the decision is individual, multidisciplinary and outside any label [99, 100].

The 2022 French PNDS (National Diagnosis and Care Protocol) summarises the evidence preceding these reports. In a mouse with residual MPI activity comparable to that of patients, oral mannose given to pregnant females caused ocular anomalies in 45% of the offspring (opacities, retinal disorganisation, small optic cup, absent lens, haemorrhage), attributed to mannose-6-phosphate accumulation; in pregnant rats, mannose increased neural tube defects, and toxicity has been described in bees. There are no human data, and extrapolation of the animal data is not possible. Six pregnancies had been published: three in the same woman, without complications and without information on mannose; two in an almost asymptomatic patient, without mannose; and one in which mannose was stopped at 8 weeks of gestation, in a patient with a history of thrombosis, on heparin, without maternal, obstetric or fetal complications. Some teams propose stopping mannose during pregnancy, which makes prevention of thrombosis and hypoglycaemia central [24].

The PNDS recommends a preconception consultation with an obstetrician, a haemostasis specialist, a hepatologist, an endocrinologist and a metabolic specialist, to estimate maternal and fetal risk from the thrombotic and bleeding history, the hypoglycaemic tendency in adulthood, fibrosis and portal hypertension, and nutritional deficiencies. The transferrin profile and antithrombin at the start of pregnancy guide the decision to anticoagulate, at a prophylactic or therapeutic dose, to be discussed at a regional or national multidisciplinary haemostasis meeting, as are the mode of delivery and the postpartum period. Hepatic fibrosis does not contraindicate pregnancy, but hypervolaemia increases the risk of variceal bleeding, so upper endoscopy early in pregnancy is discussed in patients with portal hypertension, together with oximetry and echocardiography. The insulin resistance of pregnancy, which fibrosis may aggravate, and the risk of hypoglycaemia if mannose is stopped justify targeted glycaemic surveillance. The surveillance in the PNDS annex includes: haemostasis (antithrombin, proteins C and S, factor XI, fibrinogen, prothrombin time, activated partial thromboplastin time), with lower-limb venous Doppler according to the team; blood glucose and insulin after a 12-hour fast and 2 hours after a meal, continuous interstitial glucose monitoring for 7 days in each trimester, an oral glucose tolerance test at 24–28 weeks of gestation and capillary self-monitoring if the targets (fasting between 0.70 and 0.95 g/L; postprandial below 1.20 g/L) are not achieved; liver tests with factor V in each trimester; liver ultrasound with Doppler and elastography; nutritional assessment (albumin, prealbumin, ferritin, vitamins B1, B6, B12, C, D, A and E, folate, zinc, selenium), with parenteral supplementation if oral supplementation does not correct the deficiency; TSH and free T4; renal ultrasound, glomerular filtration rate and urinary albumin/creatinine ratio [24].

Contraception in MPI-CDG. Oestrogens are contraindicated, whether or not there is a history of thrombosis, because of the vascular risk and the liver disease, in accordance with French contraception recommendations; the case in section 10.2 illustrates the risk. Oral or subcutaneous implant progestogens, the copper or levonorgestrel intrauterine device, barrier methods and spermicides are possible, with an individual decision on the intrauterine device if there is a history of gynaecological bleeding [24].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What available numbers measure

CDG frequency estimates derive from sources with different meanings and should not be mixed: published case counts (numerators without denominators), observed national registry prevalences, birth prevalence estimates calculated from allele frequencies, and Orphanet prevalence classes. PMM2-CDG is the only CDG with reasonable population estimates; for the others, mainly case counts exist, with probable underdiagnosis because of dependence on genomic sequencing [7, 16].

The gnomAD-based study notes its own limitations: it included lethal R141H homozygotes, did not manually curate variants and obtained expected prevalences higher than observed; in Estonia, including or excluding R141H homozygosity changed the estimate from 1:77,000 to 1:62,000 [16]. The difference between expected and observed may reflect underdiagnosis, fetal lethality (consistent with transmission distortion) or imperfect variant classification [3, 16].

9.2. Founder effects and regional variants

p.Phe119Leu has a Scandinavian founder effect; pan-European p.Arg141His derives from a single ancient mutational event [12]. p.Leu32Arg is frequent in Italy, where a national survey of 37 patients (1996–2012) showed that 70% of the 17 mildly affected patients carried it, with independent walking in 82% and borderline to mild intellectual disability in 64% [38]. p.Val231Met predominates in Eastern Europe, with a suggested founder effect, and is the most common Turkish variant [15, 37]. In France, p.Arg141His was present in half of 96 patients, with 45 other variants [49]. In other CDG: MPI-CDG in Saguenay–Lac-Saint-Jean (Quebec) [1]; SLC39A8-CDG with founder variant c.112G>C p.(Gly38Arg) (NM_001135146.2, MANE Select; NM_022154.5 in GeneReviews; VCV000218895) in North American Hutterites [20, 35]; SLC35C1-CDG with a founder variant in Israeli Arabs [7]; DHDDS p.Lys42Glu in Ashkenazi Jews, accounting for 33% of families with an identified genetic cause in a retinitis pigmentosa cohort [7]; B4GALT7 on Reunion Island; GALNT3 in Middle Eastern and African patients [1]. GMPPA NM_013335.4:c.265dup p.(Leu89ProfsTer28) is a founder variant in the Maya-Mam population of Concepción Chiquirichapa (Quetzaltenango, Guatemala), and TRAPPC11 c.1287+5G>A has been identified in the homozygous state in patients of Hutterite descent [9, 45, 61].

9.3. United States, Europe, Portugal and Brazil

In the United States, clinical research is organised within the Frontiers in Congenital Disorders of Glycosylation (FCDGC) consortium, part of the Rare Diseases Clinical Research Network, whose natural history study (NCT04199000) recruits up to 500 participants and provided, among other findings, neurological data from 51 PMM2-CDG patients [50, 110]. In Europe, French (96 patients), Italian (37), Spanish (AZATAX basis) series and the 222-patient cardiac cohort from eight centres document natural history; the international cohort of 137 genotyped patients included European and North American centres, including Porto’s Reference Centre for Inherited Metabolic Diseases [36–38, 49, 85]. Portugal has ongoing CDG research participation: Portuguese professionals co-authored the PMM2-CDG guideline, and a 2024 CDG treatment review was coordinated from Porto [17, 111]. No Portuguese or Brazilian prevalence data were found in the sources consulted; Brazilian centres participated in international ALG6-CDG and PIGA-CDG series, without national frequency data [53, 57]. The 2025 ACMG standard cites, regarding secondary transferrin patterns in peroxisomal disorders, an analysis of ten years’ transferrin isoelectric focusing experience at a Brazilian centre [22]. This absence concerns the sources consulted and does not demonstrate an absence of studies.

9.4. Special populations

PMM2-CDG is pan-ethnic, but each population has its own variant spectrum, influencing carrier screening panels and variant interpretation [12]. In highly consanguineous populations, homozygous genotypes predominate, with possibly milder phenotypes (homozygous p.Val231Met in Turkey) and more frequent sensorineural hearing loss in that series [15]. Mildly affected adults are underdiagnosed because transferrin may be almost normal [1, 3]. NGLY1 deficiency has mainly been described in patients of Northern European ancestry, probably reflecting ascertainment bias [23].

10. Illustrative Clinical Case

10.1. Neonatal PMM2-CDG with pericardial effusion (Slaba et al., 2020)

A Czech boy, the first child of non-consanguineous parents, had a haemodynamically insignificant fetal pericardial effusion detected at 22 weeks. Amniocentesis excluded aneuploidy. Labour was induced at 40 weeks for intrauterine growth restriction and oligohydramnios, with birthweight 2,390 g (z −1.83), length 48 cm and head circumference 34 cm. He required nasogastric feeding because of swallowing difficulties. At 4 weeks, the effusion had progressed. Examination showed central hypotonia, scant spontaneous movements, poor eye contact, a 90 g weight gain in two weeks, knee, ankle and elbow contractures and dysmorphic features: dolichocephaly, prominent forehead, low-set dysplastic ears, large fontanelle, broad philtrum, broad nasal root, hypertelorism, retrognathia, bilateral inverted nipples, abnormal fat distribution over thighs, buttocks and suprapubic region, pilonidal sinus and hammer toes (article Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC7575812/figure/F1/) [40].

Laboratory assessment showed albumin 23.1 g/L and combined coagulopathy: activated partial thromboplastin time 1.86 (ratio), INR 1.3, antithrombin 20%, factor IX 31%, factor XI 5%, protein C below 5% and fibrinogen 1.72 g/L; AST 140.96 IU/L, ALT 77.11 IU/L, alkaline phosphatase 611.45 IU/L and mildly elevated TSH, creatine kinase and lactate dehydrogenase. Abdominal ultrasound showed hyperechogenic kidneys, ascites and a small pleural effusion; echocardiography showed normal anatomy and function with chronic pericardial effusion (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC7575812/figure/F3/). Furosemide did not halt progression; albumin infusions transiently improved effusion and oedema. Transferrin isoelectric focusing showed increased disialo- and asialotransferrin and reduced tetrasialotransferrin, a type 1 pattern [40].

Exome sequencing identified paternal c.691G>A p.(Val231Met), classified as pathogenic, and a novel maternal variant c.447+3dup (NM_000303.2; currently classified in ClinVar as likely pathogenic, VCV003581391). Leukocyte RNA sequencing showed that this variant abolishes the exon 5 splice donor site (r.348_447del100), with more than 30% of transcripts lacking exon 5 and predicted consequence p.(Gly117Lysfs*4) (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC7575812/figure/F2/). At 3 months, the patient was admitted to intensive care weighing 3,060 g (−5.15 SD), with tachypnoea and dyspnoea worsened by feeding; the effusion required pericardiocentesis (serosanguineous transudate), but respiratory and circulatory failure progressed and the child died from obstructive cardiogenic shock at 3 months. MRI was not performed and autopsy was declined [35, 40].

The case combines warning signs that should have triggered transferrin testing at the first consultation: fetal and neonatal pericardial effusion, inverted nipples, fat pads, coagulopathy with simultaneous procoagulant and anticoagulant deficiencies, and hypoalbuminaemia. It also illustrates the association, documented in later European series, between p.Val231Met, cardiac involvement and early mortality [37]. One assertion in the authors’ discussion warrants correction: the phrase that isoelectric focusing “detects only 60% of CDG” refers to the proportion of CDG altering transferrin, rather than test sensitivity for PMM2-CDG, in which the type 1 pattern is present in the great majority [3, 40]. Figures were identified from the article XML in PubMed Central.

10.2. MPI-CDG revealed by cerebral venous thrombosis (Mühlhausen et al., 2020)

A 15-year-old girl, without gastrointestinal, hepatic, hypoglycaemic or thrombotic history, started an oral contraceptive and, four weeks later, after three weeks of fatigue, developed severe headache, ataxia, vomiting and progressive drowsiness requiring ventilation. MRI showed extensive thrombosis of the straight and left transverse sinuses and occipital superior sagittal sinus, with congestive infarction of the basal ganglia and thalami (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC7463055/figure/jmd212149-fig-0001/). She underwent aspiration thrombectomy of a 6 cm thrombus, intracranial pressure monitoring, drainage and decompressive craniectomy; she recovered without sequelae at 5 months. Thrombophilia testing showed persistently low antithrombin, abnormal proteins C and S and factor XI, and normal SERPINC1. Transferrin isoelectric focusing revealed a type 1 pattern, leukocyte MPI activity was absent (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC7463055/figure/jmd212149-fig-0002/) and MPI analysis showed c.655C>T p.(Arg219Trp) and c.1178G>C p.(Gly393Ala), the first maternally inherited [51].

Oral D-mannose was started at 0.9 g/kg/day in 3–4 doses; antithrombin, proteins C and S and factor XI almost normalised in two weeks and oral anticoagulation was stopped. Because of loose stools, the patient independently reduced the dose to 0.6 g/kg/day, with antithrombin falling again; with 0.75 g/kg/day in 5–6 doses, antithrombin normalised without digestive complaints (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC7463055/figure/jmd212149-fig-0003/); one year later there had been no new events [51]. The case shows that MPI-CDG may present in adolescence with a single thrombotic manifestation, that oestrogen contraception may have aggravated a prothrombotic state, and that antithrombin response serves as a practical dose-adjustment marker. The authors’ recommendation to include transferrin profiling in unexplained thrombosis or antithrombin deficiency investigation is not a formal international consensus recommendation, which recommends transferrin testing for persistent hypoglycaemia, particularly with hyperinsulinism, liver disease or enteropathy; it is nevertheless a reasonable extension for unexplained acquired antithrombin deficiency [7, 18, 51].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

In PMM2-CDG, mortality is concentrated in the early years: approximately 20% in the first year in the severe multivisceral course according to GeneReviews and Saudubray, or 15–20% in childhood, mainly infectious, according to the Atlas; all patients with antenatal or neonatal hydrops died between 29 weeks’ gestation and 3 months [1, 3, 12, 17]. In the 2019 guideline, mortality attributed to cardiac involvement was estimated at 34%, probably underestimated [17]. In the French 96-patient series, 12 died at a mean age of 3.8 years [49]; in the European cardiac series, 24 of 57 with cardiac involvement died at a median 21 months [37]. In the FCDGC consortium, among 37 deceased CDG patients (approximately one-third with PMM2-CDG), most died within the first 3 years and only 4 after 10 years; approximately one-third died of cardiorespiratory failure, and pericardial effusion was the primary cause in three PMM2-CDG infants; these numbers describe deaths in a cohort rather than a population mortality rate [112]. Most survivors reach adulthood, with stable intellectual disability and adult problems of ovarian failure, short stature, thrombotic events, osteopenia and skeletal deformities; among 93 adults (oldest 66 years), ataxia was stable in 95% and no SLE occurred after adolescence [1, 17]. The cross-sectional FCDGC cohort (280 individuals aged 0.22 to 71.4 years) classified NPCRS severity as mild in 27%, moderate in 44% and severe in 29%, with a mean symptom-to-diagnosis interval of 2.7 years (median 0.8) [113].

In other CDG: MPI-CDG mortality was 23.5% (8 of 35), all between 4 months and 5 years, six before disease or treatment was known; with mannose, survival is long, but liver disease may progress [18, 52]. In ALG6-CDG, 11 of 41 children died before 4 years, and the oldest patient was 40 [53]. In ALG1-CDG, survival ranged from 2 days to over 20 years, with lethal genotypes in the first two years [1, 54]. In multisystem DPAGT1-CDG, 23 patients died between 6 weeks and 5 years, whereas myasthenic patients were described between 6 and 58 years [1]. In severe PIGA-CDG, sudden death is frequent in childhood [1]. In PGM1-CDG, cardiac disease is the main cause of death, including sudden death in siblings aged 12 and 13 [19]. In NGLY1 deficiency, most survive into early adulthood [23].

11.2. PMM2-CDG follow-up

GeneReviews and the guideline table propose 1–2-year intervals for several parameters requested annually in the guideline text; annual testing is more conservative when previous abnormalities exist [3, 17]. Screening for adrenal insufficiency in PMM2-CDG has been raised in the literature but is not incorporated in guidelines [114].

11.3. Follow-up of other CDG

MPI-CDG: surveillance according to the 2022 French PNDS. The PNDS (French National Diagnosis and Care Protocol) requires a complete clinical examination every 6–12 months in all patients, even with minimal liver disease (weight, height, nutritional status, hepatomegaly, splenomegaly, ascites, oedema, signs of portal hypertension, dyspnoea and orthostatic hypoxaemia by oxygen saturation, diarrhoea, abdominal pain), and a paediatric hepatology consultation when portal hypertension appears; the differences from the consensus are set out in section 7.8 [24].

11.4. Reference networks and resources for families

In Europe, MetabERN has a subnetwork dedicated to congenital disorders of glycosylation and intracellular trafficking disorders [25]. For the triple A phenocopies, achalasia also falls within the remit of ERNICA (https://ern-ernica.eu/), which takes part in the core outcome set for paediatric achalasia, and neurological involvement within that of ERN-RND (https://www.ern-rnd.eu/) [26]. In the USA, the Frontiers in Congenital Disorders of Glycosylation consortium conducts natural history and trial readiness work [110, 113]. Patient organisations include CDG CARE (Community Alliance and Resource Exchange) and Foundation Glycosylation (Canada), mentioned in GeneReviews, the World CDG Organization, coordinated by the CDG & Allies – Professionals and Patient Associations International Network (CDG & Allies – PPAIN) based at Universidade NOVA de Lisboa, and the Associação Portuguesa CDG [3, 17, 117].

In France, MPI-CDG is included in ALD 17 (inherited metabolic diseases requiring prolonged specialised treatment), which exempts the patient from cost-sharing on the basis of a care protocol drawn up by the attending physician with the specialist. Follow-up takes place in the reference centres for inherited metabolic diseases of the G2M filière (coordination at the Hôpital de la Timone, Marseille; constituent sites at the Hospices Civils de Lyon, Lille, Nancy, Necker and Pitié-Salpêtrière in Paris, Toulouse and Tours; 20 competence centres), with the Filfoie filière for the hepatic component (centres for biliary atresia and genetic cholestasis in Bicêtre, Lyon, Lille, Marseille and Toulouse), the MHEMO network for inherited bleeding disorders for haemostasis, and the FIRENDO filière for rare gynaecological conditions for gynaecology. The team includes the attending physician, who monitors adherence, the metabolic specialist, the hepatologist, the gastroenterologist (artificial nutrition, endoscopy), the clinical biologist, the pharmacist, the social worker and, if necessary, the psychologist, joined case by case by haemostasis, endocrinology, nephrology and obstetrics. The associations mentioned are Les P'tits CDG and Connaître les Syndromes Cérébelleux (CSC); the websites of the G2M filière and Orphanet and the Tous à l'école portal inform families, schools and professionals [24].

12. Summary and Final Considerations

CDG comprise approximately two hundred inherited diseases of glycan synthesis, transfer, processing or degradation, with multisystem expression and neurological involvement in most. PMM2-CDG is the most frequent form: autosomal recessive, with variant p.(Arg141His) (NM_000303.3:c.422G>A) on one allele in more than half of patients and never homozygous, estimated prevalence between 1:20,000 and 1:80,000 in Northern European populations and lower elsewhere. Clinically, it combines hypotonia, strabismus, inverted nipples, fat pads, cerebellar hypoplasia/atrophy, coagulopathy with procoagulant and anticoagulant deficiencies, liver disease tending to normalise, infantile pericardial effusion, childhood SLE and adolescent/adult retinopathy, neuropathy, skeletal deformities and hypogonadism, with usually stable intellectual disability.

Serum transferrin screening remains the first biochemical test, but only for N-glycosylation CDG with sialic acid deficiency; the type 1 pattern directs towards PMM2 and MPI, requires exclusion of secondary causes and polymorphisms and may be misleading neonatally, in mildly affected adults, after transfusion and during dietary treatment; apoC-III, glycan profiles and urinary oligosaccharides complement it, and normal biochemical testing does not exclude CDG [22]. Confirmation is molecular, with MANE transcript and ACMG/AMP classification, supported by leukocyte enzyme activity when genetic results are uncertain; exome or genome sequencing is the main route in non-PMM2 CDG.

Treatment is mainly symptomatic and preventive, guided by the 2019 guideline: nutrition, seizure and SLE control, haematological management before surgery and during acute episodes, annual childhood cardiac surveillance, and hepatic, renal, endocrine, ophthalmological and bone monitoring. MPI-CDG must not be missed because it responds to oral D-mannose; PGM1-CDG responds to D-galactose, SLC39A8-CDG to manganese with galactose, some SLC35C1-CDG to fucose, and myasthenic forms to pyridostigmine, all outside any regulatory authorisation. For PMM2-CDG, acetazolamide and epalrestat did not confirm benefit in controlled trials, and liposomal mannose-1-phosphate awaits randomised trial results; in NGLY1 deficiency, AAV9 gene therapy is in a pivotal phase, with toxicity signals at the highest dose. Counselling should address the observed PMM2-CDG recurrence risk close to 1/3, the impossibility of prenatal diagnosis through glycosylation tests and the need for early sibling testing in treatable forms. In a child with achalasia and alacrima, GMPPA-CDG and TRAPPC11-related disorders reproduce triple A syndrome without reported adrenal insufficiency, with transferrin that may be normal, and diagnosis is molecular [9, 10].

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