Walker-Warburg Syndrome and Dystroglycanopathies (Muscular Dystrophy-Dystroglycanopathies)

A class of autosomal recessive disorders caused by defective glycosylation of α-dystroglycan, forming a continuous spectrum that extends from Walker-Warburg syndrome, with cobblestone lissencephaly and severe ocular malformations, through muscle-eye-brain disease, Fukuyama congenital muscular dystrophy and congenital muscular dystrophies with or without intellectual disability, to limb-girdle muscular dystrophies with onset in childhood or adulthood.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

Table 0.1 brings together the parameters of the class and of the three major syndromic entities; Table 0.2 lists all genes, with the phenotypic series of the Online Mendelian Inheritance in Man (OMIM) catalogue, the MANE (Matched Annotation from NCBI and EMBL-EBI) reference transcripts and the current designations of the limb-girdle muscular dystrophies (LGMD). OMIM numbers were obtained through the NCBI Gene links and confirmed in the OMIM entries for MDDGA1, MDDGA2, MDDGA3, MDDGA4 and MDDGA10 and for the DAG1 gene [1–4].

Table 0.1. Parameters of the class and the main entities

Table 0.2. Genes of the class, OMIM series and current designations

Sources for Table 0.2: OMIM numbers and cytobands from NCBI Gene, transcripts from VariantValidator, LGMD designations from the 229th European Neuromuscular Centre (ENMC) workshop and Orphanet, phenotypes from Table 4b of the FCMD GeneReviews chapter and Orphanet [1, 2, 5, 9, 11, 33, 34]. OMIM entry 236670 lists the 14 MDDGA forms, from POMT1 (A1) to GMPPB (A14), confirming the correspondence in the table; the NCBI links do not include MDDGB series for CRPPA, POMGNT2 and POMK or an MDDGC series for LARGE1, and those entries were not opened in OMIM [3].

1. Introduction

1.1. Scope and class rationale

The dystroglycanopathies are muscular dystrophies in which the primary defect is loss of function of α-dystroglycan, a cell-surface glycoprotein expressed in muscle, the central nervous system (CNS), the eye and other tissues, which acts as a receptor for the extracellular matrix. In almost all patients the protein is present but does not receive the glycan chain that allows it to bind laminin and other ligands with a laminin-G domain; the disease therefore results from variants in genes encoding glycosylation enzymes and not in the dystroglycan gene itself [35–37]. Severe forms combine muscle weakness and cardiac involvement with structural ocular and CNS malformations, with ID and epilepsy; mild forms are limb-girdle dystrophies with onset in childhood or adulthood, sometimes with normal cognition [13, 35].

This article covers the whole class, with Walker-Warburg syndrome as the reference entity, for four reasons. The three major classic syndromes (WWS, MEB and FCMD) share the mechanism and the brain malformation; almost all genes produce more than one syndrome; the same child may be classified differently depending on age and imaging; and OMIM has consolidated the three syndromes under the single designation of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (MDDGA, phenotypic series PS236670) [5, 16]. The FKRP spectrum (LGMD R9, MDC1C and the FKRP MEB and WWS forms), including oral ribitol and gene therapy, and LARGE1 dystroglycanopathy (MDC1D), together with LAMA2 dystrophy, appear only with the data needed for comparison within the class. Malformations of cortical development in general and Dandy-Walker malformation are included in the differential diagnosis.

1.2. Historical overview of the syndromes

The first description attributed to WWS is that of Walker in 1942, who called a picture of agyria, hydrocephalus, microphthalmia and retinal dysplasia lissencephaly; Krause (1946) and Chemke and colleagues (1975) published further cases, and the work of Warburg (1971, 1976 and 1978), who linked hydrocephalus with congenital non-attachment of the retina, made the syndrome known [3, 8]. Chemke described 3 affected children among 7 offspring of parents who were third cousins, the first evidence of autosomal recessive inheritance; Pagon (1978) showed absence of the six cortical layers at autopsy in two siblings, and Whitley (1983) reviewed 10 cases, 4 with occipital encephalocele and hydrocephalus mainly due to aqueductal stenosis [3]. In 1984, Towfighi and colleagues described 7 children from 4 families with the cerebral, ocular and muscular triad under the name cerebro-ocular dysplasia–muscular dystrophy syndrome (COD-MD), which Heggie (1987) and Dobyns (1989) considered identical to WWS; Dobyns had already highlighted CMD as a constant manifestation in 1986 [3]. The acronym HARD ± E (hydrocephalus, agyria, retinal dysplasia, with or without encephalocele) summarises the clinical picture of that era [8, 38]. In 1989, Dobyns and colleagues pooled 21 of their own patients and 42 from the literature and found that four anomalies were present in all patients assessed: type II lissencephaly (21/21), cerebellar malformation (20/20), retinal malformation (18/18) and CMD (14/14); they proposed these as necessary and sufficient criteria for diagnosis, regarding ventricular dilatation (20/21) and anterior chamber malformation (16/21) as useful but not necessary. Median survival in the series was 9 months [39].

FCMD was described in Japan by Fukuyama and colleagues in 1960 [40]. MEB was observed in Finland by Raitta and colleagues in 1978 (CMD with raised CK, severe congenital myopia, congenital glaucoma, optic disc pallor, retinal hypoplasia, ID, hydrocephalus and myoclonus) and characterised by Santavuori, who identified 14 patients in 11 sibships in 1980 [41]; the series of 19 patients defined the association of congenital hypotonia and weakness, raised CK, severe visual failure with severe myopia, exceptionally large visual evoked potentials (VEP), an unrecordable electroretinogram (ERG), severe ID and motor deterioration with spasticity from five years of age [42]. Dobyns considered WWS identical to cerebro-oculo-muscular syndrome and to MEB [39]; the distinction was re-established in 2001 by Cormand and colleagues, who classified 19 families (29 patients) using clinical criteria based on the Finnish patients: linkage to 1p32-p34, the MEB locus, was observed in 10 of the 11 families with MEB and excluded in 7 of the 8 families with WWS [43]. In that work, MEB was defined by survival beyond three years, a cobblestone complex with mild to moderate cerebellar or vermian hypoplasia, a normal or thin corpus callosum and characteristic ocular changes, and WWS by hydrocephalus, a severe cobblestone complex, encephalocele, agenesis of the corpus callosum and ocular changes [41]. In 2007, Godfrey and colleagues defined WWS as absence of motor development from the prenatal or neonatal period, with complete agyria or severe lissencephaly, marked hydrocephalus, severe cerebellar involvement and total or partial absence of the corpus callosum, and MEB as CMD with less severe brain anomalies, in which rare patients achieve late walking and a few words [3, 41, 44].

1.3. Milestones of molecular discovery

The molecular history of the class began with FCMD. In 1998, Kobayashi and colleagues identified the FKTN gene and showed that a founder haplotype, shared by more than 80% of FCMD chromosomes, carries a retrotransposal insertion of about 3 kb in the 3' untranslated region (UTR); it was the first human disease attributed to an ancestral retrotransposal integration [21]. In 2001, Yoshida and colleagues cloned the complementary DNA of POMGNT1 and described six variants in six patients with MEB; the most frequent variant abolished enzymatic activity, establishing interference with O-mannosylation as a mechanism common to muscular dystrophy and to disordered neuronal migration [45]. In the same year, Brockington and colleagues showed that LGMD2I is a milder allelic variant of MDC1C, both caused by FKRP [46]. In 2002, Michele and colleagues showed that in MEB and FCMD α-dystroglycan is present at the membrane but hypoglycosylation abolishes binding to laminin, neurexin and agrin [37], and Beltrán-Valero de Bernabé and colleagues identified POMT1 as the first WWS gene, with variants in 6 of 30 unrelated patients [47].

There followed LARGE in MDC1D in 2003 [48], POMT2 in WWS in 2005 [49], the description of O-mannose phosphorylation as a requirement for laminin binding in 2010 [50], the first pathogenic DAG1 variant, in an LGMD, in 2011 [51], and the demonstration that LARGE is a bifunctional glycosyltransferase that synthesises repeats of xylose and glucuronic acid (matriglycan) in 2012 [52]. Also in 2012, ISPD was identified in WWS [53, 54], GTDC2 (now POMGNT2) by exome sequencing in consanguineous families [55] and TMEM5 (now RXYLT1) in fetuses with severe cobblestone lissencephaly [56]. In 2013 came B3GALNT2 [57], B3GNT1 (now B4GAT1) [58], SGK196 (now POMK), described as an atypical O-mannose kinase [59], and GMPPB [60]; in 2015, Belaya and colleagues showed that GMPPB also causes a congenital myasthenic syndrome, linking disorders of the neuromuscular junction with the dystroglycanopathies [61]. The last piece of the pathway was described in 2016: tandem ribitol-5-phosphate, synthesised from the CDP-ribitol produced by ISPD and transferred sequentially by fukutin and FKRP [62–64].

1.4. Current classifications

OMIM stresses that the determinant of severity is not necessarily the gene involved but the extent to which the variant impairs dystroglycan glycosylation [3]. Five classification systems coexist, all used in practice and in databases; they are not equivalent and complement one another (Table 1.1). The "one gene, one syndrome" hypothesis has been abandoned: variants in any of the genes produce a broad phenotypic spectrum, and variability is greatest with FKTN, FKRP and ISPD, which range from WWS to LGMD or hyperCKaemia with exercise intolerance, without ID and with normal MRI [13, 16].

Table 1.1. Classification systems for the dystroglycanopathies

The 229th ENMC workshop replaced the letter numbering (LGMD2I, 2K, 2M, 2N, 2O, 2P, 2T, 2U) with R numbering: R9 (FKRP), R11 (POMT1), R13 (FKTN), R14 (POMT2), R15 (POMGNT1), R16 (DAG1), R19 (GMPPB) and R20 (ISPD); it added POMGNT2-related LGMD R24, which met the new definition without having been on the previous list [33]. Independent walking became the criterion separating LGMD from CMD, instead of an age limit; the presence or absence of ID does not distinguish the two categories [16, 33]. Patients with variants in LGMD genes may have phenotypes that do not meet the definition, and the classification serves as a guide rather than a rigid criterion [33]. POMK, B3GALNT2 and DPM3 had not received an R number in the sources consulted [33, 34]. In Orphanet, cobblestone lissencephaly subtypes A, B and C are marked as obsolete [11].

1.5. Definition of the entities

WWS is the most severe form: CMD with complete cobblestone lissencephaly, cerebellar and retinal malformation, almost universal hydrocephalus, a very small brainstem kinked at the midbrain–pons junction, severe eye malformations (microphthalmia, retinal detachment and hypoplasia, anterior chamber malformation, cataracts) and no psychomotor attainments, with death usually in the first year of life [5, 8, 39]. MEB combines CMD, a predominantly frontoparietal cortical malformation (pachygyria and polymicrogyria), an invariably small cerebellum with cysts, a small pons, severe ocular involvement (severe congenital myopia, congenital glaucoma, optic disc pallor, retinal hypoplasia) and severe ID; walking may be achieved and survival is longer [5, 16, 42]. FCMD is the most frequent form in Japan: moderate to severe dystrophy with generalised weakness from early infancy, moderate ID, a less severe cobblestone cortical malformation, mild ocular involvement, rare hydrocephalus and cardiomyopathy in the second decade [5].

In MDDGB forms, CMD is associated with ID and mild or absent brain changes (the former MDC1C due to FKRP and MDC1D due to LARGE1, and the intermediate forms due to POMT1, POMT2, POMGNT1, FKTN and GMPPB); in MDDGC forms, limb-girdle weakness begins after walking has been achieved, with or without ID and usually with normal brain MRI [16, 67, 68]. At the boundary of the class lie the CDG due to defective synthesis of dolichyl-phosphate mannose (DPM1, DPM2, DPM3) and of dolichol kinase (DOLK), which reduce O-mannosylation of α-dystroglycan together with N-glycosylation, and the GMPPB defect, which also affects glycosylation of neuromuscular junction proteins [13, 66, 69].

2. Molecular Genetics and Pathophysiology

2.1. Dystroglycan and the laminin–dystroglycan–dystrophin axis

The DAG1 gene encodes a single prepropeptide, which is glycosylated and cleaved into two subunits: α-dystroglycan, extracellular and heavily O-mannosylated, a receptor for proteins with a laminin-G domain (laminins, agrin, perlecan, neurexin), and β-dystroglycan, transmembrane, which binds dystrophin in the cytoplasm [36, 37]. The complex forms a bridge between the basement membrane and the actin cytoskeleton (laminin–dystroglycan–dystrophin–actin) and ensures sarcolemmal stability during contraction; it is also involved in laminin deposition, acetylcholine receptor clustering, peripheral myelination and cortical development [5, 36]. Laminin binding depends on a specific polymer, matriglycan, built on an O-mannosylated core glycan [5, 52].

2.2. The glycosylation pathway step by step

O-mannosylation begins in the endoplasmic reticulum (ER), where the POMT1–POMT2 complex transfers mannose from dolichyl-phosphate mannose (Dol-P-Man) to serines and threonines of α-dystroglycan; neither protein is active on its own [66–68]. Two types of core glycan are formed from O-mannose. Core M1 results from the addition of N-acetylglucosamine (GlcNAc) in β1,2 linkage by POMGnT1 in the Golgi apparatus and does not take part directly in laminin binding [70]. Core M3, the functional one, is the phosphorylated trisaccharide GalNAc-β3-GlcNAc-β4-(6-phosphate-)mannose: POMGnT2 adds GlcNAc in β1,4, B3GALNT2 adds N-acetylgalactosamine (GalNAc) and POMK phosphorylates position 6 of mannose [59, 71–73]. Onto the distal GalNAc, fukutin and FKRP transfer two ribitol-5-phosphate units from the CDP-ribitol synthesised by ISPD (CRPPA); RXYLT1 adds xylose to ribitol, B4GAT1 attaches the primer disaccharide glucuronyl-β1,4-xylose and LARGE1 polymerises matriglycan, a repeat of [-3-xylose-α1,3-glucuronic acid-β1-] [52, 62–64, 74]. GMPPB supplies GDP-mannose upstream, and the Dol-P-Man synthase complex (catalytic DPM1, regulatory DPM2 and DPM3) and dolichol kinase (DOLK) produce the mannose donor in the ER, shared by N-glycosylation, glycosylphosphatidylinositol anchors and O- and C-mannosylation [69, 75–78].

Table 2.1. Steps in functional glycosylation of α-dystroglycan

Sources: [5, 52, 59, 62–64, 69, 74, 75, 79–81].

This organisation has two practical consequences. Immunohistochemistry with antibodies directed at the glycosylated epitope (IIH6C4), which recognises matriglycan, is abnormal for all genes, so it confirms the class but does not identify the gene [13, 67]. And the ribitol pathway, common to CRPPA, FKTN and FKRP, is the target of the substrate therapies under investigation [35, 62, 63].

2.3. Tissue mechanisms

In muscle, loss of laminin binding makes the sarcolemma vulnerable to mechanical stress and produces a dystrophy with necrosis, regeneration and fibrosis; in FCMD interstitial fibrosis predominates, with less marked degeneration and regeneration than in Duchenne muscular dystrophy (DMD) [5, 66]. In the cerebral cortex, α-dystroglycan of the radial glia anchors the pial basement membrane (glia limitans); its failure leaves focal defects through which neurons and glia migrate into the subarachnoid space, forming verrucous nodules — the overmigration that defines cobblestone (type II) lissencephaly [5, 65, 66]. The resulting cortex is disorganised, with an irregular surface, lacking the layers of classic lissencephaly, which is a disorder of the neuronal cytoskeleton (PAFAH1B1, DCX, TUBA1A) [65]. In the cerebellum, cysts lined by the molecular layer with leptomeningeal tissue form beneath the malformed cortex; the medulla is flat and the basis pontis small owing to secondary hypoplasia [5]. In the retina, dysplasia may develop in the fetal period, with rosettes of immature photoreceptors [5, 82]. In the heart, dysfunction of the dystroglycan complex produces dilated cardiomyopathy (DCM) with myocardial fibrosis; in DOLK the mechanism of DCM is abnormal O-mannosylation of dystroglycan [5, 83].

2.4. Inheritance, mechanism and the relationship between residual activity and severity

All syndromic forms are autosomal recessive, through loss of function [5, 65]. Severity tracks residual pathway activity: in POMT1, severity is inversely proportional to O-mannosyltransferase activity measured in fibroblasts, and the most severe alleles also destabilise the protein [84]; in POMK and LARGE1, severity follows residual kinase or glycosyltransferase activity [73, 81]; in B3GALNT2, missense variants with 40–50% residual activity still abolish laminin binding, suggesting a threshold effect [85]. Complete loss of dystroglycan is presumably embryonic lethal: homozygous Dag1-null mice show severe abnormalities from day 6.5 of gestation, whereas heterozygotes are viable and fertile [4, 36]. Primary dystroglycanopathy is rare; OMIM records five DAG1 variants: the homozygous missense p.Thr192Met (c.575C>T in the entry's numbering) in a Turkish woman with LGMD and severe ID, which in the mouse reduces LARGE-mediated glycosylation; two compound heterozygous missense variants in a 7-year-old Japanese boy with asymptomatic hyperCKaemia; the homozygous missense in the Libyan sisters with MDDGA9; and a homozygous truncating variant in five infants from an Israeli Arab family who died shortly after birth [4, 51, 86]. α-Dystroglycan is also the cellular receptor for Lassa virus, and genetic screens for entry of this virus into haploid cells identified pathway genes such as TMEM5 [4, 87]. In 2026 a Romanian family (father and three children) was described with the heterozygous missense variant NM_004393.6:c.887G>A p.(Gly296Asp) and a mild to moderate muscle phenotype, similar to previous cases of haploinsufficiency; heterozygous truncating DAG1 variants had already been associated with asymptomatic hyperCKaemia, fatigability and myalgia [15].

2.5. Spectrum by gene

For all genes, point variants are the most common type; genomic deletions and insertion-deletions are described mainly in POMT2 and LARGE1 [13]. Severe functional defects of POMT1 and POMT2 cause WWS or MEB, and less disruptive missense variants cause CMD or LGMD with ID and normal MRI [13, 67]. POMGNT1 shows the strongest correlation with the typical MEB phenotype; in a 2003 series outside Finland, variants near the 5' end were associated with a more severe brain phenotype and those near the 3' end with a milder phenotype [13, 88]. FKRP, FKTN and ISPD have the broadest spectrum, from WWS to Becker-type LGMD [13].

In FKTN, homozygotes for the Japanese founder insertion have milder FCMD; compound heterozygosity with a more severe loss-of-function allele shifts the phenotype towards the MEB/WWS spectrum, and homozygous null variants produce a WWS-type phenotype [5, 13]. In 107 unrelated Japanese patients, the severe phenotype with WWS features (hydrocephalus, microphthalmia) was significantly more frequent in insertion + point variant compound heterozygotes [5, 89, 90]; LGMD phenotypes occur in missense + frameshift compound heterozygotes or in missense homozygotes [5, 91, 92]. In CRPPA, in a Chinese series of 16 paediatric patients (2006–2023), with phenotypes from severe MEB to LGMD, deletion of exons 6–9, on a common haplotype, was the second most frequent variant (4/16; 25.0%) [93]; a deletion of exons 9–10 detected by array comparative genomic hybridisation (array-CGH) completed the genotype of two Iranian siblings [94]. In LARGE1, a 63 kb intragenic deletion caused WWS in one family [95]. In FKRP, a biallelic null (homozygous variant in the initiation codon) was described in two siblings with WWS, the severe extreme of the spectrum [96]. In POMK, by 2020, 16 patients from 9 families with 8 variants had been published; the same homozygous nonsense variant NM_032237.5:c.325C>T p.(Gln109Ter) gave disparate phenotypes between families, from WWS to mild LGMD with walking at 25 years [14, 97].

2.6. Normalised reference variants

The MANE transcripts of POMT1 (NM_001077365.2), FKTN (NM_001079802.2), DAG1 (NM_004393.6) and GMPPB (NM_021971.4) differ from those used in some databases and publications (NM_007171, NM_006731, NM_001165928 and NM_013334, respectively); numbering should be confirmed against the transcript in the report [2, 67]. Table 2.2 presents variants with a population or historical role, normalised in VariantValidator and with the ClinVar classification as of 26 October 2026.

Table 2.2. Reference variants

The FKTN intronic variant appears in the literature with two numberings: c.647+2084G>T (counted from exon 5) and c.648-1243G>T (counted from exon 6). The position is the same, and VariantValidator returns the second form because it is closer to the following exon [2, 5]. The 30-codon difference between the two DPM3 transcripts explains why the same variant appears as p.(Tyr74Cys) or p.(Tyr44Cys) [2]. The uncertain significance classification in ClinVar contrasts with the series of five patients reported by Nagy and colleagues [98, 105].

2.7. Mechanism of the FKTN founder insertion and the deep intronic variant

The FKTN SVA insertion introduces a strong splice acceptor which, together with a rare alternative donor in exon 10, produces an aberrant transcript ("exon trapping") in which 129 amino acids of the carboxyl terminus are encoded by the retrotransposon; targeted antisense oligonucleotides (ASOs) restored normal messenger RNA and protein, α-dystroglycan glycosylation and laminin binding in patient cells and in knock-in mice [109]. The deep intronic variant c.648-1243G>T creates a splice donor in intron 5 and a 64 bp pseudoexon, with a truncated protein; patients with this variant have a more severe phenotype, and a 2'-O-methyl ASO directed at an exonic enhancer induced skipping of the pseudoexon and restored fukutin in lymphoblasts and functional glycosylation in myotubes [99]. Both results are preclinical.

2.8. Allelic disorders, overlaps and modifiers

Some genes of the class cause disease outside muscle or outside the CNS. Biallelic hypomorphic POMGNT1 alleles, which reduce but do not abolish enzymatic activity, cause non-syndromic retinitis pigmentosa (RP76), without muscle or brain involvement [70, 110]. FKTN causes a DCM with mild or absent proximal weakness (OMIM 611615), described in six Japanese patients with normal intellect and in Mexican siblings with a homozygous missense variant [111, 112]. DOLK causes a non-syndromic DCM and a multisystem neonatal form with ichthyosis [78, 113]. GMPPB bridges dystrophy and congenital myasthenic syndrome, because the variants also alter glycosylation of acetylcholine receptor subunits and other synaptic proteins [61, 69]. DPM1, DPM2 and DPM3 link the CDG with the dystroglycanopathies, with simultaneous hypoglycosylation of N-glycans and α-dystroglycan [106, 114, 115].

Intrafamilial variability is the rule in the POMT2, CRPPA and GMPPB forms, with siblings sharing the same genotype but discordant phenotypes, indicating modifiers yet to be identified [94, 116, 117]. In LGMD R9, the existence of asymptomatic c.826C>A homozygotes likewise suggests modifiers [6]. The severity of the reduction in α-dystroglycan staining correlates well with clinical course in POMT1, POMT2 and POMGNT1, but not consistently in FKTN and FKRP [6, 13]. COL4A1, a basement membrane gene, has been proposed as a cause of a WWS phenotype in humans, through a mechanism other than hypoglycosylation; Orphanet classifies it as a candidate gene [7, 118].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Overview of the spectrum

The α-dystroglycanopathy spectrum is ordered by decreasing severity of brain and eye involvement, but the correspondence between gene and phenotype is imperfect and the same variant may produce distinct pictures in different families [14, 16]. Table 3.1 summarises the features that separate the three classic syndromes according to the 2025 GeneReviews chapter, and Table 3.2 places the intermediate and mild forms.

Table 3.1. Distinguishing features of FCMD, MEB and WWS

Source: FCMD GeneReviews chapter, Table 4a [5]. The historical table in the retired CMD chapter attributes the ocular grades the other way round; the 2025 version prevails.

Table 3.2. Full spectrum of the α-dystroglycanopathies

Sources: retired CMD chapter, Table 2 (historical value), and 2014 consensus [13, 16, 67, 119].

3.2. Walker-Warburg syndrome

Central nervous system. In the historical series compiled by Smith's Recognizable Patterns (without an explicit denominator, derived from the Dobyns and Pagon series), type II lissencephaly and cerebellar malformation were present in 100% of patients, with extensive agyria and areas of macrogyria or polymicrogyria, a thick cortex without white matter interdigitations, absent or hypoplastic septum pellucidum and corpus callosum and a hypoplastic vermis; ventriculomegaly occurred in 95%, hydrocephalus, usually obstructive in the posterior fossa, in 53%, Dandy-Walker malformation in 53% and occipital encephalocele, sometimes small, in 24% [8]. In the Dobyns series, congenital macrocephaly with hydrocephalus (11/19) was more frequent than congenital microcephaly (3/19), Dandy-Walker malformation occurred in 10/19 and posterior cephalocele in 5/21 [39]. MRI shows midbrain hypoplasia, a thick tectum, fused colliculi, pontomesencephalic angulation ("kink") and a ventral pontine cleft [13]. On second-trimester fetal MRI of two siblings with POMT1 WWS, hydrocephalus with fused ventricles, hypoplastic cerebellar hemispheres, a small supraoccipital meningoencephalocele and a "Z"-shaped hypoplastic brainstem recurred in both pregnancies [120].

Eye. Retinal malformations were present in 100% (retrolental masses due to persistent hyperplastic primary vitreous, retinal dysplasia and detachment, coloboma in 24%), anterior chamber anomalies in 91% (cataracts, corneal opacity usually due to Peters anomaly, narrow iridocorneal angle with or without glaucoma) and microphthalmia in 53% [8]; Dobyns recorded microphthalmia in 8/21, colobomas in 3/15 and congenital cataracts in 7/20 [39].

Muscle and other organs. CMD is constant, with severe hypotonia, very high CK and, frequently, fatal respiratory failure in the neonatal period [8, 65]. Genital anomalies in boys occur in 65% according to Smith (5/8 in the Dobyns series), congenital contractures in 43%, cleft lip or palate in 14% and microcephaly in 16%; occasionally there is renal dysplasia or cystic kidneys, non-compaction cardiomyopathy, imperforate anus, megalocornea, microtia and testicular dysplasia [8, 39]. In a consanguineous Egyptian family with POMT2 WWS, four siblings shared lissencephaly, subcortical and subependymal heterotopia and cerebellar hypoplasia, but only one had microphthalmia, two had large cystic kidneys, and hydrocephalus and Dandy-Walker malformation were not shared [116]. Cleft lip and palate were associated with POMT1 in a 2008 series [121]. Sensorineural deafness has been described with POMK, with B3GALNT2 and in a newborn girl with FKTN variants and WWS features with severe cochlear hypoplasia [14, 122, 123].

Cohorts described in OMIM. In the Cormand series (2001), of the seven live births classified as WWS one was alive at 6 months, two died at 3 years and four before 9 months; three patients and two fetuses had encephalocele [3]. In the Turkish family that led to the identification of POMT1, after three miscarriages a boy was born with severe hydrocephalus, bifid cerebellum, cerebellar cyst, microphthalmia, hypoplastic genitalia and CK above 2000 U/L, who died at 7 months; another child died 15 minutes after birth with encephalocele and bilateral cleft lip [3]. A Japanese boy with POMT1 WWS and meningoencephalocele survived to 3.5 years, without head control [3]. With RXYLT1, a boy with occipital encephalocele and CK up to 3500 U/L died at 22 months, but two sisters from another consanguineous family were alive at 19 and 21 years [87]. In 1995, preservation of the merosin M chain in muscle distinguished WWS from CMD with total merosin deficiency [3].

Natural history. Most children die in the first year of life, owing to the severity of the brain defect or to respiratory failure; survivors usually have profound ID, and 5–10%, mainly those with less severe ID, survive beyond five years, rolling over and sitting between one and three years of age, with seizures that become frequent with age [8]. The median survival of 9 months in the 1989 series predates molecular diagnosis and current care [39]; another review states that most children die before three years [116]. In the absence of recent survival series, these figures describe patients not managed with a uniform supportive strategy and should not be taken as an individual prognosis.

3.3. Muscle-eye-brain disease

Clinical course. In the Finnish series of 19 patients, hypotonia and weakness were congenital, biopsy showed mild to moderate dystrophy, development was slow in the first years and ID severe; from five years of age there was deterioration with spasticity and contractures, and computed tomography showed ventricular dilatation and low white matter density [42]. In 20 Finnish patients studied by MRI and VEP, 15 had enlarged VEP (giant in 14), and 12 of these had pachygyria with a nodular cortical surface, a midline defect and a hypoplastic pons, without significant white matter changes; the authors proposed the combination of giant VEP and structural changes with normal signal in white and deep grey matter as a marker [124]. Survival into middle age is documented: two Finnish women followed for almost 40 years had a picture that had been stable since adolescence, with severe ID and motor disability, very limited communication, visual impairment, epilepsy, contractures, repeated bowel obstructions, dental abrasion due to bruxism, irregular sleep and periods of hypothermia with excessive sleepiness [125].

Eye. In a series of 20 patients with MEB followed for up to 20 years, myopia ranged from −6 to −27 dioptres, five infants had congenital glaucoma, nine children developed juvenile cataracts, VEP were enlarged (>50 µV) and delayed in 70% and the ERG was extinguished in 12; the changes were progressive, with retinal degeneration and optic atrophy [126]. A 2026 review of POMGNT1 cases confirms ocular motility disorders, high myopia, glaucoma, cataract, optic nerve hypoplasia and dysplastic and degenerative retinal changes, with retinal detachment and microphthalmia less frequent [127].

Epilepsy. In a 2026 systematic review (52 studies, 80 patients with MEB and epilepsy), median CK was 1600 IU/L, POMGNT1 accounted for 38.8% of cases and GMPPB for 10%; epilepsy usually began in the first six months, absences were the most common type (58.8%), followed by generalised tonic-clonic seizures (33.8%) and focal seizures (21.3%), drug resistance reached about 21.3%, and the electroencephalogram (EEG) showed focal or multifocal discharges in about half and slow, disorganised background activity in 92.9% [128]. Refractory seizures and ID with marked behavioural changes are more typical of POMGNT1 MEB [16].

Cohorts described in OMIM. In 18 of 19 Finnish patients with MEB, the POMGNT1 intron 17 splice variant was homozygous, with phenotypic variability among homozygotes suggesting other factors [41, 129]. Outside Finland, two siblings with POMGNT1 variants had hydrocephalus, early-onset glaucoma, high myopia, optic nerve hypoplasia, raised CK and a facies with an everted lower lip, short nasal bridge, mild micrognathia and midface hypoplasia; an Italian woman homozygous for a POMGNT1 variant had no ocular anomalies and walked without weakness at 30 years, with severe ID and seizures [41]. With POMT2, in seven MEB-type patients onset ranged from the neonatal period to 4 years, only one achieved walking, all had low IQ and almost all microcephaly; in a series of four patients, three died at 15 and 16 years [44, 130].

Imaging. In a blinded MRI assessment of 27 patients with dystroglycanopathy (POMT1 4, POMT2 9, POMGNT1 7, FKTN 4, LARGE1 3), MRI was normal in 3, showed non-specific changes in 5 and structural defects in 19; polymicrogyria occurred in 11/27 and pontine clefts in 5 patients with an MEB phenotype; prominent cerebellar cysts always occurred with POMGNT1 and were rare with POMT1 and POMT2 [131].

3.4. Fukuyama congenital muscular dystrophy

Clinical forms. FCMD is classified by maximal motor function: typical (sits unsupported or shuffles while sitting, never standing), mild (stands or walks, with or without support) and severe (sits only with support or lacks head control) [5]. The proportions differ between sources: 50% typical, 38% severe and 12% mild in the Ishigaki series cited by GeneReviews; 75% typical, 10% severe and 15% mild according to Murakami; about 70% typical, 10% severe and 15% mild in the official Japanese information sheet [5, 40, 132]. The difference reflects the definition of severity and the population of each series.

Neuromuscular course. Onset is in early infancy, with weak sucking and crying, predominantly proximal hypotonia and motor delay; the myopathic facies becomes evident between 6 and 12 months, the cheeks, calves and forearms become pseudohypertrophic at the end of the first year and in the second year (50%), and the open mouth, prognathism and macroglossia become more pronounced in childhood [5]. Contractures of the hips, knees and interphalangeal joints begin early; the Japanese information sheet describes limited extension of the interphalangeal joints with the wrist in dorsiflexion from infancy, followed by the ankle, hip, knee and elbow [5, 40]. Motor function peaks at around 5–6 years and then declines with diffuse atrophy; many patients are bedridden after 15 years and frequently die before 20 from respiratory failure or cardiomyopathy [5, 132]. CK is usually in the thousands of units [5, 40].

Cognition and behaviour. All patients have developmental and language delay; the intelligence quotient (IQ) usually lies between 30 and 60, above 35 in the mild form and below 30 in the severe form; in the typical case, a few dozen words is the maximum [5]. Social development is relatively preserved, with eye contact, recognition of family members and requests by vocalisation even in the severe forms; autistic traits are rare [5].

Epilepsy. Seizures occur in 33–80% depending on the series, both febrile and afebrile [5]. In the Japanese national registry, 69 of 207 patients (33%) had febrile convulsions or epilepsy [133]. In homozygotes for the founder insertion, the mean age at onset of febrile seizures was 5.4 years and of afebrile seizures 4.6 years, compared with 3.6 and 3.7 years in insertion + other variant compound heterozygotes [134]. Seizures may appear in advanced stages of the disease [135].

Eye. Refractive errors (myopia and hypermetropia) affect 40–53%, and retinal anomalies 32% of the most severely affected patients; in the Japanese registry, myopia occurred in 8.6% and strabismus in 5.9% [5, 133]. Retinal dysplasia may be present in the fetal period and be found at pathology without ophthalmological expression [82]. The characteristic findings of MEB and WWS (anterior chamber anomalies, glaucoma) are not part of FCMD [5]. In a Korean series of nine patients (2005–2024), 7/9 were compound heterozygous for the insertion and the deep intronic variant; high myopia occurred in 44.4%, optic disc anomalies in 77.8% and peripheral pigmentary degeneration in 44.4%, and persistent fetal vasculature and tractional detachment occurred only in the founder compound heterozygotes [136].

Heart. Cardiac involvement is slowly progressive and milder than in DMD [137]. In an echocardiographic study of 34 patients, left ventricular (LV) fractional shortening was normal before 10 years and reduced in 10/12 (83%) patients over 15 years [5, 138]. In the Japanese registry, with a median age of 6 years, cardiac dysfunction affected 16% [133]. B-type natriuretic peptide did not correlate with age or ejection fraction [137].

Swallowing, breathing and infections. Dysphagia and gastro-oesophageal reflux disease (GORD) affected 46/207 (22%) and increase with age, occurring in severe forms even before five years (6/93) [5, 133]. Respiratory support was needed in 16% of registry patients and increases with age [133]. A few days after a febrile viral infection, sudden worsening of weakness with a marked rise in CK and myoglobinuria may occur, sometimes fatal [40, 139]; a fall in CK with a rise in C-reactive protein during febrile episodes has also been described, attributed to increased endogenous cortisol [140].

Brain. Early MRI shows cobblestone lissencephaly with frontal, parietal and temporal pachygyria, polymicrogyria-like areas, dilated lateral ventricles, T2 white matter hyperintensity due to delayed myelination (which fades mainly after four years), cerebellar polymicrogyria and cysts, mild brainstem hypoplasia in some and poorly developed opercula [5, 40]. In juveniles and adults, the agyric areas are more focal and restricted to the occipital lobes [5].

Genotype. In the Japanese registry, 80% of patients were homozygous for the insertion and 20% compound heterozygous [133]. A newborn girl compound heterozygous for the insertion and p.(Arg47Ter) presented with marked hypotonia, respiratory compromise at birth, extensive cobblestone lissencephaly and sensorineural deafness due to cochlear hypoplasia, without hydrocephalus [123].

3.5. Intermediate forms and congenital dystrophies without major malformation (MDDGB)

MDDGB forms lie between FCMD and LGMD. With POMT1, MDDGB1 combines CMD, ID and a mild structural brain anomaly; a normal brain MRI does not exclude the gene [67, 141]. With POMGNT1, MDDGB3 combines ID with mild changes (white matter, cerebellar cysts, pontine hypoplasia) and ocular involvement limited to myopia and optic atrophy [70]. With GMPPB, MDDGB14 presents with severe weakness in childhood, ID and sometimes microcephaly, cardiac dysfunction, seizures or cerebellar hypoplasia [69]. The CRPPA form without ID presents with motor delay, cerebellar atrophy, hypotonia, facial diplegia and Achilles tendon contracture [142]. MDC1C due to FKRP (no walking, muscle hypertrophy, very high CK, secondary laminin α2 deficiency) and MDC1D due to LARGE1 (profound ID, white matter changes and subtle structural anomalies) complete the spectrum [48, 80].

3.6. Limb-girdle muscular dystrophies due to dystroglycanopathy (MDDGC)

LGMD R11 (POMT1). Mild proximal weakness with significant developmental delay, microcephaly without structural brain anomaly and ID in all patients described, CK 10–40 times the upper limit of normal (ULN), onset between one and three years, hypertrophy of the calves and thighs and walking maintained for at least 15 years after onset; the p.(Ala200Pro) variant is a founder variant in Turkey [6, 84]. Three compound heterozygotes (two with LGMD and near-normal cognition, one with CMD and normal MRI) had LV dilatation or reduced contractility [143].

LGMD R14 (POMT2). In the largest series (12 patients aged 18 to 63 years), the initial complaints were difficulty walking, pain on exercise, motor delay and learning difficulties; weakness was greatest in the hip and knee flexors and extensors, muscle MRI showed involvement of the hamstrings, paraspinal and gluteal muscles, all 12 had some cognitive impairment and brain MRI was abnormal in 3/10 [119]. In a Chinese cohort of 11 patients with POMT2 variants, 3 had an MEB phenotype, 5 CMD with ID and 3 LGMD [144].

LGMD R15 (POMGNT1). One woman had normal motor milestones, progressive weakness from 12 years with loss of walking at 19, proximal weakness of the neck, pelvic girdle and shoulder abductors, hypertrophy of the calves and quadriceps, ankle contractures, severe myopia and normal cognition; another patient had proximal weakness in the second decade with normal intellect [6, 44]. Weakness and atrophy are often more prominent in the upper than in the lower limbs [70].

LGMD R13 (FKTN). Outside Japan, FKTN causes LGMD with normal intelligence and brain, very high CK and proximal weakness with hypertrophy of the calves, thighs and triceps; in three children from two Caucasian families, severe weakness after intercurrent illness responded remarkably to corticosteroids [91]. Onset ranges from four months to four years, CK from 4 to 50 times the ULN, and biopsy often shows inflammatory infiltrates [6]. DCM may be the first or only manifestation: six Japanese patients had minimal weakness, normal intellect and severe DCM [111]; in 2026, a 30-year-old Indian man with DCM, prolonged QT, subepicardial late enhancement and hyperCKaemia, with skeletal myopathy revealed later [145], and a 22-year-old woman transplanted for advanced DCM, with LGMD diagnosed later and CK raised before weakness [146], were described.

LGMD R16 (DAG1). The signature is limb-girdle weakness with onset in early infancy and ID with normal brain MRI [36, 51]. In a Chinese family, the 64-year-old proband had mild late-onset disease, with dystrophic biopsy and markedly reduced α-dystroglycan [147]. The DAG1 MDDGA9 form was described in two Libyan sisters with an MEB-type picture, macrocephaly and extensive multicystic white matter disease [86].

LGMD R19 (GMPPB). This is the most common presentation of GMPPB: mild proximal weakness from childhood, lower limbs more than upper, facial, ocular, bulbar and respiratory muscles largely spared, sometimes mild ID or seizures; at the mild extreme there is recurrent rhabdomyolysis without weakness, and CK ranges from 2 to more than 50 times the ULN [69, 148]. Some patients have fluctuating, fatigable weakness due to a neuromuscular transmission defect: in the Belaya series, seven cases from five families were identified by decrement of the compound muscle action potential (CMAP) on repetitive stimulation [61]. The p.(Asp334Asn) variant, a founder variant in southern India, caused LGMD or a mild myasthenic syndrome in 12 patients from 7 families, with onset between childhood and 40 years and decrement in all [108]. Two siblings with the same homozygous variant had discordant phenotypes: the brother, fatigable proximal weakness; the sister, a myopathic phenotype with very high CK [117].

LGMD R20 (CRPPA). Limb-girdle weakness with very high CK and calf pseudohypertrophy; occasionally (5–29%) macroglossia, cardiovascular anomaly and reduced vital capacity [142, 149]. Two Iranian siblings with the same genotype had childhood onset with weakness of all four limbs (sister, CK 1193 U/L) and late onset limited to the lower limbs (brother, CK 460 U/L) [94].

LGMD R24 (POMGNT2) and POMK. The mild form of POMGNT2 is an LGMD with ID without brain malformation, of highly variable severity, with some patients asymptomatic [33, 150]. At the mild extreme, POMK causes LGMD with proximal weakness, motor delay and cognitive impairment without structural malformation [73, 97].

3.7. Heart

Myocardial involvement is frequent in the dystroglycanopathies, especially with FKRP and FKTN, particularly at the LGMD extreme, and less so with POMT1 [13, 25]. DCM has been described with FKRP before five years and in FCMD in the second decade; admissions for heart failure cluster in mid and late adolescence in patients with FKRP, FKTN and POMT1 variants [25]. In 2010 heart disease had not been described in WWS and MEB, but the consensus considered them at risk because of the common pathway; non-compaction cardiomyopathy has been reported in an infant with WWS [8, 25]. Severe arrhythmias had not been described in the dystroglycanopathies, unlike the laminopathies [25]. With B3GALNT2, two siblings developed dystroglycanopathy with DCM [24]. In LGMD R9, LV hypokinesia, DCM and heart failure affect 30–80% of patients in the series, regardless of the variant and of muscle severity [151, 152]. In CMD in general, 8–30% of patients with merosin-positive CMD had depressed cardiac function on echocardiography [26]. For the dystroglycanopathies as a whole, the 2026 Lancet Neurology review estimates dilated cardiomyopathy in about 30% of patients, sometimes requiring heart transplantation; the estimate rests on unpublished data from one of the authors and does not break down by gene or age [35].

3.8. Overlap syndromes with the CDG

DPM1-CDG. An ultra-rare, severe, multisystem disorder of early onset, with global delay, hypotonia, seizures and dysmorphic features; one of the published children died at 11 weeks of fulminant sepsis, and one infant presented as a dystroglycanopathy-type CMD [115, 153–155].

DPM2-CDG. Three children from two families had profound delay, intractable epilepsy, progressive microcephaly, severe hypotonia with raised CK, dystrophy with deficient O-mannosylation on biopsy and early death [114]; milder forms have been described in a 23-year-old man with axial hypotonia, congenital heart disease and ID and in two Chinese siblings with mild ID and raised CK [156, 157].

DPM3-CDG. Presents as an α-dystroglycanopathy, with proximal weakness and very high CK. The index patient, diagnosed at 27 years, had low-normal IQ, mild weakness and a waddling gait from 11 years, DCM at 20 and a stroke-like episode at 21 [18, 106]; one woman had isolated pelvic girdle weakness that became symptomatic only at 42 years [158]; five patients from four families homozygous for p.(Tyr74Cys) had global delay, mild to severe ID, microcephaly, seizures, periventricular white matter changes, weakness and variable cardiomyopathy [105, 159].

DOLK-CDG. This is bimodal. In the cardiac form, nine patients from three Israeli families had predominant cardiac disease without CNS involvement, from slight dilatation to heart failure; two children died suddenly before diagnosis, and three with initially mild DCM deteriorated within a few days after an acute infection [113]. In the multisystem neonatal form there is ichthyosis or collodion-type skin, circumferential constrictions of the digits, DCM, multiorgan failure and death within days to weeks; intermediate forms include West syndrome with ID without extracerebral features [18, 78, 160].

3.9. Summary by system

Table 3.3. Manifestations by system and age

Sources: [5, 8, 25, 42, 113, 116, 123, 125, 126, 128].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Prenatal suspicion arises with ventriculomegaly or hydrocephalus, occipital encephalocele, cerebellar and vermian hypoplasia, Dandy-Walker malformation, microphthalmia or persistent primary vitreous on ultrasound or fetal MRI; ventriculomegaly of autosomal recessive cause with these features should raise the possibility of MEB and WWS [14, 161]. In the presence of Dandy-Walker malformation, additional ultrasound findings greatly increase the probability of a syndromic association (ciliopathy, WWS, Smith-Lemli-Opitz syndrome), generally autosomal recessive and with a high recurrence risk; when there is no evidence of a Mendelian or chromosomal cause, the recurrence risk is of the order of 1–5% [162]. A "Z"-shaped hypoplastic brainstem on second-trimester fetal MRI, especially with a family history, is a pattern suggestive of WWS [120]. Ultrasound diagnosis of lissencephaly is not reliable and is not possible before 28 weeks, but the associated features (microcephaly, hydrocephalus, cerebellar hypoplasia) may guide earlier; fetal MRI is more accurate [65]. In the published series, hydrocephalus was detected at 13 weeks in an at-risk pregnancy, occipital encephalocele at 18 weeks and retinal dysplasia at 35 weeks; in fetuses, muscle changes may not be demonstrable, so the disease should not be excluded on fetal muscle histology [3]. Recurrent severe fetal ventriculomegaly with cerebellar hypoplasia was recognised as B4GAT1-related only after a second affected pregnancy in an Indian family [107].

4.2. Newborn and infant

In the hypotonic infant, CK should be normal in all central causes of hypotonia; a raised CK requires the diagnosis to be reconsidered and the CMDs to be considered, including WWS and MEB, in which hypotonia is of mixed central and muscular origin [163]. In a newborn with muscle weakness and meningoencephalocele, initial CK measurement is recommended, because encephalocele has been described with POMT1, ISPD and POMK [14]. The clues favouring a dystroglycanopathy among the CMD subtypes are CNS involvement with psychomotor delay or ID, muscle pseudohypertrophy (calves and tongue), cardiomyopathy, abnormal head circumference and pyramidal signs; the history should include fetal movements, perinatal history, feeding and records of siblings who died in the neonatal period [16]. Ophthalmological examination looks for retinal dysplasia, and the three-generation pedigree for consanguinity [38, 65]. The gene-specific clues described are microcephaly (POMT1, POMT2), macrocephaly with epilepsy (POMGNT1), cleft lip and palate in WWS (POMT1), macrocephaly with multicystic leukodystrophy (DAG1) and cardiac involvement (FKRP, FKTN, POMT1) [16, 86, 121].

4.3. Child

In FCMD, suspicion arises with hypotonia and weakness before 9 months with contractures of the hips, knees and interphalangeal joints, severe motor and language delay with relative social preservation, myopathic facies, pseudohypertrophy of the calves and forearms, febrile or afebrile seizures, visual impairment, dysphagia, respiratory problems, cardiomyopathy and a family history compatible with autosomal recessive inheritance; the absence of a family history does not exclude it [5]. In the Italian cohort, suspicion of dystroglycanopathy arose mainly from weakness and atrophy predominating in the upper limbs with very high CK and, in a minority, from CNS involvement in the first months with CK above five times normal [23]. The North American guideline recommends using ethnicity and geography, the pattern of weakness and contractures, the presence of CNS involvement, involvement of other organs and CK to guide diagnosis (Level B), bearing in mind the founder variants in Japanese and Korean people (FCMD), Ashkenazi Jews (WWS) and Turkish people (POMT1 NM_001077365.2:c.598G>C p.(Ala200Pro)) [26].

4.4. Adolescent and adult

In adulthood, dystroglycanopathy presents as limb-girdle weakness with raised CK, asymptomatic hyperCKaemia, exercise intolerance or recurrent rhabdomyolysis [15, 69, 164]. Limb-girdle weakness with hyperCKaemia and fatigability should prompt repetitive nerve stimulation, because GMPPB may cause a treatable neuromuscular transmission defect and be mistaken for seronegative myasthenia gravis [117, 165]. Non-ischaemic DCM with raised CK, even without apparent weakness, may be the first manifestation of FKTN or B3GALNT2 variants, and warrants genetic testing with segregation [24, 145, 146].

4.5. Red flags

Red flags are neonatal respiratory failure; in children under two years, subtle respiratory signs (weak cry, ineffective cough, choking, poor weight gain, repeated infections, paradoxical breathing), with immediate assessment if peripheral oxygen saturation (SpO2) is below 94% or below baseline during an acute infection [25]; sudden worsening of weakness with dark urine in the days following a febrile viral infection in FCMD [40, 139]; prolonged seizures, which may progress to status epilepticus [25]; signs of raised intracranial pressure due to hydrocephalus [166]; and, in patients with DOLK variants, any acute infection, because of the possibility of cardiac deterioration within days [113].

4.6. Newborn screening

There is no newborn screening directed at the dystroglycanopathies in the programmes described in the sources consulted. In 1992, a newborn with hydrocephalus due to WWS was identified by the Manitoba DMD newborn screening programme, which measured CK in dried blood on filter paper, as a false positive for DMD; raised neonatal CK is therefore an expected finding in WWS [3]. Targeted carrier screening is possible in founder populations, such as the Ashkenazi Jewish population for FKTN c.1167dup (Section 8) [102].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

The Dobyns criteria for WWS (1989) require type II lissencephaly, cerebellar malformation, retinal malformation and CMD; ventricular dilatation and anterior chamber malformation are useful but not necessary [39]. No published consensus clinical criteria exist for FCMD [5]; the Japanese Information Center for Specific Pediatric Chronic Diseases publishes an official diagnostic sheet [40]. For all entities, the diagnosis is established by identifying biallelic pathogenic or likely pathogenic variants in a gene of the class; two variants of uncertain significance (VUS), or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [5]. For the LGMD category, the ENMC definition requires independent walking, raised CK, degenerative changes on muscle MRI and dystrophic histology [33].

5.2. Creatine kinase

CK is raised in most but not all patients [13]. In FCMD it is 10 to 60 times normal before 6 years, 5 to 20 times from 7 years and normal in bedridden patients [5]; the Japanese sheet gives values of several thousand (10 to 30 times normal) [40]. In the historical CMD chapter, the dystroglycanopathies had CK of 2 to 15 times normal (reference value 35–160 U/L), and primary or secondary merosin deficiency was distinguished from the subtypes with normal or mildly raised CK (collagen VI, SELENON) [16]. In the twins with POMK WWS, CK was 7159 and 8769 U/L [14]; a CK of about 3000 IU/L is given as a guide in the child with hydrocephalus [166]. In LGMD R11 it is 10 to 40 times the ULN, in R13 4 to 50 times and in R19 from 2 to more than 50 times [6, 69]. There is no clinically validated biomarker specific to the dystroglycanopathies: CK is used to monitor progression and response to treatment, but it varies with muscle mass and physical activity, which limits its interpretation in patients with advanced muscle loss [35]. The observational study Biomarker Development in LGMD2i (NCT04202627; sponsor ML Bio Solutions; 101 participants; December 2019 to October 2022, completed) sought to define LGMD R9 phenotypes with clinical assessments and to validate biomarkers for disease monitoring [35, 167].

5.3. Brain magnetic resonance imaging

The guideline of the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) recommends brain MRI when a dystroglycanopathy is suspected, if the risk of sedation is acceptable and an experienced radiologist is available (Level B); MRI predicts the subtype in some dystroglycanopathies [26]. The radiological hallmark is the "cobblestone" complex, from complete type II lissencephaly to focal, predominantly frontal, pachygyria or polymicrogyria, with possible occipital dysplasia; in the infratentorial compartment there is midbrain hypoplasia, a thick tectum, fused colliculi, pontomesencephalic angulation, a ventral pontine cleft, pontocerebellar hypoplasia, abnormal cerebellar foliation and cerebellar cysts [13]. Frontal polymicrogyria without infratentorial involvement suggests POMT1, POMT2 or LARGE1; isolated infratentorial involvement suggests ISPD; cerebellar cysts are frequent with POMGNT1 and FKRP [13, 131]. White matter hyperintensity, unlike in LAMA2 dystrophy, may regress and is not typical of patients with preserved intelligence [13, 16]. A normal brain MRI does not exclude POMT1 or POMGNT2 [71, 141].

5.4. Muscle biopsy

Histology is dystrophic, similar to the dystrophinopathies and sarcoglycanopathies, and may be subtle in neonatal biopsies; in FCMD, the main feature is interstitial fibrosis without marked degeneration and regeneration [5, 13]. Immunohistochemistry should use an antibody against the glycosylated epitope of α-dystroglycan (IIH6C4), and not against the core protein; the result is absent, nearly absent or reduced staining in all or some fibres, with normal β-dystroglycan, which distinguishes the secondary deficiency from the dystrophinopathies [13, 68]. Western blot shows reduction and a downward shift of the broad band of glycosylated α-dystroglycan [13]. There may be secondary reduction of laminin α2, with preserved laminin β1 and γ1 and intramuscular nerves with retained laminin α2, unlike LAMA2 dystrophy [13]. Single fixation of frozen sections in ethanol increased the intensity and consistency of the IIH6C4 membrane signal and reduced background, improving detection of low matriglycan levels [168].

Biopsy has three limitations. Abnormal staining confirms a dystroglycanopathy but does not identify the gene, because at least 18 genes give the same result [67]. The degree of deficiency does not necessarily correlate with severity, especially with FKTN and FKRP [6, 13]. And commercial antibodies require validation [13]. The AAN recommends biopsy with immunohistochemistry when the subtype is not apparent after the initial studies and if the anaesthetic risk is acceptable (Level C), performed and interpreted in experienced centres (Level B) [26]; the 2014 consensus favours biopsy when performed, interpreted and stored by experts, but accepts omitting it when clinical suspicion is strong and genetic testing is readily accessible [13]. With molecular testing, biopsy is no longer necessary for the diagnosis of FCMD [5]. O-mannosyltransferase and POMGnT1 activity in fibroblasts, laminin overlay and complementation assays are mainly research tools [13, 67, 72].

5.5. Electrophysiology, ophthalmology and other investigations

Electromyography shows a myopathic pattern (low-amplitude, short-duration, polyphasic motor unit potentials) and is not diagnostic [5, 13]. A decremental response to repetitive stimulation is not compatible with CMD and suggests congenital myasthenic syndrome, with the exception of GMPPB: for this gene, CMAP decrement at low frequency (2–3 Hz) is sought in proximal muscles, because a study limited to facial muscles may be normal [13, 61, 69]. Full ophthalmological examination includes refraction, intraocular pressure, fundoscopy and ERG [70]; giant VEP help to recognise MEB [124, 126]. There is no specific blood metabolite or serum marker [67]. Transferrin isoelectric focusing, the screening method for CDG, detects only N-glycosylation defects with sialic acid deficiency and does not detect isolated O-mannosylation defects [66]; even in dolichol defects it may be normal, as in 1 of 3 patients with DPM3-CDG [169]. Echocardiography is part of the initial assessment [26, 67].

5.6. Genetic testing: strategy and yield

The AAN recommends targeted testing in subtypes with a well-characterised molecular cause (Level C) and exome or genome sequencing when no variant is found in the usual genes or the phenotype is not characterised (Level C) [26]. In FCMD, outside Japanese, Korean or Chinese ancestry, FKTN is sequenced and deletion or duplication is sought if one or no variant is found; in patients of Japanese, Korean or Chinese ancestry, targeted analysis for the founder insertion precedes sequencing, supplemented in Korean ancestry by testing for c.648-1243G>T [5]. In populations with other founders, targeted testing for POMGNT1 c.1539+1G>A (Finland), FKTN c.1167dup (Ashkenazi Jews) or GMPPB p.(Asp334Asn) (southern India) may precede the panel [22, 102, 108]. In WWS, cleft lip or palate points to POMT1 [121], but clinical features and imaging do not predict the gene: in the Manzini cohort, patients with POMT1, POMT2, FKTN or FKRP variants were indistinguishable from one another and from patients without a variant [103].

Diagnostic yield has increased over time and depends on the population. In the 2015 guideline, detection was 20–46% in CMD in general, 30–66% in the dystroglycanopathies, up to 100% in FCMD, up to 100% in POMGNT1 MEB in founder populations and only 40% in WWS [26]. In 92 probands with dystroglycanopathy without FKRP variants (up to 2007), six genes then known explained 34% [44]; in WWS, POMT1 was estimated to account for about 20% of cases in 2002 and 7% in a series of 30 patients of diverse origins in 2005, and seven genes explained 50–60% in 2012 [3, 47, 55]. In fetuses with severe cobblestone lissencephaly (French series up to 2012), a molecular diagnosis was obtained in 58/90 (64%): POMT1 24 (42%), POMT2 10 (17%), POMGNT1 10 (17%), ISPD 5 (9%), TMEM5 5 (9%), LARGE1 2 (3%), FKRP 2 (3%) and FKTN 0 [56, 65]. In Italy, 75 of 135 dystroglycanopathies had a molecular diagnosis in 2015, with analysis ongoing in the rest [23]. These figures are not current sensitivities of exome or genome sequencing; the sources consulted do not describe contemporary yield by gene with genome sequencing.

Table 5.1. Proportion of pathogenic FKTN variants detected by method and ancestry

Source: FCMD GeneReviews chapter, Table 1 [5]. The values are the proportion of alleles or patients with each variant in the series, not the clinical sensitivity of the test.

5.7. Limitations of testing

The 3062 bp SVA insertion in FKTN is a structural variant of the 3' UTR that is sought by targeted analysis, with allele-specific polymerase chain reaction (PCR); long-read sequencing (Oxford Nanopore) has also identified it, and GeneReviews advises genome sequencing because several pathogenic FKTN variants, including a founder variant, are deep intronic [5]. Deep intronic variants, such as FKTN c.648-1243G>T, and regulatory variants escape exonic sequencing; genome sequencing and analysis of complementary DNA from muscle or fibroblasts help to identify them [5, 13, 90]. Intragenic deletions, described in POMT2, LARGE1 and CRPPA, require CNV analysis by quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA) or microarray, because the exome has lower sensitivity for CNVs [5, 13, 93]. Apparent homozygosity should be confirmed by parental testing, because it may correspond to hemizygosity due to a deletion on the other allele or to uniparental isodisomy [5, 13]. When the exome finds only one allele, transcriptomics may resolve the second: two siblings with B3GALNT2 variants had a maternal splice variant and a paternal 357 bp promoter deletion, identified by RNA sequencing of urine-derived cells and by genome sequencing [24]. A negative result does not exclude the disease; the 2014 consensus recommends keeping a record of patients without genetic confirmation [13].

5.8. Report content and variant interpretation

The report should state the gene, the transcript with version (preferably MANE), Human Genome Variation Society (HGVS) nomenclature at DNA and protein level, zygosity, the phase of the variants when known and the classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [2, 5]. For VUS, parental testing, in silico analysis, assessment of synonymous variants with a possible effect on splicing, α-dystroglycan glycosylation in muscle or fibroblasts and complementation assays help with reclassification [13]; in one patient with POMT2 variants, IIH6C4 immunostaining resolved a VUS [144]. The diagnostic algorithm can be used in reverse to assess the plausibility of a variant found on a panel [13]. In DAG1, ClinVar is dominated by VUS (455 VUS versus 23 pathogenic), and the published variants required functional support, segregation and absence in controls; the combination of LGMD + ID + normal MRI should be communicated to the laboratory [36]. The VUS count in ClinVar reflects panel use and not disease frequency [67].

5.9. Prenatal and preimplantation diagnosis

When the familial variants are known, prenatal diagnosis is performed on chorionic villi from 11 weeks, and preimplantation genetic testing is possible [5, 65]. In families with the Japanese founder insertion, haplotype analysis with markers close to the gene in chorionic villus DNA at 10–12 weeks is considered the most accurate method by the author of the GeneReviews chapter [5, 170]. Without a known variant, assessment of a pregnancy with suggestive malformations relies on fetal MRI and diagnostic genomic sequencing. The 2026 recommendations of the European Society of Human Genetics (ESHG) and the International Society for Prenatal Diagnosis indicate prenatal genomic sequencing for fetuses with a major anomaly or multisystem anomalies suggestive of a genetic cause, or with a pattern suggesting recurrence of an undiagnosed familial condition, and not as screening in the absence of ultrasound anomalies; they prefer trio testing, with informed CNV analysis and testing for maternal cell contamination, require variant classification to use the fetal phenotype and call for clear reanalysis policies [171]. Reporting a VUS with strong evidence ("hot VUS") is considered only in selected scenarios, after a documented decision by the multidisciplinary team [171].

5.10. Practical algorithm

Table 5.2. Diagnostic algorithm

6. Differential Diagnosis

The differential depends on the mode of presentation: cobblestone cortical malformation or fetal hydrocephalus, retinal dysplasia, a hypotonic infant with raised CK, LGMD with or without ID, DCM with hyperCKaemia, or fatigable weakness. Table 6.1 brings together the main entities.

Table 6.1. Differential diagnosis

The first decision is to separate the dystroglycanopathies from cortical malformations without muscle disease. Cobblestone lissencephaly due to ADGRG1, LAMB1, LAMC3, COL3A1 and TMTC3 has a similar cortical surface, but without ocular or muscle involvement; normal CK and absence of retinal dysplasia point to these genes [11, 17]. The tubulinopathies are distinguished by dysgyria with normal cortical thickness and by basal ganglia anomalies [172]. Classic lissencephaly has a thick cortex with a gradient and no CMD [65]. With occipital encephalocele, WWS is distinguished from Knobloch syndrome, the ciliopathies and the aneuploidies by very high CK, cobblestone lissencephaly and ocular malformations [14].

Among the CMDs, LAMA2 dystrophy is the closest differential, because it shares high CK, partial laminin α2 deficiency and brain anomalies; MRI with extensive, persistent white matter hyperintensity and absence of laminin α2 in intramuscular nerves favour LAMA2 [13, 16]. Congenital myasthenic syndromes present with normal or mildly raised CK, except the GMPPB form, which is at the same time a dystroglycanopathy and a myasthenic syndrome [19, 61]. MEB is distinguished from FCMD by spasticity, very large VEP and severe ocular involvement [42], and from WWS by the Finnish clinical criteria and, historically, by linkage to 1p32-p34 [43].

In the adolescent or adult with DCM and late-onset LGMD, FKTN dystroglycanopathy should be distinguished from LMNA laminopathy: both may have raised CK before weakness, but laminopathy carries an arrhythmic and sudden-death risk with an indication for an implantable cardioverter-defibrillator, which has not been described in the dystroglycanopathies [25, 146]. Isolated hyperCKaemia may correspond to a heterozygous DAG1 variant or to mild FKTN forms [15, 164]. LGMD with ID and normal brain MRI suggests POMT1, POMT2, POMGNT2 or DAG1 [36, 119, 150]. In seronegative myasthenia with a poor response to immunotherapy, the German guideline recommends considering a congenital myasthenic syndrome and performing genetic diagnosis [165].

7. Treatments and Risk Management Strategies

7.1. Principles and reference documents

There is no curative treatment and no medicine authorised for any dystroglycanopathy in the US or the EU as of 26 October 2026; management is supportive, multidisciplinary and anticipatory [26, 28, 35]. There is no guideline specific to the dystroglycanopathies and no published clinical practice guideline for FCMD [5, 67]. There are three reference documents. The evidence-based AAN and AANEM guideline (Kang 2015), reaffirmed by the AAN on 12 July 2024, covers the evaluation, diagnosis and management of the CMDs, including the dystroglycanopathies [26, 174]. The consensus of the International Standard of Care Committee for Congenital Muscular Dystrophies (Wang 2010), reached through a literature review, two surveys of experts and families and a three-day meeting, covers seven domains (diagnosis, neurology, pulmonology, orthopaedics and rehabilitation, gastroenterology, nutrition, speech and oral health, cardiology and palliative care) and is a consensus, not trial evidence [25, 67]. The FCMD GeneReviews chapter (2025) translates these documents into initial evaluations, treatment of manifestations and surveillance [5]. The 2014 AAN guideline on LGMD has been retired and should not be used as current practice [175].

Table 7.1. Recommendations of the AAN/AANEM guideline (2015) applicable to the dystroglycanopathies

Source: [26]. The guideline considers the evidence insufficient to determine the efficacy of specific respiratory, orthopaedic or nutritional interventions, whose recommendations rest on general principles [26, 68].

7.2. Respiratory care

In the dystroglycanopathies, respiratory failure may be early and is generally proportional to weakness and developmental delay; respiratory infections are the most frequent cause of admission and death in the CMDs and in FCMD [5, 25]. Assessment includes spirometry sitting and lying, crying vital capacity by mask in children who cannot cooperate, and tidal volume under two years. A difference of more than 20% between sitting and lying vital capacity indicates diaphragmatic weakness and predicts nocturnal hypoventilation; a forced vital capacity (FVC) below 60% predicted predicts sleep-disordered breathing and below 40%, nocturnal hypoventilation; a peak cough flow of 160–270 L/min is acceptable for airway clearance, and below this value the risk of infection increases [16, 25]. Early signs of nocturnal hypoxaemia (disturbed sleep, morning tiredness, changes in mood and concentration) precede those of hypercapnia (morning headaches, nausea, use of accessory muscles, fear of falling asleep) [25].

Assisted cough by mechanical insufflation-exsufflation is standard of care, especially with a peak cough flow below 270 L/min, combined with air stacking using a manual resuscitation bag and, when indicated, intrapulmonary percussive ventilation [25]. Non-invasive ventilation (NIV) is indicated, after reversible factors have been treated, for symptomatic daytime hypercapnia, symptomatic or asymptomatic nocturnal hypoventilation, growth failure, recurrent respiratory infections (more than three per year) and documented respiratory muscle weakness; in young children, the mask may cause midface hypoplasia, so interfaces are alternated [25]. In FCMD, nocturnal NIV should begin before acute respiratory difficulty, and survivors beyond 20 years may need tracheostomy or continuous non-invasive support [5, 176]. Tracheostomy is considered in severe bulbar involvement with chronic aspiration, uncontrolled secretions, intolerance of NIV for the number of hours needed, or by preference [25].

In acute illness, the child should be assessed immediately if SpO2 is below 94% or below baseline; carbon dioxide is measured before and during oxygen therapy, because oxygen alone may depress respiratory drive, and in carbon dioxide retention positive-pressure ventilation is preferred; NIV is the first option in respiratory failure, with intubation reserved for NIV failure, inability to clear secretions or loss of airway protection [25]. All patients should receive pneumococcal and influenza vaccines [16, 25]. The 2010 consensus recommended palivizumab (Synagis®) as prophylaxis against respiratory syncytial virus (RSV) in children under two years [25]; the current label of the long-acting antibody nirsevimab (Beyfortus®) specifies 50 mg intramuscularly in infants weighing less than 5 kg and 100 mg in those weighing 5 kg or more in the first season, and 200 mg (2 × 100 mg) in children up to 24 months who remain vulnerable in their second season [177]. Severe CMDs are not a named indication on the label, and extrapolation to the group of children with neuromuscular disease depends on national guidance.

7.3. Feeding, swallowing, digestive tract and oral health

In dystroglycanopathies with neurological impairment, problems of oral coordination (drooling, chewing, swallowing, aspiration) are frequent [25]. At each visit, meal duration (more than 30 minutes is prolonged), frequency, pulmonary infections, choking or coughing, texture modifications, independence and position are assessed; videofluoroscopic swallowing study is performed by a speech and language therapist [5, 25]. Thickening or cooling food helps; a nasogastric tube is for short-term use only, and gastrostomy (or jejunostomy) is indicated for dysphagia, poor weight gain, meals longer than 30 minutes or risk of aspiration, with no consensus on associated Nissen fundoplication [5, 25, 26]. GORD and dysmotility (slow gastric emptying, constipation) are common: reflux is treated with a proton pump inhibitor or H2 antagonist, with or without a prokinetic; constipation with texture, fluids, mobilisation and laxatives, with stool softeners or osmotic agents that are safe for continuous use; mineral oils should be avoided because of the risk of aspiration [5, 25]. The repeated bowel obstructions described in adult women with MEB warrant attention to constipation throughout life [125]. Assessment by a paediatric dentist should take place before two years or at diagnosis, with reviews at least every six months, and by an orthodontist at around six years [25]. Serum vitamin D is part of the nutritional assessment, with supplementation if indicated [5, 16].

7.4. Epilepsy, hydrocephalus and neurodevelopment

Epilepsy. Seizures in the α-dystroglycanopathies begin from the neonatal period to adolescence, are often provoked by fever, are focal or multifocal with secondary generalisation, and may progress to status epilepticus; treatment is more often difficult [25]. The drugs described in the consensus include phenobarbital, valproic acid, carbamazepine, phenytoin, levetiracetam, clonazepam, zonisamide and acetazolamide, with no data on the ketogenic diet, vagus nerve stimulation or epilepsy surgery; no source indicates a preferred drug [25]. GeneReviews recommends standard antiseizure medications managed by an experienced neurologist, limiting the number of drugs and educating carers [5]. In MEB, about 21% of patients with epilepsy are drug-resistant, and control may require polytherapy; one woman with POMGNT1 variants needed four antiseizure medications and had status epilepticus in adulthood [128]. As an example of dosing, the FDA label of levetiracetam (Keppra®) for focal seizures specifies 7 mg/kg twice daily between 1 and 6 months, increasing by 7 mg/kg twice daily every two weeks to 21 mg/kg twice daily; 10 mg/kg twice daily from 6 months to 4 years, up to 25 mg/kg twice daily; 10 mg/kg twice daily from 4 to 16 years, up to 30 mg/kg twice daily; and 500 mg twice daily from 16 years, up to 1500 mg twice daily, with oral solution below 20 kg and adjustment for renal function [178]. This is the general indication for focal seizures, not an indication specific to the disease. Amifampridine is contraindicated in patients with a history of seizures (Section 7.9) [179].

Hydrocephalus and encephalocele. With significant ventricular dilatation, imaging is repeated to decide on the indication for surgery [5]. Ventriculoperitoneal shunting (VPS) and neurosurgical repair of the meningoencephalocele in the perinatal period were used in the twins with POMK variants (Section 10) [14]; in a single case of WWS, endoscopic third ventriculostomy with choroid plexus cauterisation maintained cerebrospinal fluid flow at 14 months [180]. These approaches are case reports and not comparisons between techniques.

Neurodevelopment, behaviour and vision. Psychometric assessment, early intervention (0–3 years), special preschool, an individual education plan and augmentative and alternative communication, which does not hinder speech, are part of care [5, 25]. Behavioural changes and autistic traits are referred to child psychology or psychiatry; anxiolytics are weighed against sedation [5, 25]. Cortical visual impairment should be included in early intervention and school programmes [5].

7.5. Ophthalmology

In the α-dystroglycanopathies, a detailed early eye examination is recommended, with refraction, intraocular pressure, fundoscopy and ERG, and follow-up for cataracts, glaucoma, retinal detachment and visual impairment, with low-vision services [16, 25, 70]. In MEB, juvenile cataracts, congenital glaucoma and myopia of −6 to −27 dioptres require continued follow-up, because the changes are progressive [126]. In isolated POMGNT1 RP76, the measures are those of the retinal dystrophies (UV-filter lenses, low-vision aids, cataract extraction when it dominates visual loss, treatment of cystoid macular oedema); voretigene neparvovec (Luxturna®) is indicated only in biallelic RPE65 retinal dystrophy and does not apply [70].

7.6. Heart

The AAN guideline recommends baseline cardiac assessment in all children with CMD, with intervals set by the result and subtype (Level B) [26]. The international consensus specifies for the dystroglycanopathies an electrocardiogram (ECG) and echocardiogram at diagnosis and then at least annually, and at least every six months if there are symptoms, conduction abnormalities or myocardial involvement; it regards an LV ejection fraction (LVEF) below 50% as abnormal and recommends starting medical treatment even in mild dysfunction, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers being the most appropriate cardioprotective agents; radionuclide ventriculography replaces echocardiography when chest deformity prevents a good window [25]. The FCMD GeneReviews chapter recommends prompt treatment with ACE inhibitors and beta-blockers for worsening ventricular dysfunction [5]. Severe heart failure is managed as in the general paediatric population [25].

No dystroglycanopathy guideline specifies doses. The FDA label of enalapril oral solution (Epaned®) specifies, in paediatric hypertension above one month of age, 0.08 mg/kg (up to 5 mg) once daily; in adult heart failure, 2.5 mg twice daily up to 20 mg twice daily, and in asymptomatic left ventricular dysfunction, 2.5 mg twice daily up to 10 mg twice daily [181]. The paediatric dose for heart failure is not on the label, and use in the cardiomyopathy of the dystroglycanopathies is an extrapolation. The label of carvedilol (Coreg®) states that efficacy below 18 years has not been established: in a double-blind trial of 161 children (2 months to 17 years) with heart failure, both doses reduced heart rate by 4–6 beats per minute, without a significant effect on clinical outcomes at 8 months [182]. The choice and titration of beta-blockers in children therefore rests with paediatric cardiology.

Heart transplantation is established in DOLK-CDG: three children with rapidly deteriorating DCM underwent transplantation, two were stable at 1–5 years and one died unexpectedly, in the first successful organ transplant in a CDG; the authors recommend testing DOLK in DCM and diagnosing early [113]. Transplantation was also performed in a 22-year-old woman with advanced FKTN DCM [146]. In mild DOLK DCM, stability does not predict a benign course, and acute infections require close cardiac monitoring [78, 113]. Severe arrhythmias have not been described in the dystroglycanopathies, and the indication for an implantable cardioverter-defibrillator described in the consensus refers to the laminopathies [25].

7.7. Orthopaedics, rehabilitation and spasticity

Physiotherapy and occupational therapy maintain mobility and prevent contractures, scoliosis and hip dislocation; they include daily stretching (limbs, iliotibial bands, neck, spine, jaw), splints, standing programmes and serial casting, orthoses that respect respiratory function, wheelchairs and adapted seating [5, 25]. Lower limb surgery is decided only after discussion; Achilles tendon lengthening may cause loss of walking if there is pelvic weakness, and the knee is operated on when a contracture greater than 90° prevents sitting [25]. In early-onset scoliosis, treatment is initially conservative, followed by non-fusion techniques (growing rods, vertical expandable prosthetic titanium rib) if it fails; in the older child, arthrodesis is performed with neuromonitoring, extending to the upper thoracic spine and the pelvis in non-ambulant patients, with intensive respiratory physiotherapy for up to six months postoperatively [25]. Spinal arthrodesis preserves respiratory function and sitting balance; a class III study showed correction and prevention of progression of scoliosis and pelvic obliquity at two years, with uncertain respiratory impact [5, 26]. The Garchois-type spinal orthosis, which does not compress the chest, may defer surgery until puberty, with spirometry with and without the orthosis [16, 25]. In a pilot series of three non-ambulant children with FCMD, a hip orthosis for six months stabilised or slightly improved the Reimers migration percentage in two and did not prevent progression in one, compared with three historical controls who worsened; efficacy cannot be determined with this design [183].

For hypertonia or dystonia, the FCMD GeneReviews chapter mentions baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs and orthopaedic procedures [5]. The FDA label of oral baclofen specifies titration from 5 mg three times daily, with increases every three days up to 20 mg three times daily (usual optimal dose 40–80 mg/day, maximum 80 mg/day), slow tapering on withdrawal, and states that safety and efficacy below 12 years have not been established [184]. The tizanidine label specifies 2 mg up to three times in 24 hours, with increases of 2–4 mg per dose every 1–4 days, maximum 36 mg/day, and states that paediatric safety has not been established [185]. In the dystroglycanopathies, both are off-label use in the paediatric age groups. Botulinum toxin should generally be avoided (AAN Level C), and the label of onabotulinumtoxinA (Botox®) carries a boxed warning about distant spread of toxin effect, with generalised asthenia, dysphagia and breathing difficulty, the risk probably being greater in children treated for spasticity [26, 186].

7.8. Corticosteroids

The evidence on corticosteroids in the dystroglycanopathies consists of small series and one open-label trial. Three children with FKTN LGMD, from two Caucasian families, had severe weakness after intercurrent illness with a remarkable response to corticosteroids [91]; the 2014 consensus describes a rapid myositis-like decline, partially responsive to corticosteroids, in some patients [13]; and the historical GeneReviews chapter on CMD states that corticosteroids at DMD guideline doses appear to prolong walking in responders [16]. In FCMD, a single-arm open-label trial (UMIN000020715, 2016–2019) treated nine children aged 3 to 10 years with verified motor decline (eight homozygous for the insertion, one compound heterozygous; one mild form, seven typical, one severe) with oral prednisolone 0.5 mg/kg on alternate days, increased to 1.0 mg/kg if the response was insufficient; the final doses were 0.5 mg/kg (2 patients), 0.7 mg/kg (1) and 1.0 mg/kg (6) on alternate days, with a mean age at start of 8.1 years and a mean duration of 8.9 months [132]. The total Gross Motor Function Measure (GMFM) score rose by a mean of 1.23 points (standard deviation 1.10; P = 0.015), with an increase in 8 of 9 patients, and there was less drooling (3), a stronger voice (1) and greater motivation (6) [132]. Adverse effects were irritability or insomnia (4), increased appetite (1) and moon face (1), with no discontinuations; all the children disliked the bitter taste of prednisolone, and the study ended when the Japanese clinical trials law came into force [132]. The small n, absence of a control group, differing doses and short duration preclude conclusions on efficacy, and the dose of 0.5 mg/kg on alternate days is equivalent to 0.25 mg/kg/day, below the minimum effective dose in DMD cited by the authors (0.3 mg/kg/day) [132]. The FCMD GeneReviews chapter mentions corticosteroid therapy as contributing to maintaining or improving motor function in deteriorating patients [5]. The 2026 Lancet Neurology review places corticosteroids as empirical use in some forms, aimed at reducing muscle inflammation, and stresses that, unlike in DMD, they are not an accepted standard treatment in the dystroglycanopathies [35].

In LGMD R9, the phase 3 trial of deflazacort (Emflaza®; NCT03783923) was terminated with 11 participants [167]. Corticosteroid labels carry no indication in the dystroglycanopathies (Table 7.2). Before starting corticosteroids, live vaccines should be given at least 4–6 weeks beforehand, and growth suppression should be considered if treatment begins early [132, 187, 188].

Table 7.2. Corticosteroids: published and label doses (off-label use in the dystroglycanopathies)

7.9. Patients with GMPPB variants and a neuromuscular transmission defect

In the subgroup of patients with GMPPB variants and clinical and electrophysiological evidence of a neuromuscular transmission defect, acetylcholinesterase inhibitors improve strength, alone or combined with 3,4-diaminopyridine (amifampridine) or salbutamol [27, 61, 192]. The GeneReviews chapter on myasthenic syndromes classifies the response as improvement, and GMPPB is not among the subtypes that are refractory to or worsened by pyridostigmine (slow channel, COLQ, DOK7) [19, 69]. The treatabolome review recommends acetylcholinesterase inhibitors, accepts additional benefit from 3,4-diaminopyridine and salbutamol (or ephedrine) and notes that no effect on the dystrophy is expected [27]. Three siblings treated with pyridostigmine in Barcelona improved within hours, markedly within two days, remained stable for 12 months and then had a moderate decline in two, remaining above baseline at 40 months; starting before scoliosis was considered possibly protective [193]. In the series with the southern Indian founder variant, 10 of 12 patients had variable improvement with pyridostigmine, salbutamol or both [108]. In a systematic review of salbutamol in congenital myasthenic syndromes (70 studies, 236 patients), the 14 patients with GMPPB variants improved, with rare and mild adverse effects (tremor, palpitations) [194]. The response is not uniform: between two siblings with the same variant, the brother improved in a sustained way with pyridostigmine and the sister, with a myopathic phenotype, responded poorly to pyridostigmine and improved with β-adrenergic agonists [117].

The junctional component is not universal; pyridostigmine should follow evidence of a transmission defect and not the genotype alone, and fatigable weakness in an established dystroglycanopathy should prompt repetitive stimulation [69]. There is no randomised trial; the evidence comes from case series and expert classification [27, 69]. The myasthenic phenotype has not been described with DAG1, and extension of acetylcholinesterase inhibitors to other genes of the class has not been tested [36].

Table 7.3. Neuromuscular junction drugs (off-label use in GMPPB dystroglycanopathy)

3,4-Diaminopyridine requires special caution in dystroglycanopathies with epilepsy, because a history of seizures is a contraindication on the US label [179]. In pregnancy, the safety of pyridostigmine has not been established, experience in myasthenia has not shown unfavourable effects on the course of pregnancy, pyridostigmine crosses the placenta and the newborn should be monitored; it passes into breast milk in amounts considered negligible [195].

7.10. Anaesthesia, sedation and agents to avoid

The AAN recommends discussing with the family the increased risk of complications of general anaesthesia and prolonging postoperative monitoring (respiratory, nutritional, mobility and gastrointestinal motility complications) (Level B), without a specific recommendation on agents [26]. The 2010 consensus adds assessment of cough and nocturnal oximetry before surgery, anaesthesia or sedation in patients at risk, preoperative training with an insufflator-exsufflator, introduction of NIV preoperatively when it is likely to be needed, early extubation to NIV and nutritional optimisation; it warns of the risk of malignant hyperthermia-like reactions, greatest in patients with SELENON variants, and of the risks of elective surgery outside a specialist paediatric hospital [25]. The label of suxamethonium (suxamethonium; Quelicin®) carries a boxed warning of acute rhabdomyolysis with hyperkalaemia, ventricular arrhythmias, cardiac arrest and death in children with undiagnosed myopathy, especially DMD, and reserves its paediatric use for emergency intubation [198]. The sevoflurane label describes rare perioperative hyperkalaemia with arrhythmias and death in children with latent or overt neuromuscular disease, especially DMD [199]. Applying these warnings to the dystroglycanopathies, which are dystrophies with raised CK, is a class extrapolation, because no guideline consulted issues a specific recommendation. The agents to avoid or use with caution are therefore suxamethonium, volatile anaesthetics (weighed case by case), botulinum toxin outside a clear indication, amifampridine in patients with epilepsy, oxygen alone without carbon dioxide monitoring in hypercapnia, and mineral oils [25, 26, 179, 198, 199].

7.11. Infections, fever and rhabdomyolysis

In FCMD, sudden worsening of weakness with very high CK and myoglobinuria a few days after a febrile viral infection may be fatal; reports preceding the Murakami trial described benefit from short courses of corticosteroids in this post-viral worsening [132, 139]. The sources consulted do not describe a standardised protocol; the general principles are hydration, monitoring of CK and renal function, and prompt treatment of respiratory infections [5, 25]. In DPM1-CDG, death from fulminant sepsis warrants a low threshold for escalating care in intercurrent infections, without a characterised immunodeficiency [75, 153]. Oral mannose, effective in MPI-CDG, has no role in DPM-CDG, because the block is downstream [75].

7.12. Palliative care, communication, transition and pregnancy

Disclosure of the diagnosis should address the diagnosis, prognosis, recurrence risk, treatment plan and support for the family [25]. Palliative care should begin at diagnosis; in the most severe, life-limiting forms, such as WWS, end-of-life conversations should take place before the first life-threatening event, with a written emergency plan, a care coordinator, multifactorial pain assessment, psychological support, bereavement resources and the option of tissue donation for research [25, 67]. Family support includes social services, carer respite, home nursing and adapted sport [5]. Transition to adult care should be planned from about 10 years of age in FCMD [5].

No reproduction by people with FCMD is known [5]. In LGMD forms, pregnancy is possible; the sources consulted do not describe pregnancy series in the non-FKRP dystroglycanopathies, and in LGMD R9 there is published experience, including heart failure in pregnancy. The applicable principles are cardiac and respiratory assessment before conception, monitoring of cardiomyopathy during pregnancy and anaesthetic planning for delivery according to Section 7.10, with the label information available on pyridostigmine (Section 7.9) [25, 26, 195].

7.13. Regulatory status

Table 7.4. Regulatory status in the US and EU (26 October 2026)

The sources consulted did not include the status at the Brazilian Health Regulatory Agency (ANVISA).

7.14. Clinical trials and interventional studies

Table 7.5. Trials and interventional studies relevant to the class

The FORTIFY trial is the only controlled study in the class and concerns FKRP; the primary endpoint values and confidence intervals are not in the press release, the analysis is interim and the study has not been published in a journal [200]. The ribitol dose reported in the phase 1 study (9 g and 12 g twice daily for 30–50 kg and over 50 kg) is an investigational dose, with no label [201]. No interventional trials for WWS, MEB, FCMD or non-FKRP dystroglycanopathies were found on ClinicalTrials.gov; Japanese registries were not searched systematically, and a negative search does not demonstrate that no studies exist [167]. Terminated trials or those without published results (deflazacort, domagrozumab) do not allow benefit to be concluded, and results from different studies should not be compared indirectly.

7.15. Research and developments in the last twelve months

Between October 2025 and October 2026, the developments of greatest clinical reach were regulatory and concern FKRP: the FORTIFY interim analysis (press release of March 2026) and acceptance of the BBP-418 NDA with priority review (press release of May 2026), with a stated intention to study ribitol in LGMD R13 and R20 [28, 200]. The 2026 Lancet Neurology review confirms that management is purely symptomatic and that adeno-associated virus (AAV) gene therapy for FKRP and ribitol-based therapies are in trials [35].

At the preclinical level, heterozygous Gmppb p.(Pro32Leu) mice (published designation, murine protein) develop progressive dystrophy, loss of Purkinje cells and peripheral demyelination, with diffuse hypoglycosylation and suppression of the Wnt/β-catenin pathway; activation of the Wnt pathway with the GSK3β inhibitor CHIR-99021 restored myogenic capacity, and AAV GMPPB gene replacement restored α-dystroglycan glycosylation and corrected the motor and electrophysiological deficits [202]. In cells from seven patients with GMPPB-CDG, glycogen accumulation and reduced acid α-glucosidase activity were corrected in vitro by the recombinant enzyme, without clinical data [203]. ASOs for the SVA insertion and the deep intronic FKTN variant remain preclinical [99, 109], as do CDP-ribitol or ribitol supplementation in ISPD-deficient cells and AAV9 gene therapy for FKTN and FKRP in mouse models, which is more effective when given early [62, 63, 204, 205]. Also published were a spontaneous primate model of POMT1 α-dystroglycanopathy [206], basic biology studies on matriglycan polymerisation by LARGE1 and the xylose phosphatase activity of dystroglycan [207, 208], optimisation of IIH6C4 immunohistochemistry [168] and quantification of glycosylated α-dystroglycan as a severity biomarker in LGMD R9 [209].

7.16. Convergence and divergence between sources

The AAN (2015) and the international consensus (2010) converge on neuromuscular coordination, cardiac and respiratory assessment, and nutritional and orthopaedic support; they diverge in specificity, because the AAN leaves cardiac intervals to the subtype whereas the consensus sets them at least annually in the dystroglycanopathies and every six months when abnormalities are present [25, 26]. The FCMD GeneReviews chapter proposes annual echocardiography from 10 years if the baseline is normal (Table 5) and, in general, every six months above 10 years (Table 7) [5]; the cardiogenetics textbook proposes annual assessment in FCMD, especially after 10 years, and every two years in FKTN LGMD, extrapolating from LGMD R9 [151]. The recommendation adopted in this article, consistent with the most specific sources, is ECG and echocardiography at diagnosis, then at least annually in all dystroglycanopathies and every six months in FCMD above 10 years and in any patient with symptoms, conduction abnormalities or ventricular dysfunction (Section 11). The palivizumab of the 2010 consensus has since been joined by a long-acting antibody on the current label [25, 177].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All syndromic forms and the LGMDs of the class are autosomal recessive. The parents of an affected individual are presumed to be heterozygous, and molecular testing of the parents is recommended; heterozygotes are asymptomatic and are not at risk of the disease [5, 65]. In each pregnancy of the couple, the risk of an affected child is 25%, of an asymptomatic carrier 50% and of an unaffected non-carrier child 25% [5]. The parents' siblings have a 50% probability of being carriers [5]. Intrafamilial variability is large, especially with POMT2, CRPPA and GMPPB: the same genotype may give discordant phenotypes between siblings, so the phenotype of one sibling does not reliably predict that of another [94, 116, 117].

If only one parent is a carrier, with confirmed paternity, a de novo variant in the proband or a postzygotic variant in a mosaic parent should be considered [5]. Apparent homozygosity should raise the possibility of a deletion of one or more exons on the other allele, not detected by sequencing, or of uniparental isodisomy [5, 13]. The heterozygous DAG1 variants associated with mild phenotypes, described in 2026, were transmitted from a father to three children; in these families autosomal dominant counselling is appropriate, whereas LGMD R16 and MDDGA9 are counselled as recessive [15, 36].

8.2. Carrier testing and cascade testing

Carrier detection requires prior identification of the familial variants [5]. Partners of known carriers should be tested, especially if they share the same ancestral origin, in populations with the Japanese, Korean and Chinese FKTN founder variants [5]. In the Ashkenazi Jewish population, the carrier frequency of FKTN c.1167dup is 0.7% (2/299 healthy adults in the US; 0.7% in Israel), which makes targeted testing and carrier screening useful [102, 103]. In Finland, the carrier frequency of POMGNT1 c.1539+1G>A is about 1/60 [22]. Counselling should be provided by genetics professionals, with non-directive information and referral to support groups [5, 210]. The optimal time to assess risk and discuss prenatal diagnosis is before pregnancy, including counselling of young adults who are carriers or at risk [5].

8.3. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis is performed on chorionic villi from 10–12 weeks, and preimplantation genetic testing is possible; in families with the Japanese founder insertion, haplotype analysis is used in Japan [5, 65, 170]. In the absence of a known variant, ultrasound looks for the associated features (hydrocephalus, encephalocele, cerebellar hypoplasia, microphthalmia), bearing in mind that lissencephaly is not reliably detected on ultrasound before 28 weeks and that fetal MRI is more accurate [38, 65]. The 2026 ESHG/ISPD recommendations favour trio genomic sequencing in fetuses with suggestive anomalies, with an explicit policy on reporting VUS and incidental findings and with manual inspection of reads for apparently de novo variants, so as not to miss low-level parental somatic mosaicism that alters the recurrence risk [171]. Views on the use of prenatal and preimplantation diagnosis differ between families and professionals, and the decision is personal [5].

8.4. Counselling on the offspring of patients and on minors

No reproduction by people with FCMD is known [5]. Patients with LGMD forms may have children; all children of an affected individual are obligate carriers, and the risk of an affected child depends on the partner's carrier status, being higher in consanguineous unions or within the same founder population [5, 6]. The sources consulted do not issue a specific recommendation on carrier testing in asymptomatic minors. Diagnostic testing of a sibling with signs, even mild ones such as hyperCKaemia, is justified by the baseline cardiac assessment and respiratory surveillance that follow from it [26, 164].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The available figures measure different things and are not comparable with one another (Table 9.1). The birth prevalence of WWS of 1.65/100,000 in Europe is an expert estimate validated by Orphanet, without a published study; the figure of 1.2/100,000 in Italy, which Orphanet attributes to the study by Mostacciuolo (1996), comes from a CMD study in north-eastern Italy predating gene identification [7, 67, 211]. The point prevalence of 0.03/100,000 in northern England comes from a muscle disease clinic population that included a single patient with an α-dystroglycan defect [20]. The roughly 50-fold difference between birth prevalence and point prevalence reflects early mortality [67]. Paul and colleagues cite a prevalence of about 1/60,500 by indirect attribution [14].

Table 9.1. Epidemiological estimates

The divergence between the 7–12/100,000 births of GeneReviews and the 2.8/100,000 of Orphanet for FCMD in Japan is not explained in the sources; both cite the same origin [5, 10]. In the Italian series, mild or late-onset cases may not have been referred, and the measure is the prevalence of patients under follow-up, not incidence [23]. The 2016 meta-analysis stresses the great heterogeneity of ascertainment methods [213].

9.2. Relative distribution of the genes

In Italy (2013), among the dystroglycanopathies, POMT1 was the most frequent gene (15.5%), followed by FKRP (12.59%), POMGNT1 (10.37%) and POMT2 (9.62%); of the 68 patients without a variant in the six classic genes, only 18 were studied for recent genes, with variants in 8 (ISPD 3, DPM2 2, GMPPB 2, B3GALNT2 1) [23]. In the United Kingdom and an international cohort (up to 2007), among 92 probands without FKRP variants, the most frequent genes were POMT2 (9), POMT1 (8), POMGNT1 (7), FKTN (6) and LARGE1 (1) [44]. In the Australian series of 101 CMDs cited by Norwood, defects of glycosylated α-dystroglycan were the most common group (25%) [20]. In the European MYO-SEQ project, 24 patients out of more than a thousand sequenced had a dystroglycanopathy, with variants in FKRP, POMT1, POMT2, FKTN and GMPPB; in a Finnish population of 182 LGMD patients, FKRP explained 32 and GMPPB 2 [33]. In WWS (up to 2008), the distribution depended on origin: in the Middle East, POMT1 in 5/14, POMT2 in 2/14 and FKRP in 1/14; in Europe and the Americas, FKTN in 5/27, POMT1 in 2/27; in the three Ashkenazi patients, FKTN in 3/3 [103]. LGMD R9 is probably the most common LGMD in European populations of the United Kingdom and Denmark, but explains only 8% of families with LGMD in the Netherlands [151, 214].

9.3. Founder populations

Table 9.2. Founder variants and populations

In populations with consanguineous marriages (Middle East, Turkey, Morocco, Pakistan, Egypt), WWS and MEB due to POMT1, POMT2, POMGNT2 and POMK occur mainly in homozygosity, and homozygosity mapping guides testing [3, 14, 55, 103, 116, 130]. The FKTN founder insertion is absent in non-Asian patients, so the Japanese targeted test does not apply outside East Asia [5].

9.4. Portugal and Brazil

The main sources consulted do not present epidemiological data or series of dystroglycanopathies from Portugal or Brazil. The Brazilian textbook of genetic syndromes gives, for the CMDs as a whole, a prevalence of 1/60,000 at birth and 1/100,000 in the population, without a primary source [210]. The international committee that drew up the 2010 consensus included members from Brazil (São Paulo) [25]. The absence of data in these sources does not demonstrate the absence of published studies.

9.5. Special populations

Newborns and infants with severe forms account for most of the mortality and admissions, especially in the first six months [25]. Adolescents with FKRP, FKTN and POMT1 variants account for most admissions for heart failure [25]. Adults with LGMD or isolated DCM may reach diagnosis through cardiology, sometimes after transplantation [145, 146]. Adults with MEB survive into middle age with permanent care needs [125].

9.6. Reference networks and patient associations

The relevant European network is ERN EURO-NMD, for rare neuromuscular diseases [29]. International resources include Cure CMD and the CMDIR registry (NCT01403402), TREAT-NMD, the Muscular Dystrophy Association (US), AFM-Téléthon (France), Muscular Dystrophy UK, the Japan Muscular Dystrophy Association, which maintains the national FCMD registry, The Speak Foundation and LGMD-info for the LGMDs, and the European Neuromuscular Centre [5, 30, 31, 133]. In Portugal, the Associação Portuguesa de Neuromusculares (APN); in Brazil, the Associação Brasileira de Distrofia Muscular (ABDIM) [32]. The natural history study "Clinical Trial Readiness for the Dystroglycanopathies" (NCT00313677, University of Iowa) is recruiting, with a target of 190 participants and primary completion expected in 2030 [167].

10. Illustrative Clinical Case

10.1. Monozygotic twins with POMK Walker-Warburg syndrome

Paul and colleagues described, at Essen University Hospital (Germany), two monozygotic twins with WWS and meningoencephalocele [14]. The parents were healthy first cousins; of their nine children, six were healthy, one had died postnatally from complications of hydrocephalus, with no material available for study, and three paternal cousins had non-specific developmental delay (Figure 1 of the article, pedigree). Prenatal ultrasound at 22–23 weeks showed occipital encephaloceles, hydrocephalus and cerebellar hypoplasia in both fetuses (Figure 2), and prenatal MRI at 23+4 weeks confirmed the hypoplastic cerebellum, occipital meningocele, persistent primary vitreous and internal hydrocephalus (Figure 3, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC7488248/figure/Fig3/) [14].

The twins, monochorionic and diamniotic, were born at 35+2 weeks by caesarean section, weighing 2330 g, 47 cm long and with a head circumference of 31 cm (−1.3 standard deviations) the first, and 2230 g, 47 cm and 30.5 cm (−1.6 standard deviations) the second [14]. The first had right microphthalmia and a left coloboma; the second, bilateral persistent hyperplastic primary vitreous and a left posterior staphyloma; both were blind, and postnatal ultrasound showed lissencephaly with polymicrogyria (Figure 4). They had severe sensorineural deafness on brainstem auditory evoked potentials, severe generalised hypotonia, hyporeflexia and little spontaneous movement, and an occipital protuberance that histology confirmed as a meningoencephalocele (Figure 5, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC7488248/figure/Fig5/). CK was 7159 U/L and 8769 U/L, with raised transaminases and lactate dehydrogenase. Brain and spinal MRI on the second and third days showed a midline occipital meningocele with the fourth ventricle open dorsally, hypoplasia or aplasia of the vermis, a long, narrow thoracic cord, internal hydrocephalus, dysgyria with a generalised polymicrogyria-type cobblestone malformation and bitemporo-occipital subcortical band heterotopia (Figure 6, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC7488248/figure/Fig6/) [14].

A WWS gene panel (FKRP, FKTN, ISPD, B3GNT1, COL4A1, LARGE, POMK, TMEM5) identified the homozygous nonsense variant NM_032237.4:c.640C>T p.(Gln214Ter) in POMK, confirmed by Sanger sequencing, with both parents heterozygous; on the current MANE transcript (NM_032237.5) and in the genome, the variant corresponds to NC_000008.11:g.43122464C>T [2, 14]. Management included neurosurgical repair of the meningoencephalocele and VPS in the perinatal period, treatment of structural epilepsy with generalised seizures (with refractory status epilepticus in the first twin), hearing aids, physiotherapy, early education and follow-up by a palliative care team, with repeated admissions for refractory seizures and severe respiratory infections [14]. Neither twin achieved developmental milestones, including head control, and both became tetraplegic; the second died at 17 months of cardiorespiratory failure due to aspiration, and the first, at 30 months, had no psychomotor development and a head circumference of 44 cm (−5.0 standard deviations) [14].

The case brings together the features that define WWS according to Dobyns (cobblestone lissencephaly, cerebellar malformation, retinal malformation and dystrophy with very high CK), the hydrocephalus and encephalocele that extend the HARD ± E acronym, and the sensorineural deafness described with POMK [14, 39]. It also illustrates three practical points: prenatal diagnosis of the structural findings at 22–23 weeks, the usefulness of CK measurement in a newborn with weakness and encephalocele, and the combination of comfort-oriented neurosurgical interventions with palliative care from the outset [14, 25]. The review accompanying the case showed that, by 2020, only 5 of 9 families with POMK variants had WWS (8 individuals, 4 terminations of pregnancy), and that the homozygous nonsense variant NM_032237.5:c.325C>T p.(Gln109Ter) produced, in different families, phenotypes ranging from WWS to an LGMD with walking at 25 years [14]. The neurosurgical management described is that of an individual case and not a routine recommendation; the guidelines do not compare shunting techniques and recommend that, in life-limiting forms, decisions be taken within a previously discussed palliative care plan [25].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends on the position in the spectrum. In WWS, median survival in the 1989 series was 9 months, most children die in the first year of life and 5–10% survive beyond five years; there are survivors up to 3.5 years with POMT1 and up to 19 and 21 years with RXYLT1, which shows that the WWS designation is not equivalent to an individual prognosis [3, 8, 39, 87]. In MEB, survival is longer: deterioration with spasticity begins at about five years, but the picture may stabilise from adolescence, with survival documented into middle age; with POMT2, three patients in one series died at 15 and 16 years [42, 125, 130]. In FCMD, motor function peaks at 5–6 years and then declines; many patients are bedridden after 15 years, and deaths frequently occur before 20 years from respiratory failure or cardiomyopathy, respiratory infections being the most frequent cause of admission and death; survivors beyond 20 years may need ventilatory support [5, 40, 132]. In the LGMDs of the class, walking is maintained for years (at least 15 years after onset in LGMD R11), cognition varies with the gene and life expectancy depends mainly on the heart and breathing [6, 119]. In cardiac DOLK-CDG, the course may be stable or deteriorate within days, and transplantation has changed the prognosis [113]. Survival data for WWS and FCMD come largely from series predating current respiratory and nutritional care, and the sources consulted do not describe recent survival series with standardised care.

11.2. Surveillance

Table 11.1. Surveillance plan

The cardiac intervals in the table follow the sources most specific to the class; the FCMD GeneReviews chapter accepts annual echocardiography from 10 years if the baseline is normal, and the cardiogenetics textbook proposes two-yearly intervals in FKTN LGMD (Section 7.16) [5, 151].

11.3. Registries and trial readiness

Participation in registries and natural history studies allows progression to be measured and trials to be prepared: the "Clinical Trial Readiness for the Dystroglycanopathies" study (NCT00313677) has been recruiting since 2006, the Cure CMD CMDIR registry (NCT01403402) collects data on patients with congenital muscle diseases, the Japanese national FCMD registry had gathered 207 patients by 2013 and the Global FKRP Registry (NCT04001595) has had unknown status since 2024 [133, 167]. The 2014 consensus recommends keeping a record of patients without genetic confirmation [13].

12. Summary and Concluding Remarks

The dystroglycanopathies form a class of autosomal recessive disorders in which lack of α-dystroglycan matriglycan prevents the cell from binding to the basement membrane. Walker-Warburg syndrome lies at the severe end of a continuous spectrum that includes muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital dystrophies with or without intellectual disability and the limb-girdle dystrophies, and that is caused by variants in 13 genes of the glycosylation pathway, in DAG1 itself and in genes for synthesis of the mannose donor. The OMIM classification into types A, B and C by gene, the ENMC LGMD R designation and the CDG terminology coexist, and none replaces molecular diagnosis.

Recognition rests on the combination of raised CK with cobblestone cortical malformation, cerebellar and brainstem changes, ocular malformations and, in later-onset forms, proximal weakness with or without intellectual disability, cardiomyopathy or fatigable weakness. Brain MRI and biopsy with an antibody directed at the glycosylated epitope confirm the class, but the gene is identified by sequencing, with attention to founder variants (Japan, Korea, China, Ashkenazi Jews, Finland, Turkey, Druze, southern India), to the deep intronic and structural FKTN variants and to intragenic deletions.

There is no authorised treatment. Management is that of the congenital muscular dystrophies according to the AAN guideline and the international consensus: respiratory surveillance with non-invasive ventilation and assisted cough, nutritional support and gastrostomy, seizure control, ophthalmological care, rehabilitation and orthopaedics, at least annual cardiac surveillance with ACE inhibitors and beta-blockers for ventricular dysfunction, anaesthetic precautions and palliative care from diagnosis in severe forms. Acetylcholinesterase inhibitors have documented benefit in series of patients with GMPPB variants and a neuromuscular transmission defect, and the evidence for corticosteroids is limited to small series and one open-label trial in FCMD. The first regulatory decision on a pathway-directed treatment, oral ribitol for FKRP LGMD R9, is expected in November 2026, and substrate therapies, antisense oligonucleotides and gene therapy for other genes of the class remain preclinical.

13. References

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