Syndromic congenital muscular dystrophy (α-dystroglycanopathies)
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A neonate has hypotonia, weak cry, and feeding difficulty. Brain MRI shows lissencephaly type II ("cobblestone cortex") and cerebellar hypoplasia. Eye exam reveals retinal dysplasia and microphthalmia. CK is markedly elevated (2,000+). Biopsy shows dystrophic muscle and reduced α-dystroglycan glycosylation.
Congenital muscular dystrophies (CMDs) where muscle disease occurs with structural CNS and/or eye anomalies: the α-dystroglycanopathies. These share a common biochemical defect: aberrant glycosylation of α-dystroglycan, which uncouples it from its extracellular matrix anchor.
The classical clinical entities, in decreasing severity:
| Syndrome | Brain | Eye | Survival |
|---|---|---|---|
| Walker-Warburg syndrome (WWS) | Type II lissencephaly + Dandy-Walker + hydrocephalus | Severe (microphthalmia, retinal dysplasia) | <3 yrs |
| Muscle-eye-brain disease (MEB) | Pachygyria, polymicrogyria, brainstem hypoplasia | Severe myopia, retinal dysplasia | Childhood |
| Fukuyama CMD (FCMD) | Cobblestone cortex (milder than WWS) | Variable, mild | Teens-young adult |
| CMD with cerebellar atrophy / mental retardation | Variable cerebellar findings | Usually normal | Variable |
WWS has its own dedicated leaf; see Walker-Warburg syndrome. MEB and Fukuyama are covered below.
All AR. Genes encode enzymes/proteins involved in α-dystroglycan O-mannosyl glycosylation:
- POMT1, POMT2, POMGNT1, POMGNT2, FKTN (Fukutin), FKRP, LARGE1 (formerly LARGE), CRPPA (formerly ISPD), B3GALNT2, B4GAT1 (formerly B3GNT1), GMPPB, others
Genotype-phenotype correlation is loose but trends:
- POMT1, POMT2, CRPPA (formerly ISPD) → most often WWS (severe end)
- POMGNT1 → MEB
- FKTN (Fukutin) → Fukuyama CMD (the founder mutation in Japanese populations)
- FKRP → broader spectrum, can also cause LGMD2I (limb-girdle muscular dystrophy without CNS involvement)
- Muscle: congenital weakness, hypotonia, markedly elevated CK (5-50× normal)
- Brain: type II ("cobblestone") lissencephaly; gradient of severity from WWS (worst) to FCMD (mildest)
- Cerebellum/brainstem: hypoplasia, kinking; common across the spectrum
- Hydrocephalus: frequent in WWS
- Eye: microphthalmia, retinal dysplasia, anterior segment defects, severe myopia
- Cognition: moderate-to-severe intellectual disability
- Brain MRI: cobblestone cortex + cerebellar/brainstem hypoplasia is highly suggestive
- CK elevation prompts neuromuscular workup
- Muscle biopsy: dystrophic features + immunostaining shows reduced α-dystroglycan glycosylation
- Multigene panel for the α-dystroglycanopathy genes (12+); exome if panel negative
- Pure CMD without CNS involvement: α-dystroglycanopathies CAN present without obvious CNS findings (LGMD-overlap), especially FKRP
- Other CMD subtypes:
- Merosin-deficient CMD (LAMA2): white matter changes on MRI but no cobblestone cortex
- Ullrich CMD (COL6A1/2/3): joint contractures, distal hyperlaxity, no CNS
- Lissencephaly without muscle involvement: LIS1, DCX, TUBA1A
- Nemaline myopathy: normal CK, characteristic biopsy
- Multidisciplinary care: neurology, pulmonology, ophthalmology, orthopedics, GI, palliative
- Respiratory support: non-invasive ventilation often needed
- Seizure management when present
- Cardiac surveillance: some α-dystroglycanopathies have cardiomyopathy risk
- Family counseling: AR with 25% recurrence; prenatal diagnosis available once family mutation known
"Severity gradient: Walker-Warburg > Muscle-eye-brain > Fukuyama": same biochemical defect, decreasing severity. The brain MRI tells you which end of the spectrum you're on.
"Cobblestone brain + bad eyes + high CK = α-dystroglycanopathy": three-feature combination that picks the syndromic CMDs out of the broader CMD differential.