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Muscular dystrophy-dystroglycanopathy, type A (formerly muscle-eye-brain disease) is an autosomal recessive congenital muscular dystrophy characterized by early hypotonia, ocular abnormalities and type II lissencephaly. Patients present with congenital muscle weakness, structural brain malformations and ocular defects such as microphthalmia and severe myopia. POMGNT1 encodes protein O-mannose β1,2-N-acetylglucosaminyltransferase 1, a glycosyltransferase essential for α-dystroglycan O-mannosylation. Loss of proper O-mannose glycan elongation on α-dystroglycan disrupts its binding to extracellular matrix ligands, impairing muscle integrity and neuronal migration. The disorder spans a spectrum from severe Walker-Warburg–like presentation to milder limb-girdle phenotypes.
Biallelic POMGNT1 variants were first linked to disease in six independent MEB patients demonstrating severe loss of enzyme activity (PMID:11709191). A multi-ethnic cohort study identified seven novel mutations in six non-Finnish and Asian MEB or WWS patients, expanding the clinical spectrum (PMID:12588800). To date, >50 unrelated probands from >15 families have been reported with POMGNT1-related dystroglycanopathy. Segregation analysis across these families confirms autosomal recessive inheritance with consistent cosegregation of biallelic variants.
The variant spectrum includes splice-site mutations (e.g., c.1539+1G>A), frameshift and nonsense variants, as well as missense alleles. A representative missense change, c.1468T>G (p.Cys490Gly), has been observed in Italian MEB patients (PMID:17030669). Hypomorphic alleles underlie milder limb-girdle muscular dystrophy presentations (LGMD2M), and noncoding promoter alterations reduce gene expression. A founder intragenic deletion (g.6668-8257del) has also been reported in multiple MEB patients.
Segregation studies document at least eight additional affected relatives across sibships with homozygous or compound heterozygous POMGNT1 variants (PMID:17881266). All reported families exhibit full penetrance and no evidence of dominant-negative effects.
Functional assays robustly support loss-of-function as the disease mechanism. In vitro expression of splicing and missense mutants shows undetectable or severely reduced enzymatic activity (PMID:12788071). POMGNT1 activity in patient muscle extracts is markedly decreased compared to controls (PMID:12849864). A POMGNT1 knockout mouse model recapitulates key MEB features including muscular dystrophy, ocular defects, and neuronal migration abnormalities (PMID:16458488).
No studies have refuted the association, and POMGNT1 is not implicated as a major WWS gene outside of rare phenotypic overlap. Comprehensive genetic and biochemical testing for POMGNT1 variants is therefore critical in the diagnostic evaluation of congenital muscular dystrophies with brain and eye involvement.
Key take-home: Biallelic loss-of-function variants in POMGNT1 are a definitive cause of muscular dystrophy-dystroglycanopathy, type A, and should be included in gene panels and enzymatic screening for autosomal recessive congenital muscular dystrophy with ocular and neuronal malformations.
Gene–Disease AssociationDefinitiveMultiple independent publications reporting >50 unrelated probands across >15 families with autosomal recessive POMGNT1 variants and concordant functional data Genetic EvidenceStrong~50 probands from >15 unrelated families; diverse variant classes; autosomal recessive inheritance Functional EvidenceStrongLoss-of-function enzymatic assays for multiple alleles; POMGNT1-null mice recapitulate human phenotype |