Mutations in POMT2 are most commonly associated with Walker-Warburg syndrome and Muscle-Eye-Brain disease, but can also cause limb girdle muscular dystrophy (LGMD2N). We report a case of LGMD due to a novel mutation in POMT2 unmasked by uniparental isodisomy. The patient experienced proximal muscle weakness from three years of age with minimal progression. She developed progressive contractures and underwent unilateral Achilles tenotomy. By age 11, she had borderline low left ventricular ejection fraction and mild restrictive lung disease. Muscle biopsy showed mild dystrophic changes with selective reduction in α-dystroglycan immunostaining. Sequencing of POMT2 showed a novel homozygous c.1502A>C variant that was predicted to be probably pathogenic. Fibroblast complementation studies showed lack of functional glycosylation rescued by wild-type POMT2 expression. Chromosomal microarray showed a single 15 Mb copy number neutral loss of heterozygosity on chromosome 14 encompassing POMT2. RNAseq verified homozygosity at this locus. Together, our findings indicate maternal uniparental isodisomy causing LGMD2N.

Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling.

Limb girdle muscular dystrophy 2I is a slowly progressive muscular dystrophy due to mutations in the Fukutin-related protein (FKRP) gene. Clinicians are frequently asked if physical activity is harmful for pediatric patients with limb girdle muscular dystrophy 2I. The primary objective of this study was to determine if there is a relationship between self-reported childhood activity level and motor function and respiratory function in older children and adults with limb girdle muscular dystrophy 2I. We compared retrospective self-reported middle school activity level and sport participation with age at onset of weakness, 10-meter walk test and forced vital capacity later in life in 41 participants with FKRP mutations. We found no relationship between activity level in childhood and disease course later in life, suggesting that self-directed physical activity in children with limb girdle muscular dystrophy 2I does not negatively affect disease progression and outcome.