Clinical, genetic, and pathologic characterization of Mexican founder mutation c.1387A>G.

Objective: To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the c.1387A>G mutation.

Methods: Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in . Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.

Results: We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in . Onset of symptoms was G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including . All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous c.826C>A limb-girdle muscular dystrophy.

Conclusions: The clinical features and muscle pathology in these newly reported patients homozygous for c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200-1,500 years).