G.P.311: A new homozygous ISPD mutation is associated with either early limb-girdle or congenital muscular dystrophy within the same family depending on different levels of alpha-dystroglycan glycosylation

Abstract

Dystroglycanopathies represent an important subgroup of recessively inherited disorders within the group of muscular dystrophies. Their severity may vary from the mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies with cerebral and ocular involvement. Although mutations in at least 17 genes have been identified so far, about 50% of the cases with dystroglycanopathy still remain unsolved. Recently, mutations in the isoprenoid synthase domain containing (ISPD) gene have been reported as a common cause of congenital muscular dystrophy and LGMD. We report clinical, histopathological, immunochemical, genetic and muscular MRI findings in 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation (Gly123Arg) in the ISPD gene. Case 1 is a 8year-old female with an early limb-girdle phenotype, who lost ambulation at the age of 7.5years. Case 2 is a 2.5year-old male and second degree cousin of case 1, showing a congenital muscular dystrophy phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both the patients. Western blot showed greater reduction of alpha-dystroglycan glycosylation in patient 2, and may be responsible for the greater severity of his clinical presentation. To our knowledge, this is the first report on the co-occurrence of both early limb-girdle and congenital muscular dystrophies within the same family carrying a new homozygous ISPD mutation.