A novel noncoding FKRP mutation in early onset limb-girdle muscular dystrophy.

Abstract

Limb-girdle muscular dystrophy 2I (LGMD2I, LGMD R9) (OMIM: muscular dystrophy—dystroglycanopathy [limb-girdle], type C, 5) is an autosomal recessive disorder caused by mutations in the fukutin-related protein ( FKRP ) gene.1 The phenotypic spectrum associated with FKRP is heterogeneous; the most severe phenotype, Walker-Warburg-like syndrome, is characterized by congenital hypotonia, progressive muscle weakness and atrophy, ocular and brain malformations, severe motor developmental delay, and profound intellectual disability. Milder phenotypes include the onset of disease from infancy to adulthood and variable clinical course including asymptomatic elevated serum creatinine kinase (CK), early onset rapidly progressive course with loss of ambulation in teenage years, late onset with slow progression, and primary cardiomyopathy with minimal skeletal muscle weakness.1,2 LGMD2I is typically characterized by proximal muscle weakness, calf hypertrophy, hypotonia, elevated CK level, normal cognition, and no structural brain abnormalities. Dilated cardiomyopathy and respiratory muscle weakness can be seen.1 Mutations in the FKRP gene reduce specific O-mannose-linked glycosylation of alpha-dystroglycan, leading to the instability of the linkage between the dystrophin–glycoprotein complex and laminin alpha 2 in the basement membrane of skeletal muscle.3 The most common FKRP mutation seen in LGMD2I is c.826C>A (p.Leu276Ile). Patients who are homozygous for this mutation typically have a milder phenotype, whereas compound heterozygotes have a relatively severe clinical course. In patients heterozygous for c.826C>A, clinical severity may correspond best to the mutation in the second allele.1,4 We describe a 9-year-old boy with LGMD2I who has the c.826C>A mutation in FKRP on 1 allele and a novel variant on the second allele. The authors acknowledge Ms. Terese Nelson who performed the histology and immunostaining and Mr. Joel Carl for assembling the figure