FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts

Background: Congenital muscular dystrophies (CMD) are autosomal recessive disorders that present within the first 6 months of life with hypotonia and a dystrophic muscle biopsy. CNS involvement is present in some forms. The fukutin-related protein gene ( FKRP ) is mutated in a severe form of CMD (MDC1C) and a milder limb girdle dystrophy (LGMD2I). Both forms have secondary deficiencies of laminin α2 and α-dystroglycan immunostaining. Structural brain involvement has not been observed in patients with FKRP gene mutations. Methods: The authors studied two unrelated patients who had a pattern of muscle involvement identical to MDC1C, mental retardation, and cerebellar cysts on cranial MRI. The FKRP gene was analyzed along with the skeletal muscle expression of laminin α2 and α-dystroglycan. Results: The muscle biopsy of both patients showed severe dystrophic findings, a reduction in laminin α2, and profound depletion of α-dystroglycan. Both patients had homozygous FKRP gene mutations not previously reported (C663A [Ser221Arg] and C981A [Pro315Thr]). Conclusions: Mutations within the FKRP gene can result in CMD associated with mental retardation and cerebellar cysts. This adds structural brain defects to the already wide spectrum of abnormalities caused by FKRP mutations. The severe depletion of α-dystroglycan expression suggests that FKRP is involved in the processing of α-dystroglycan.