The phenotype of limb-girdle muscular dystrophy type 2I

Background: Mutations in the fukutin-related protein gene FKRP cause limb-girdle muscular dystrophy (LGMD2I) as well as a form of congenital muscular dystrophy (MDC1C). Objective: To define the phenotype in LGMD2I. Methods: The authors assessed 16 patients from 14 families with FKRP gene mutations and LGMD and collected the results of mutation analysis, protein studies, and respiratory and cardiac investigations. Results: Thirteen patients, most with adult presentation, were homozygous for the common C826A mutation in FKRP. The three other cases were compound heterozygotes for C826A and two of them presented in childhood, with more progressive disease. The pattern of muscle involvement, frequently including calf hypertrophy, was similar to dystrophinopathy. Complications in patients with LGMD2I were common and sometimes out of proportion to the skeletal muscle involvement. Six patients had cardiac involvement, and 10 had respiratory impairment: five required nocturnal respiratory support. All patients had serum creatine kinase at least 5 to 70 times normal. The most consistent protein abnormality found on muscle biopsy was a reduction of laminin α2 immunolabeling, either on muscle sections or immunoblotting alone. Conclusions: LGMD2I due to FKRP mutations appears to be a relatively common cause of LGMD, with respiratory and cardiac failure as prominent complications.