A distinct phenotype of distal myopathy in a large Finnish family.

OBJECTIVES: The authors carried out clinical, histopathologic, immunocytochemical, electrophysiologic, and imaging investigations and molecular genetic analysis in seven patients with distal myopathy belonging to a Finnish family. RESULTS: The disease showed autosomal dominant inheritance. Age at onset ranged from 32 to 45 years. The first symptoms for referral were clumsiness with the hands and frequent stumbling from a steppage gait. Muscle weakness was characterized by early involvement of the small muscles of the hands, gluteus medium, and both anterior and posterior muscle compartments of the legs. The disease progressed to involve other intrinsic muscles of the hands, as well as the forearm muscles, triceps and infraspinatus, and proximal lower limbs. Asymmetry of muscle involvement was common. EMG showed myopathic features, serum CK was normal or slightly elevated, and muscle biopsy showed many rimmed vacuoles and dystrophic changes. There was no evidence of linkage to Welander distal myopathy or tibial muscular dystrophy loci. CONCLUSION: These patients may have a distinct distal myopathy. Genome-wide scan is undertaken in order to identify the disease locus.

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 alpha2 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.

Dysferlin expression after normal myoblast transplantation in SCID and in SJL mice.

Limb girdle muscular dystrophy type 2B form and Miyoshi myopathy are both caused by mutations in the recently cloned gene dysferlin. In the present study, we have investigated whether cell transplantation could permit dysferlin expression in vivo. Two transplantation models were used: SCID mice transplanted with normal human myoblasts, and SJL mice, the mouse model for limb girdle muscular dystrophy type 2B and Miyoshi myopathy, transplanted with allogeneic primary mouse muscle cell cultures expressing the beta-galactosidase gene under control of a muscle promoter of Troponin I. FK506 immunosuppression was used in the non-compatible allogeneic model. One month after transplantation, human and mouse dysferlin proteins were detected in all transplanted SCID and SJL muscles, respectively. Co-localization of dysferlin and human dystrophin or beta-galactosidase-positive fibers was observed following the transplantation of myoblasts. Dysferlin proteins were monitored by immunocytochemistry and Western blot. The number of dysferlin-positive fibers was 40-50% and 20-30% in SCID and SJL muscle sections, respectively. Detection of dysferlin in both SCID mice and dysferlin-deficient SJL mouse shows that myoblast transplantation permits the expression of the donor dysferlin protein.