CASE REPORT The effect of calpain 3 deficiency on the pattern of muscle degeneration in the earliest stages of LGMD2A

Limb girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 gene. In a large fam-ily affected by LGMD2A with four severely affected mem-bers, three additional asymptomatic relatives had very high serum creatine kinase concentrations. All were homo-zygous for the R110X mutation and showed a total absence of calpain 3 in the muscle. Histological analysis of muscle in these three rare preclinical cases showed a consistent but unusual pattern, with isolated fascicles of degenerating fibres in an almost normal muscle. This pat-tern was also seen in one patient with early stage LGMD2A who had a P82L missense mutation and a partial deficiency of calpain 3 in the muscle, but was not seen in early stage patients affected by other forms of LGMD. These findings suggest that a peculiar pattern of focal degeneration occurs in calpainopathy, independently of the type of mutation or the amount of calpain 3 in the muscle. The limb girdle muscular dystrophies (LGMDs) are aheterogeneous group of progressive disorders mainlyaffecting the pelvic and shoulder girdle musculature, ranging from a severe form with onset in the first decade and rapid progression, to a mild form with later onset and slower progression. The diagnostic criteria established by the ENMC-LGMD consortium include raised serum creatine kinase activ-ity, myopathic electromyography, and muscle biopsy with fea-tures ranging from mildly myopathic to frankly dystrophic.1 The inheritance may be autosomal dominant (LGMD1) or recessive (LGMD2). During the past decade, at least 15 LGMD genes, five autosomal dominant (AD) and 10 autosomal recessive (AR), have been mapped. The AD forms are relatively rare and mutations in these genes are found in less than 10% of all patients with LGMD. The five forms of AD LGMD are: LGMD1A, at 5q22, which encodes the protein myotilin; LGMD1B at 1q11, which encodes lamin A/C; LGMD1C at 3p25, which encodes caveolin 3; LGMD1D at 6q23; and LGMD1E a