In 4 affected members of a French family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Penisson-Besnier et al. (2007) identified a heterozygous c.503G-A transition in exon 5 of the TPM3 gene, resulting in an ARG167HIS substitution. Although most patients had symptoms in childhood, all remained ambulatory as adults. Clarke et al. (2008) noted that based on numbering from the first met codon this mutation is designated ARG168HIS (R168H).
In a father and daughter with congenital myopathy, Clarke et al. (2008) identified the R168H mutation in the TPM3 gene. Both patients had onset of hypotonia in infancy and were able to run in late adolescence. At age 60, the father could walk, had impaired nocturnal ventilation, showed distal more than proximal weakness, and had scoliosis with lumbar lordosis. Skeletal muscle biopsy was consistent with nemaline myopathy. At age 20, the daughter was able to run, had decreased forced vital capacity, mild proximal weakness, and mild scoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD) The findings of both nemaline myopathy and CFTD in patients with the same mutation showed that TPM3 mutations can cause a range of histologic changes, and suggested that there is a close relation between nemaline myopathy and CFTD.
De Paula et al. (2009) reported a 42-year-old man with the R168H mutation who showed cap myopathy on skeletal muscle biopsy. He had hypotonia in the first months of life, delayed motor development, and distal weakness of the lower limbs with frequent falls in childhood. At age 7 years, he had flat feet in valgus, long narrow face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes were absent. The clinical course was stable until presentation at age 42 with inability to run, difficulty climbing stairs, and predominant distal muscle weakness. Skeletal muscle biopsy at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1 fibers, irregularity of fiber size, occasional central nuclei, and peripheral eosinophilic-basophilic densely stained substances consistent with 'caps.' The caps were present in about 10 to 15% of muscle fibers, were negative for ATPase staining, were present just beneath the sarcolemma, and consisted of abnormally arranged myofibrils. Z-lines were thickened with some rod-like structures. The authors noted that this case had first been reported as a congenital myopathy with selective hypotrophy of type 1 fibers (Serratrice et al., 1975), and that the biopsy results discussed in that report would have been consistent with CFTD. The findings suggested a relationship between nemaline myopathy, CFTD, and cap myopathy, and indicated that cap structures may develop over time.
