A novel nemaline myopathy in the Amish caused by a mutation in troponin T1

The nemaline myopathies are characterized by weakness and eosinophilic, rod like (nemaline) inclusions in muscle fibers. Amish nemaline myopathy is a f orm of nemaline myopathy common among the Old Order Amish. In the first mon ths of life, affected infants have tremors with hypotonia and mild contract ures of the shoulders and hips. Progressive worsening of the proximal contr actures, weakness, and a pectus carinatum deformity develop before the chil dren die of respiratory insufficiency, usually in the second year. The diso rder has an incidence of similar to 1 in 500 among the Amish, and it is inh erited in an autosomal recessive pattern. Using a genealogy database, autom ated pedigree software, and linkage analysis of DNA samples from four sibsh ips, we identified an similar to 2-cM interval on chromosome 19q13.4 that w as homozygous in all affected individuals. The gene for the sarcomeric thin -filament protein, slow skeletal muscle troponin T (TNNT1), maps to this in terval and was sequenced. We identified a stop codon in exon 11, predicted to truncate the protein at amino acid 179, which segregates with the diseas e. We conclude that Amish nemaline myopathy is a distinct, heritable, myopa thic disorder caused by a mutation in TNNT1.