We describe the natural history of '
Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T
nonsense mutation of TNNT1, which encodes the slow fiber
isoform of
troponin T (TNNT1; a.k.a.
TnT). The TNNT1 c.505G>T allele has a carrier frequency of 6.5% within Old Order Amish settlements of North America. We collected natural history data for 106 ANM patients born between 1923 and 2017. Over the last two decades, mean age of molecular diagnosis was 16 ± 27 days. TNNT1 c.505G>T homozygotes were normal weight at birth but failed to thrive by age 9 months. Presenting neonatal signs were axial
hypotonia, hip and shoulder stiffness, and
tremors, followed by progressive
muscle weakness,
atrophy and
contractures. Affected children developed thoracic rigidity,
pectus carinatum and restrictive
lung disease during infancy, and all succumbed to
respiratory failure by 6 years of age (median survival 18 months, range 0.2-66 months). Muscle histology from two affected children showed marked fiber size variation owing to both Type 1 myofiber smallness (hypotrophy) and Type 2 fiber
hypertrophy, with evidence of nemaline rods, myofibrillar disarray and vacuolar pathology in both fiber types. The truncated slow TNNT1 (
TnT) fragment (p.Glu180Ter) was undetectable in ANM muscle, reflecting its rapid proteolysis and clearance from sarcoplasm. Similar functional and histological phenotypes were observed in other human cohorts and two transgenic murine models (Tnnt1-/- and Tnnt1 c.505G>T). These findings have implications for emerging molecular
therapies, including the suitably of TNNT1 gene replacement for newborns with ANM or other TNNT1-associated
myopathies.