TNNT1 nemaline myopathy: natural history and therapeutic frontier

Abstract

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.

Novel Recessive TNNT1 Congenital Core‐Rod Myopathy in French Canadians

“…Typical histological features of TNNT1 NM include rods in type I and II fibers, increased fiber size variation, fiber type disproportion, and selective type II fiber hypertrophy . Except for mild to moderate fiber size variation, these findings were lacking in our cases.…”

“…Certain core clinical features were reminiscent of the severe recessive phenotype, including the association of limb‐girdle weakness with multiple contractures, rigid spine, and kyphoscoliosis. Our patients nonetheless lacked neonatal hypotonia and tremors as well as pectus carinatum . Despite proximal weakness, most retained independent ambulation, even up into their 60s for older patients.…”

“…Our patients nonetheless lacked neonatal hypotonia and tremors as well as pectus carinatum. 4,11 Despite proximal weakness, most retained independent ambulation, even up into their 60s for older patients. They also suffered from variable restrictive lung disease as a result of chest wall rigidity and kyphoscoliosis.…”

“…The recessive phenotype was first described in the Old Order Amish settlements of Pennsylvania, and presents with neonatal tremors and axial hypotonia, followed by progressive joint contractures, weakness, pectus carinatum, and restrictive lung disease . Death from respiratory insufficiency ensues by the second year of life . Six additional recessive TNNT1 mutations were subsequently identified in non‐Amish populations .…”

“…4 Death from respiratory insufficiency ensues by the second year of life. 11 Six additional recessive TNNT1 mutations were subsequently identified in non-Amish populations. [5][6][7][8][9] More recently, a dominant TNNT1 missense variant was reported to cause a milder and heterogeneous phenotype.…”