CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.228Severe nemaline myopathy manifesting as 'Amish phenotype' related to homozygous mutation in TNNT1

Abstract

Amish nemaline myopathy is a severe form of nemaline myopathy (NM) common among the old order Amish. The phenotype is characterized by early onset of severe hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity develop before the children die of respiratory insufficiency, usually by the second year of life. This phenotype has been associated to the p.Glu180Ter mutation in exon 11 of TNNT1 (TnT). We report on two Italian siblings affected by a severe form of congenital myopathy with a clinical picture very similar to the Amish phenotype. Both girls actually aged 12 and 1 years, by the age of 3 months, started to manifest rapid and progressive muscle weakness that predominantly involved distal muscles, associated to severe chest deformity (pectus carinatum) rigid spine and respiratory insufficiency that required mechanical ventilation in the first year of life. A muscle biopsy, performed in the older sister at the age of 7 months was consistent with a NM. Next generation sequencing approach revealed d a biallelic c.661G>T mutation in exon 12 of TNNT1 converting the Glu221 to a premature stop codon. The deletion of the C-terminal 58 aminoacids of TnT causes a loss of the binding sites for the Troponin inhibitory subunit (TnI) and the Troponin Ca2+-binding subunit (TnC) in the T2 region of TnT. The phenotype described in the Amish community is not a distinct myopathy associated exclusively to the founder Glu180Ter TNNT1 mutation.