Re-evaluation of the phenotype caused by the common MATR3 p.Ser85Cys mutation in a new family

Late-onset autosomal dominant vocal cord and pharyngeal distal myopathy (VCPDM) was first described in an American family.1 A p.Ser85Cys mutation in MATR3 gene was later identified in this family, and also in one Bulgarian family and very recently, in seven families—six German and one Asian.2–4 Muscle pathology of VCPDM was dominated by rimmed-vacuolar fibre degeneration.1 ,2 This year, two other mutations in MATR3 , p.Phe115Cys and p.Thr622Ala, have been reported to cause autosomal dominant amyotrophic lateral sclerosis (ALS).5 The original American p.Ser85Cys mutated family was re-evaluated and the authors stated: “These clinical findings supported reclassification of this condition as slowly progressive ALS, and the presence of upper motor neuron signs in the form of brisk reflexes ruled out myopathy as the only cause of disease in this family.”5 We report a new family with the p.Ser85Cys mutation in MATR3 , in which muscle atrophy and weakness are caused by progressive degenerative myopathy without any evidence of lower motor neuron defects. We investigated an American family with four affected siblings. Patients II.1, II.2 and II.4 were more extensively examined and followed for 7, 9 and 8 years, respectively. The father and one of his brothers were affected (figure 1A). Muscle MRI was performed in the proband (II.2) and in the younger brother (II.4). Muscle biopsies were obtained from three patients and examined by standard histochemical and immunohistochemical stainings with antibodies for Matrin 3, TDP-43, p62, SMI-31 and myosin A4.74, slow (MHCs), neonatal (MHCn) and developmental (MHCd) isoforms. Immunofluorescence analysis was performed with conventional methods using antibodies for G3BP and TIA1 C-terminus. Matrin 3 distribution was analysed from soluble cytoplasmic and nuclear fractions using western blotting. Figure 1 Pedigree and muscle findings of the family. Pedigree of the family (A). Wasting of the first dorsal interossei and thenar …