Expanding the Phenotypic Spectrum of Vocal Cord and Pharyngeal Weakness With Distal Myopathy due to the p.S85C MATR3 Mutation

Abstract

ObjectivesThe c.254C>G (p.S85C) MATR3 variant causes vocal cord and pharyngeal weakness with distal myopathy (VCPDM), which is characterized by progressive, asymmetric, predominantly distal muscle weakness, dysphonia, dysphagia, and respiratory impairment. Herein, we describe an Italian patient who harbored the p.S85C MATR3 variant and showed a composite phenotype of VCPDM and sensorimotor polyneuropathy.MethodsThe proband underwent neurologic evaluation, muscular MRI of the lower limbs, neurophysiologic assessment, muscle biopsy, and spirometry. After excluding common acquired and genetic causes of sensorimotor polyneuropathy, a larger group of genes involved in inherited forms of neuropathy, distal myopathy, and motor neuron disorders were analyzed by next-generation sequencing targeted panels.ResultsThe patient, affected by progressive distal muscle weakness and hypotrophy, myalgias, dysphonia, dysphagia, respiratory impairment, and sensory abnormalities, harbored the heterozygous c.254C>G (p.S85C) MATR3 substitution. Neurophysiologic assessment revealed a severe sensorimotor polyneuropathy. Variation of fiber size, central nuclei, and nonrimmed vacuoles were evident at muscle biopsy.DiscussionThis finding extends the MATR3-associated VCPDM phenotypic spectrum and suggests considering MATR3 analysis in suspected congenital polyneuropathies with odd features, including dysphonia, dysphagia, and respiratory insufficiency.

MATR3’s Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases

“…The S85C mutation was initially linked to another adult-onset disorder, namely vocal cord and pharyngeal weakness with distal myopathy (VCPDM) [ 79 , 80 ], but was later reclassified as slowly progressive ALS due to the presence of neurogenic features involving motor neuron symptoms [ 24 ]. Notably, MATR3 S85C has also been associated to VCPDM in several additional families with or without similar neurogenic features [ 81 , 82 , 83 , 84 , 85 , 86 , 87 ], suggesting that this mutation may cause a spectrum of phenotypes ranging from pure myopathy to motor neuron disease. Similarly, mice that harbor the S85C mutation in the mouse Matr3 gene also show robust phenotypes, including motor function defects, muscle atrophy, and early death [ 70 ], suggesting that the S85C mutation is a genetic determinant of myopathy and ALS.…”