First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease

Abstract

Mutations in the MATR3 gene are associated to distal myopathy with vocal cord and pharyngeal weakness (VCPDM), as well as familiar and sporadic motor neuron disease. To date, 12 VCPDM families from the United States, Germany, Japan, Bulgary, and France have been described in the literature. Here we report an Italian family with a propositus of a 40-year-old woman presenting progressive bilateral foot drop, rhinolalia, and distal muscular atrophy, without clinical signs of motor neuron affection. Her father, deceased some years before, presented a similar distal myopathy phenotype, while her 20-year-old son is asymptomatic. Myopathic changes with vacuolization were observed in muscle biopsy from the propositus. These results, together with the peculiar clinical picture, lead to MATR3 gene sequencing, which revealed a heterozygous p.S85C mutation in the propositus. The same mutation was found in her son. Over a 5-year follow-up, progression is mild in the propositus, while her son remains asymptomatic. Clinical, radiological, and pathological data of our propositus are presented and compared to previously reported cases of VCPDM. VCPDM turns out to be a quite homogenous phenotype of late-onset myopathy associated to p.S85C mutation in MATR3 gene. MATR3-related pathology, encompassing myopathy and motor neuron disease, represents an illustrative example of multisystem proteinopathy (MSP), such as other diseases associated to mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 genes. The present report contributes to a further characterization of this still poorly understood pathology and points out the diagnostic utility of muscle biopsy in challenging cases.

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.…”

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

“…Vocal cord and pharyngeal weakness with distal myopathy (VCPDM), due to the c.254C>G, p.S85C MATR3 variant, is characterized by progressive, asymmetric, predominantly distal muscle weakness, dysphonia, dysphagia, respiratory impairment, and myalgias. [1][2][3][4][5][6][7] Although the Achilles deep tendon reflexes (DTRs) are absent, the others can show a slight or brisk response. 2,4 Creatine phosphokinase (CPK) levels are normal to mildly elevated.…”