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

Objectives The 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. Methods The 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. Results The 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. Discussion This 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.


Ethics Statement
The Comitato Etico Milano Area 2 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy) approved the study. Written informed consent was obtained from the patient.
The proband is a 70-year-old man of Italian origin born to nonconsanguineous, asymptomatic parents. The father died at age 65 years of ischemic stroke. The mother died in childbirth at age 33 years together with the proband's brother. His 67-year-old sister is asymptomatic, and he has only 1 adopted son. The complete family pedigree is represented in eFigure 1 (links.lww.com/NXG/A534). At age 40 years, the proband began complaining of myalgias at thighs. In the following years, he developed gait disturbances with recurrent falls, wrist drop, variably flexed fingers, hypophonia, swallowing difficulties, and exertional dyspnea; spirometry performed at 63 years showed a reduced peak expiratory flow rate (PEFR 79%), reduced forced expiratory volume (FEV1) (1.8 L), and forced vital capacity (FVC) (2.2 L), with a preserved FEV1/FVC ratio. Clinical examination revealed marked bilateral muscle weakness, more pronounced distally. DTRs were absent, except for the patellar ones. Vibratory sense was gradually reduced from the knee to the first metatarsal heads. Proprioception was lost at the metatarsophalangeal joint of the great toe.  A-C). The results of the last nerve conduction study, performed at 63, were consistent with a severe sensorimotor polyneuropathy (Table 1). Needle examination findings are reported in Table 2. Common genetic (PMP22, MFN2, MPZ, GJB1, NEFL, GDAP1, TRPV4, and HSP22/27) and acquired (diabetes; alcohol consumption; medications; malnutrition;  deficiency of copper and vitamins B12 and E; and monoclonal gammopathy) causes of sensorimotor polyneuropathy were excluded. A targeted next-generation sequencing panel addressing genetic forms of distal myopathy revealed the heterozygous c.254C>G, p.S85C MATR3 variant (NM_ 199189), which was absent in the asymptomatic sister (eFigure 2). DNA from other relatives was not available. We also investigated a large group of genes involved in inherited forms of neuropathy and motor neuron disorders without detecting any additional suspicious variant in the proband (eTable 2).
In addition to typical VCPDM features (progressive, mainly distal muscle weakness; distal forearms, hands, and distal legs hypotrophy; dysphonia and dysphagia; and moderate respiratory impairment), 1-6 our patient showed sensory abnormalities, and, intriguingly, neurophysiologic studies and muscle biopsy pointed toward a mixed neuropathic and myopathic process. The presence of a composite phenotype, made of both myopathic and neuropathic alterations, has been previously noticed in 2 Asian patients with VCPDM and sensorimotor polyneuropathy. 4 However, the neuropathic abnormalities described were milder compared with those of our patient. Furthermore, the sensory symptoms developed by the 3 patients were markedly different. The first patient showed impairment of exteroceptive sensations and sparing of vibration and position senses, whereas our proband displayed altered proprioception, accompanied by bilateral paresthesias in feet and ankles. On the other hand, touch, pinprick, vibration, and position sensations were conserved in the second case described and only dysesthesia in the toe tips was described.
Although we cannot exclude the possibility of a double-trouble in the absence of additional unrelated patients with a similar phenotype, the clinical features and the exclusion of other acquired and genetic causes of neuropathy is strongly suggestive for VCPDM. Therefore, our case apparently confirms the clinical, neurophysiologic, and histologic variability of VCPDM and suggests considering MATR3 analysis in the differential diagnosis of suspected congenital polyneuropathy with odd characteristics, including dysphonia, dysphagia, and respiratory insufficiency.

Acknowledgment
This work was promoted within the European Reference Network (ERN) for Neuromuscular Diseases. The authors thank Associazione Centro Dino Ferrari for its support. Muscle biopsy and DNA samples were provided by the Bank of muscle tissue, peripheral nerve, DNA, and Cell Culture, member of Telethon Network of Genetic biobanks, at Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.

Study Funding
This study was (partially) funded by the Italian Ministry of Health-Current Research IRCCS (to G.P.C.).

Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.

Publication History
Received by Neurology: Genetics November 9, 2021. Accepted in final form May 4, 2022. Submitted and externally peer reviewed. The handling editor was Margherita Milone, MD, PhD.