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

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. The patient complained of paresthesias bilaterally in feet and ankles. Ambulation was possible only with unilateral support. CPK levels were mildly elevated (274 U/L, normal values 25–200). At 46 years, a gastrocnemius biopsy revealed mixed neurogenic and myopathic changes (Figure 1, D–F). Muscle MRI, performed at 70 years, demonstrated remarkable fatty degeneration and atrophy of muscles, with a distoproximal gradient (Figure 1, 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).

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Figure 1 Turbo Spin Echo Axial T1 MRIs From the Thigh (A and B) to the Leg (C), Showing a Remarkable Fatty Degeneration of Muscles, With a Distoproximal Gradient: At the Leg Level, All Muscle Lodges Are Involved, With a Complete Fatty Infiltration Associated With a Less Severe Atrophy

Turbo Spin Echo (TSE) axial T1 MRI images from thigh (A–B) to leg (C), showing a remarkable fatty degeneration of muscles, with a disto-proximal gradient: at leg level all muscle lodges are involved, with a complete fatty infiltration associated with a less severe atrophy. At thigh level there is a selective degeneration of mesial and posterior muscle lodges, in particular semimembranous (red arrow) and biceps femoris short head muscle (dotted red arrow), with a symmetrical pattern. Atrophy and fatty degeneration also of adductor longus (dotted red star) and magnus (red star) and sartorius, with a relative spare of quadriceps, except for rectus femoris, mildly atrophic and infiltrated. (D) ATPase pH 4.3 (magnification: 200x) shows normal sized fibers with fiber type grouping and two hypotrophic angulated fibers (arrows). (E) Hematoxylin and eosin (magnification: 200x) stain showing subsarcolemmal cytoplasmic vacuoles (black arrowheads), small angulated fiber (arrows), splitting fiber (asterisk), small nuclear clumps (white arrowheads). (F) Gomori trichrome stain (magnification: 200x) showing pale degenerating fiber (asterisk) and myophagocytosis (arrow), muscle fiber splitting (circle), subsarcolemmal (black arrowhead) and cytoplasmic vacuoles containing amorphous material (white arrowhead).

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.