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Vocal cord and pharyngeal distal myopathy
Vocal cord and pharyngeal distal myopathy (VCPDM) is a rare autosomal dominant distal myopathy characterized by adult onset of muscle weakness in the feet and hands (slowly progressing to involve proximal limb muscles) combined with vocal or swallowing dysfunction and frequent respiratory muscle involvement in later stages. Normal to mildly elevated creatine kinase (CK) serum levels and rimmed-vacuolated dystrophic muscle fiber changes are associated laboratory and pathologic findings.
ORPHA:600Classification level: Disorder
Worldwide prevalence is unknown but more than 70 patients (of North American, European, and Japanese origin) have been reported to date.
Onset of muscle weakness is between 30-63 years (mean in the forties) and may initially be asymmetric. It most frequently begins with involvement of ankle and toe extensors with foot drop or may manifest in the hands. Weakness in the ankles renders the gait very unstable resulting in a waddling and steppage gait. In the hands, the extensors of the fingers and the abductor pollicis brevis (with atrophy) are affected to varying degrees. Progression of muscle weakness and wasting to proximal upper and lower limb muscles is common. Bulbar involvement with dysphonia and dysphagia may be initially absent but appear as disease progresses. Initially, voice is usually nasal or hoarse and dysphagia mild (with difficulty swallowing solid food), but progressive vocal cord weakness eventually leads to aspiration. Some patients display respiratory impairment with a low vital capacity that may progress to respiratory failure. Ocular muscle involvement is not observed.
VCPDM is caused by a c.254C>G mutation in the MATR3 gene (5q31.3) which results in substitution of a conserved amino acid (S85C) in the nuclear protein Matrin-3. It harbors nuclear import and export motifs in addition to several DNA and RNA binding sites. Currently, the mechanism by which S85C alteration in Matrin-3 leads to myopathy remains largely unknown.
The diagnosis of VCPDM is clinical and involves vocal cord examination by laryngoscopy (which reveals bowing of the vocal cords and constantly flowing secretions, resulting from incomplete closure of the glottis and pharyngeal muscle weakness). Needle EMG shows myopathic changes. Muscle biopsies reveal chronic non-inflammatory myopathy with variations in fiber size, fiber splitting and subsarcolemmal rimmed vacuoles, with pathologic changes being scant in the quadriceps and severe in the gastrocnemius. CK serum levels range from normal to an 8 fold increase. Molecular genetic screening revealing mutation in the MATR3 gene confirms diagnosis.
Differential diagnosis includes Welander distal myopathy, oculopharyngeal muscular dystrophy, and oculopharyngodistal myopathy.
VCPDM is inherited in an autosomal dominant manner. Genetic counseling can inform affected individuals about the 50% risk of disease transmission to their offspring.
Management and treatment
Currently, there is no cure for VCPDM. Ankle-foot orthotic braces and/or canes are used to aid in ambulation. For patients suffering from vocal cord weakness, injection of agents that add bulk and act as stiffeners (teflon, gel foam, fat), or bilateral silastic-implant medialization of the vocal folds, may aid in reducing aspiration. Ventilation or oxygen therapy may be needed if patient presents severe respiratory muscle involvement.
Prognosis of patients suffering from vocal cord and pharyngeal weakness is highly influenced by the quality of long-term respiratory care, if it is needed. Moreover, as distal upper limb muscles weaken, hand may partially curl closed, leading to a general loss of grip and dexterity. Ambulation is usually preserved.
A summary on this disease is available in Deutsch (2018) Español (2018) Italiano (2018) Nederlands (2018) Français (2014) Hebrew (2021, pdf) Russian (2018, pdf)