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      Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy.


      Adolescent, Adult, Charcot-Marie-Tooth Disease, complications, genetics, pathology, physiopathology, Child, Child, Preschool, DNA Mutational Analysis, methods, Diaphragm, Female, Humans, Laryngoscopy, Larynx, Male, Middle Aged, Mutation, Nerve Tissue Proteins, Neural Conduction, Pedigree, Phrenic Nerve, Respiratory Function Tests, Sural Nerve, Vocal Cord Paralysis, etiology, Young Adult

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          Cranial nerve involvement in Charcot-Marie-Tooth disease (CMT) is rare, though there are a number of CMT syndromes in which vocal cord paralysis is a characteristic feature. CMT disease due to mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) has been reported to be associated with vocal cord and diaphragmatic palsy. In order to address the prevalence of these complications in patients with GDAP1 mutations we evaluated vocal cord and respiratory function in nine patients from eight unrelated families with this disorder. Hoarseness of the voice and inability to speak loudly were reported by eight patients and one had associated symptoms of respiratory insufficiency. Patients were investigated by means of peripheral and phrenic nerve conduction studies, flexible laryngoscopy, pulmonary function studies and polysomnography. Nerve conduction velocities and pathological studies were compatible with axonal CMT (CMT2). Flexible laryngoscopy showed left vocal cord palsy in four cases, bilateral cord palsies in four cases and was normal in one case. Restrictive respiratory dysfunction was seen in the eight patients with vocal cord paresis who were all chair-bound. These eight had confirmed phrenic nerve dysfunction on neurophysiology evaluation. The patient with normal vocal cord and pulmonary function had a less severe clinical course.This study shows that CMT patients with GDAP1 mutations develop severe disability due to weakness of limb muscles and that laryngeal and respiratory muscle involvement occurs late in the disease process when significant proximal upper limb weakness has developed. The early and predominant involvement of the left vocal cord innervated by the longer left recurrent laryngeal nerve suggests a length dependent pattern of nerve degeneration. In GDAP1 neuropathy, respiratory function should be thoroughly investigated because life expectancy can be compromised due to respiratory failure.

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