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

Abstract

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.

CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene

“…For example, it has been described relatively often in association with CMT4A caused by mutations in the gangliosideinduced differentiation-associated protein gene (GDAP1). 20 Other cranial nerves may also be involved in CMT2C as evidenced by the 2 persons in our families with third cranial nerve deficits. Pupillary abnormalities have been described in a variety of patients with CMT2 21 and oculomotor nerve abnormalities have been reported with patients with axonal neuropathy and mutations in TUBB3.…”

A Family with Vocal Cord Paralysis Associated with GDAP1 Mutation in Giresun, Turkey

“…Voice change can be an initial symptom in severe cases, but vocal cord paralysis is usually observed in the advanced stages of the disease. The existence of vocal cord paralysis in the whole clinical picture of hereditary neuropathy can be regarded as the indicator of the disease severity (9). Various studies have reported the co-existence of vocal cord paralysis in different types of hereditary neuropathy (3,4,5,6,7,8).…”

“…Some studies have suggested that the clinical picture in different types of hereditary neuropathy associated with GDAP1 gene mutations is accompanied by vocal cord paralysis (6,9,12). Furthermore, one study reported death associated with respiratory failure caused by vocal cord paralysis (9).…”

“…A comprehensive study suggested that vocal cord paresis was an important symptom that decreased life expectancy by causing disability, aspiration pneumonia, and respiratory failure in hereditary neuropathies associated with the gangliosideinduced differentiation-associated protein 1 (GDAP1) gene mutation (9).…”

Fenótipos Raros de Neuropatia Hereditária: Charcot-Marie-Tooth Tipo 4

“…As manifestações nos membros superiores progridem na segunda década. A forma axonal está relacionada à paralisia do diafragma e das cordas vocais no início da meia idade 29,30 . Formas autossômicas dominantes têm em geral início mais tardio, progressão lenta e fenótipo mais brando 31 .…”