Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptom

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Vocal cord paresis and diaphragmatic dysfunction are severe and

frequent symptoms of GDAP1-associated neuropathy

http://brain.oxfordjournals.org

Brain Advance Access published online on September 23, 2008

Brain, doi:10.1093/brain/awn228

Sevilla1,2, Jaijo3,4, Dolores Nauffal5, Diego Collado6,

María José Chumillas7, J. Vilchez1,2, Nuria Muelas1,

Bataller1,2, lía Domenech5, Carmen Espinós3,4 and Francesc

Palau3,4

1Department of Neurology, University Hospital La Fe, 2CIBER de

Enfermedades Neurodegenerativas (CIBERNED), 3Laboratory of Genetics

and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC,

4CIBER de Enfermedades Raras (CIBERER), 5Department of Pneumology,

6Department of Otolaryngology and 7Department of Clinical

Neurophysiology, University Hospital La Fe, Valencia, Spain

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.