Autonomic and respiratory dysfunction in Charcot–Marie–Tooth disease due to Thr124Met mutation in the myelin protein zero gene

Abstract

Objective: To report the clinical and electrophysiological characteristics of a family presenting Charcot -Marie-Tooth disease (CMT) associated with autonomic nervous system disturbances.Methods: We studied nerve conduction values, postural adaptation, sympathetic skin reflex, the variation in heart rate by the Valsalva ratio and pupillometry in 7 members of a French family in which CMT due to a Thr124Met mutation in the myelin protein zero (MPZ) gene was diagnosed.Results: Clinical and laboratory evidence of autonomic nervous system disturbances were found in the affected individuals. The clinical phenotype was characterized by sensorimotor peripheral neuropathy, defined as axonal type by electrophysiological studies, and was associated with severe pain, bladder dysfunction, sudorimotor disturbances and abolished pupillary reflex to light. Moreover, two patients had severe restrictive respiratory insufficiency requiring noninvasive mechanical ventilation.Conclusions: Our study demonstrates that autonomic disturbances may be one of the major clinical signs associated with CMT secondary to MPZ gene mutation in codon 124. Testing of pupillary reflex allows the discrimination of affected and unaffected subjects in our family. However, involvement of the autonomic nervous system in this type of neuropathy is unclear and further studies are required to elucidate the role of the MPZ gene in the autonomic nervous system.

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype

“…As mentioned, the Thr124Met mutation has been found to be responsible for CMT in families from Italy (Schiavon et al, 1998), Belgium (De Jonghe et al, 1999), France (Chapon et al, 1999;Stojkovic et al, 2003), Japan Misu et al, 2000), Spain (Gallardo et al, 2009), Germany (Senderek et al, 2000, and Costa Rica (this study). The haplotype analysis of the Costa Rican family showed similarity between those of Costa Rica and Belgium: both present a 257 bp-allele in D1S2771, whereas for the marker D1S2705, the difference between the allele related with the mutation in the CR-C family (152 bp) and the allele related in the Belgian family (150 bp) is only 2 bases, which could be explained by a single mutation.…”

Compound heterozygous deletions of PMP22 causing severe Charcot‐Marie‐Tooth disease of the Dejerine‐Sottas disease phenotype

“…Chronic cough, with nothing to confirm GERD, was described in a unique form of CMT associated with Thr124Met mutation in myelin protein zero gene (MPZ). This mutation was associated with early involvement of the autonomic nervous system, with affected individuals later developing predominantly an axonal form of neuropathy [Stojkovic et al, 2003;Baloh et al, 2004;Kurihara et al, 2004]. There was nothing to suggest autonomic dysfunction in our patient.…”

Bladder dysfunction in peripheral neuropathies

“…3 Acetylcholine (ACh) is the main neurotransmitter for both pre-and postganglionic parasympathetic fibers. [4][5][6] The preganglionic sympathetic efferent fibers arise from the thoracolumbar segment of the spinal cord at T10-L2. 3,7 Those fibers intermingle with somatic efferents from spinal nerves and synapse in one of the nearby paravertabral ganglia of the sympathetic chain, which continue peripherally with associated somatic segmental fibers.…”