Elsevier

The Lancet

Volume 357, Issue 9252, 27 January 2001, Pages 267-272
The Lancet

Articles
Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study

https://doi.org/10.1016/S0140-6736(00)03614-XGet rights and content

Summary

Background

Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of hereditary motor and sensory polyneuropathies in which sleep apnoea has rarely been reported and no causal relation shown. We looked for an association between the most common subtype of CMT disease (CMT1A) and sleep apnoea syndrome.

Methods

Having diagnosed sleep apnoea and CMT in one family member (index case), we prospectively investigated 13 further members not previously suspected of having neuropathy or apnoeas. All had a neurological examination, electroneuromyography, polysomnography, and genetic testing for CMT disease.

Findings

11 of the 14 family members had the autosomal dominant demyelinating form of CMT disease with PMP22 gene duplication on chromosome 17. Whatever their neurological disability, all 11 individuals had sleep apnoea syndrome with a mean (SD) apnoea-hypopnoea index of 46·6/h (28·5) of sleep (normal value <15/h). The remaining three family members were free from neuropathy and sleep apnoea syndrome. Sleep apnoea and neuropathy severity were highly correlated; the compound muscle action potential (CMAP) amplitude of the median nerve was inversely correlated with the apnoea-hypopnoea index (r=−0·69, p=0·029). The severity of neuropathy and sleep apnoea were higher in male CMT individuals and were correlated with age and body mass index. No wake or sleep diaphragmatic dysfunction was shown.

Interpretation

We think that sleep apnoea syndrome is related to a pharyngeal neuropathy. Upper airway dysfunction, previously described in the CMT2C subtype, might be a clinical expression of the CMT1A subtype, to which familial susceptibility could predispose.

Introduction

Charcot-Marie-Tooth (CMT) disease is the most common inherited polyneuropathy (1/2500), and consists of a clinically and genetically diverse group of chronic polyneuropathies.1 Motor nerve conduction velocity (MNCV) of the median nerve is used to distinguish two major disease types: CMT1 (demyelinating neuropathy with decrease in MNCV) and CMT2 (axonal neuropathy with normal or mild decrease in MNCV).2 Further subdivision is based mainly on genetic analysis. CMT1A is the most common subtype (60–90% of CMT1 cases)3 and is often caused by an autosomal dominantly inherited duplication of a DNA region on chromosome 17 (17p11.2–12),4, 5 which contains the gene for the peripheral myelin protein PMP22.6 This duplication leads to overexpression of the protein PMP22 (gene dosage effect),7 then demyelination and further axonopathy.8 The slowly progressive polyneuropathy of CMT1A is characterised by degeneration of peripheral nerves and roots. It results in distal muscle weakness and atrophy and sensory impairment, beginning in the feet and legs, then the hands, with differing clinical severity in the same family.9, 10 Phrenic neuropathy causing diaphragmatic dysfunction9, 11, 12, 13, 14, 15, 16, 17 and leading to acute or chronic hypoventilation has been mainly reported in severely affected CMT1 and CMT2 patients; vocal cord palsies are more specifically associated with the CMT2 type.17, 18 Sleep apnoea is a common disease (affecting 9% of middle-aged men and 4% of women).19 However, reports of sleep apnoea associated with CMT are rare and poorly documented.16 No causal relation has been proved between CMT and sleep apnoea.

We diagnosed CMT1A in a 66-year-old man with severe central sleep apnoea syndrome shown by polygraphic recordings. He had no diaphragmatic dysfunction. We postulated that pharyngeal neuropathy might lead to a high frequency of sleep apnoea in CMT disease, so we prospectively investigated 13 members of the man's family for the two conditions.

Section snippets

Methods

The first patient (index case) had been investigated for sleep apnoea syndrome in the sleep laboratory and referred to the neurological outpatient clinic for postural hand tremor. CMT was clinically suspected then confirmed by electroneuromyography and molecular analysis. 13 family members not previously thought to have neuropathy or sleep apnoea were then prospectively investigated for CMT and sleep apnoea syndrome.

Results

Of the 16 family members who had a clinical examination, two refused electroneuromyographic and polysomnographic investigations. Thus, including the first patient, nine male and five female people (aged 9–72, and 20–60 years, respectively) were assessed for CMT and sleep apnoea (figure 1).

CMT and non-CMT individuals

Sex ratio, body mass index (table 1), pharyngeal size, and daytime respiratory function indices did not differ between the two groups. There was a slightly reduced PaCO2 in those with CMT (p 0·11). The only significant difference between the groups was in age, which was higher in the CMT group.

Discussion

We have shown, in a 14-member family study, a systematic association between Charcot-Marie-Tooth disease and sleep apnoea syndrome. The severity of both sleep apnoea and peripheral neuropathy were highly correlated. In CMT individuals, the clinical severity of neuropathy was mild or moderate and the electrophysiological studies showed a homogeneous slowing of nerve conduction velocities for all nerves studied, whatever the clinical presentation, age, or sex. CMAP amplitude was most reduced in

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