Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene

Abstract

A French family had Charcot-Marie-Tooth disease type 2 (CMT2) which was characterised by late onset of peripheral neuropathy involvement, Argyll Robertsonlike pupils, dysphagia, and deafness. Electrophysiological studies and nerve biopsy defined the neuropathy as axonal type. Genetic analysis of myelin protein zero (MPZ) found a mutation in codon 124 resulting in substitution of threonine by methionine. One of the patients, presently 30 years old, showed only Argyll Robertson-like pupils as an objective sign but no clinical or electrophysiological signs of peripheral neuropathy. (J Neurol Neurosurg Psychiatry 1999;66:779-782)

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

“…Abnormal or abolished pupillary reflex may be the first sign of CMT disease associated with MPZ mutation, since asymptomatic carriers may present pupillary abnormalities before they reach the age of onset (De Jonghe et al, 1999). Deafness was an additional phenotypic feature in previously reported families (Chapon et al, 1999;Misu et al, 2000;Mastaglia et al, 1999;De Jonghe et al, 1999). Although seldom described in CMT patients, involvement of the cochlear nerve has been reported in different forms of CMT, whether demyelinating or axonal (Pareyson et al, 1995).…”

“…In this respect, the serine palmitoyltransferase long chain base subunit-1 gene was recently associated with an autosomal dominant form of hereditary sensory and autonomic neuropathy (Bejaoui et al, 2001;Dawkins et al, 2001), which does not however, share the electrophysiological features of the affected individuals of our family, who had significantly reduced motor conduction velocities. Indeed, several CMT families carrying an MPZ gene mutation and showing an axonal phenotype with late onset have been described (Marrosu et al, 1998;Chapon et al, 1999;Mastaglia et al, 1999;De Jonghe et al, 1999;Misu et al, 2000). On the basis of this new phenotype, this form of CMT with MPZ gene mutation has been classified in the group of axonal form or CMT2 (Gemignani and Marbini, 2001).…”

“…Three clinical and electrophysiological phenotypes have been associated with MPZ gene mutations: CMT1B, which is characterized by slow MNCV (, 25 m/s) and onset in the first two decades of life, Dejerine -Sottas syndrome with onset in infancy and extremely reduced MNCV (, 10 m/s), and congenital hypomyelination (Warner et al, 1996). However, several axonopathies in CMT disease have been associated with a mutation in the MPZ gene (Marrosu et al, 1998;Chapon et al, 1999;Mastaglia et al, 1999;Misu et al, 2000;Senderek et al, 2000;Young et al, 2001). Recently, a family with a distinct clinical phenotype characterized by marked sensory abnormalities, deafness, pupillary abnormalities and variable slowing of MNCV was reported to carry a new mutation (Thr124Met) in the MPZ gene (De Jonghe et al, 1999).…”

Perceptual Consequences of Disrupted Auditory Nerve Activity

“…The etiologies for AN are multiple, ranging from genetic, including mutations in several genes (MPZ, NDRG1, and PMP22) that are critical for peripheral nerve myelination and axonal survival (Chapon et al 1999;De Jonghe et al 1999;Kalaydjieva et al 2000;Maier et al 2003), to infectious (measles, mumps), metabolic (diabetes, hypoxia), congenital (atresia), and neoplastic (tumors) (Starr et al 1996). The prevalence of AN has been estimated to be as high as 10% of the children identified as having hearing loss (Berlin et al 2003a;Rance et al 1999).…”

Auditory nerve is affected in one of two different point mutations of the neurofilament light gene

“…Recent studies have focused attention on auditory function in CMT by identifying hearing disorder as a prominent feature in several distinct genetic variants including primary demyelinating forms (CMT1) due to mutation of PMP22 gene duplication (Boerkoel et al, 2002;Kovach et al, 2002;Hattori et al, 2003;Joo et al, 2004), primary axonal forms (CMT2) due to mutations of MPZ gene (Chapon et al, 1999;De Jonghe et al, 1999;Misu et al, 2000;Hattori et al, 2003;Starr et al, 2003), connexin 31 (GJB3) gene (Lopez-Bigas et al, 2001), Connexin 32 (Cx32) gene (Boerkoel et al, 2002;Hattori et al, 2003), and in a mixed demyelinating/axonal autosomal recessive motor-sensory neuropathy, HMSN-Lom, particular to Roma populations due to a mutation of the NDRG1 gene (Kalaydjieva et al, 1998;Butinar et al, 1999;Kalaydjieva et al, 2000).…”