Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene

Abstract

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Dejerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q (CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

“…Mutations in PMP22 gene encoding fourtransmembrane myelin protein lead to variable clinical phenotypes including CMT1A, Dejerine-Sottas syndrome (DSS) and HNPP (Mostacciuolo et al, 2001;Numakura et al, 2002). MPZ gene, which encodes a major component of myelin, is frequently associated with CMT1B, CMT2 and DSS (Marrosu et al, 1998;Huehne et al, 2003). Mutations in GJB1, which encodes a gap-junction protein in the peripheral nervous system, lead to CMTX (Silander et al, 1998;Nelis et al, 1999).…”

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

“…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).…”

Clinical and genetic study of a large Charcot–Marie–Tooth type 2A family from southern Italy

“…The CMT2A phenotype, however, is distinct from that observed in CMT2 families associated with MPZ and Cx32 gene mutations. 7,8 In these latter cases, NCV can be slightly reduced or nearly normal, but in elderly patients the NCV may drop to 25 m/second. Thus, the NCV range is much broader than in our Southern Italian CMT2A family, and the lower limit is much lower.…”

“…6 Interestingly, distinct point mutations in the myelin protein zero (MPZ) gene also may be responsible for a CMT2-like phenotype. 7,8 Most recently, a novel CMT2 locus (CMT2E) has been reported on chromosome 8p21, and a disease-causing mutation was found in the neurofilament light gene. 9 Until now, significant evidence for linkage to chromosome 1p35-p36 was reported only for five CMT2A families, from Japan or North America, 2,3 making it difficult to assess the geographic distribution and clinical features of this disorder.…”