Marrosu, M. G. et al. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology 50, 1397-1401

Department of Neurophysiopathology, University of Cagliari, Italy.
Neurology (Impact Factor: 8.29). 06/1998; 50(5):1397-401. DOI: 10.1212/WNL.50.5.1397
Source: PubMed


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.

2 Reads
  • Source
    • "report a c.117A4C c.131C4T p.Ser44Phe 2 2 Marrosu et al., 1998; Shy et al., 2004; Benedetti et al., 2010 c.136delG p.Val46fs 1 1 This report c.208C4T p.Pro70Ser 4 3 Laura et al., 2007; Benedetti et al., 2010 (continued) "
    [Show abstract] [Hide abstract]
    ABSTRACT: We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 08/2015; DOI:10.1093/brain/awv241 · 9.20 Impact Factor
  • Source
    • "As in this study, not only demyelination , but also axonal degeneration is associated with MPZ mutations (Marrosu et al., 1998; Senderek et al., 2000; Young et al., 2001). It has been suggested that axonal degeneration is most likely secondary to myelin dysfunction, possibly due to impaired axoglial interactions (Marrosu et al., 1998). Experimental studies in MPZ-deficient mice showed axonal degeneration (Giese, Martini, Lemke, Soriano, & Schachner, 1992; Frei et al., 1999) which agrees with these observations in humans. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers ́ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive
    Revista de biologia tropical 12/2014; 62(4):1285-1293. DOI:10.15517/rbt.v62i4.13473 · 0.52 Impact Factor
  • Source
    • "DNM2 dynamin 2 GTPase endocytosis/cytoskeletal remodeling Fabrizi et al., 2007 CMT2C TRPV4 transient receptor potential cation channel, subfamily V, member 4 calcium channel calcium homeosthasis Klein et al., 2011; Landouré et al., 2010 CMT2I/2J MPZ myelin protein zero structural myelin protein myelin assembly Marrosu et al., 1998; Chapon et al., 1999; De Jonghe et al., 1999 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders of the peripheral nervous system, mainly characterized by distal muscle weakness and atrophy leading to motor handicap. With an estimated prevalence of 1 in 2,500, this condition is one of the most commonly inherited neurological disorders. Mutations in more than 30 genes affecting glial and/or neuronal functions have been associated with different forms of CMT leading to a substantial improvement in diagnostics of the disease and in the understanding of implicated pathophysiological mechanisms. However, recent data from systematic genetic screening performed in large cohorts of CMT patients indicated that molecular diagnosis could be established only in ∼50-70% of them, suggesting that additional genes are involved in this disease. In addition to providing an overview of genetic and functional data concerning various CMT forms, this review focuses on recent data generated through the use of highly parallel genetic technologies (SNP chips, sequence capture and next-generation DNA sequencing) in CMT families, and the current and future impact of these technologies on gene discovery and diagnostics of CMTs.
    Molecular syndromology 11/2012; 3(5):204-14. DOI:10.1159/000343487
Show more