A novel PMP22 mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes

Department of Clinical Neurosciences, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Neurogenetics (Impact Factor: 2.88). 10/2004; 5(3):171-5. DOI: 10.1007/s10048-004-0184-1
Source: PubMed


We describe a Cypriot family in which some family members presented with episodes of pressure palsies, while other family members had a slowly progressive chronic polyneuropathy typical of the Charcot-Marie-Tooth type 1 phenotype. All family members were evaluated clinically, with nerve conduction studies, and with genetic testing. In all affected individuals there was clinical and electrophysiological evidence of diffuse demyelinating sensorimotor polyneuropathy and a novel point mutation in the PMP22 gene (Ser22Phe) was identified.

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    • "To date, mutations in more than 70 genes have been reported as underlying causes of CMT (Rossor et al., 2013). CMT occasionally exhibits nonstrict genotype-phenotype correlations: defects in different genes can cause similar phenotypes and conversely, defects in the same gene can cause different phenotypes (Kleopa et al., 2004; Nakhro, Park, Choi et al., 2013). CMT is usually classified as either demyelinating neuropathy (CMT1), with median motor nerve conduction velocity (MNCV) of <38 m/s, or axonal neuropathy (CMT2) with MNCV 38 m/s (Harding & Thomas, 1980). "
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    ABSTRACT: Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating subtype of peripheral enuropathies caused by mutations in the FGD4 gene. Most CMT4H patients are in consanguineous Mediterranean families characterized by early onset and slow progression. We identified two CMT4H patients from a Korean CMT cohort, and performed a detailed genetic and clinical analysis in both cases. Both patients from nonconsanguineous families showed characteristic clinical manifestations of CMT4H including early onset, scoliosis, areflexia, and slow disease progression. Exome sequencing revealed novel compound heterozygous mutations in FGD4 as the underlying cause in both families (p.Arg468Gln and c.1512-2A>C in FC73, p.Met345Thr and c.2043+1G>A (p.Trp663Trpfs*30) in FC646). The missense mutations were located in highly conserved RhoGEF and PH domains which were predicted to be pathogenic in nature by in silico modeling. The CMT4H occurrence frequency was calculated to 0.7% in the Korean demyelinating CMT patients. This study is the first report of CMT4H in Korea. FGD4 assay could be considered as a means of molecular diagnosis for sporadic cases of demyelinating CMT with slow progression.
    Annals of Human Genetics 09/2015; 79(6). DOI:10.1111/ahg.12134 · 2.21 Impact Factor
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    • "Genotype-phenotype correlations are often less strict in CMT patients, and CMT displays clinically wide phenotypic heterogeneity depending on causative mutations within the same gene. Kleopa et al. suggested that mutations in the PMP22 gene are relevant in the broad phenotypic spectrum (Kleopa et al. 2004). Some MPZ gene mutations have revealed considerable clinical heterogeneity in the affected individuals, not only among families, but also within the same family (Szabo et al. 2005; Mazzeo et al. 2008). "

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    ABSTRACT: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: a demyelinating and an axonal type. Further subdivisions within these 2 main categories exist and intermediate forms have more recently been described. Inheritance can be autosomal dominant, recessive or X-linked. CMT is associated with more than 30 loci, and about 25 causative genes have been described thus far. We studied epidemiological, clinical and genetic characteristics of CMT in the Cypriot population. The prevalence of CMT in Cyprus on January 15, 2009, is estimated to be 16 per 100,000. Thirty-three families and 8 sporadic patients were ascertained. CMT was demyelinating in 52%, axonal in 33% and intermediate in 15% of the patients. Thirteen families had PMP22 duplication, 3 families had the PMP22 S22F mutation, 4 families had GJB1/Cx32 mutations, 2 families had different MPZ mutations, 1 of them novel, and 2 families had different MFN2 mutations. Nine families and 8 sporadic patients were excluded from the common CMT genes. The most frequent CMT mutation worldwide, the PMP22 duplication, is also the most frequent CMT mutation in the Cypriot population. Five out of the 8 other mutations are novel, not reported in other populations.
    Neuroepidemiology 10/2010; 35(3):171-7. DOI:10.1159/000314351 · 2.56 Impact Factor
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