A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype

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. Rev. Biol. Trop. 62 (4): 1285-1293. Epub 2014 December 01. Key words:Charcot-Marie-Tooth, peripheral neuropathy, Myelin protein zero, mutation, Costa Rica.Hereditary motor and sensory neuropathy (HMSN), also called Charcot-Marie-Tooth disease (CMT), is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. It is characterized by progressive muscular weakness and atrophy of the distal muscles (Lupski, 1998). By means of electrophysiological and morphological studies, CMT can be divided into two major forms: a predominantly demyelinating (HMSN type I) and an axonal form (HMSN type II) (Dyck, Chance, Lebo, & Carney, 1993).MPZ had been initially related with a hereditary motor and sensorial neuropathy type I (HMSN I), presenting myelin disturbances resulting in reduced nerve conduction velocity (NCV<38m/s) (Hayasaka et al., 1993a). However, families with normal NCV values (HMSN II) have also been associated with MPZ (Senderek et al., 2000). The mutation Thr124Met in the third exon of the protein was found to be responsible for CMT in families with a clinically distinct phenotype, including axonal involvement, frequently deafness, Argyll Robertson-like pupils and dysphagia (Chapon, Latour, Diraison, Schaeffer, & Vandenberghe, 1999;De Jonghe et al., 1999). This mutation has been found in several CMT families. When the polymorphic markers close to the gene and an intronic polymorphism were analyzed it was associated with the same haplotype as two Belgian families. Due to this, it has been suggested that a common ancestor was the founder of this particular mutation (De Jonghe et al., 1999). Nevertheless, Senderek et al. (2000) reported a family with an identical mutation embedded in a distinct haplotype, thus suggesting the existence of a hot-spot in this codon. Not only Belgian (De Jonghe et al., 1999) families with the mutation p.Thr124Met have been reported, also French (Chapon et al., 1999), German (Senderek et al., 2000;Hanemann et al., 2001), Italian (Schiavon et al., 1998), North American (Baloh, Jen, Kim, & Baloh, 2004 and Japanese Kurihara et al., 2002;Numakura, Lin, Ikegami, Guldberg, & Hayasaka, 2002;Kurihara, 2003).Here we report a ...

Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

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Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the <b><i>MPZ</i></b> Gene

“…Progressive sensorineural hearing loss has been described as part of the clinical presentation in several genetic forms of CMT, including various mutations in the MPZ gene [Chapon et al, 1999;De Jonghe et al, 1999;Alcin et al, 2000;Misu et al, 2000;Starr et al, 2003;Kochanski et al, 2004;Seeman et al, 2004;Leal et al, 2014;Tokuda et al, 2015;Duan et al, 2016], in kinships demonstrating mutations in the peripheral myelin protein (PMP22) gene [Alcin et al, 2000;Boerkoel et al, 2002;Kovach et al, 2002;Joo et al, 2004], in X-linked phosphoribosyl pyrophosphate synthetase-1 (PRPS-1) mutations [Synofzik et al, 2014;Gandia et al, 2015], and in CMT4C [Sivera et al, 2017].…”