Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families

Abstract

Charcot-Marie-Tooth neuropathy type 1 (CMT1), the most common hereditary neurological disorder in humans, is characterized by clinical and genetic heterogeneity. It is caused mainly by a 1.5 Mb duplication in 17p11.2, but also by mutations in the myelin genes PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero), Cx32 (connexin 32; also called GJB1), and EGR2 (early growth response 2). In this study, we have screened 172 index cases of Italian families in which there was at least one subject with a CMT1 diagnosis for the duplication on 17p11.2 and mutations in these genes. Among 170 informative unrelated patients, the overall duplication frequency was 57.6%. A difference could be observed between the duplication frequency in familial cases (71.6%) and that observed in non-familial cases (36.8%). Among the non-duplicated patients, 12 were mutated in Cx32, four in MPZ, two in PMP22, and none in the EGR2. In the non-duplicated cases, the overall point mutation frequency for these genes was 25.0%. We describe the mutations identified, and consider possible genotype-phenotype correlation.

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

“…However, the results were similar to those of Italian (57.6%) (Mostacciuolo et al, 2001) and Russian (53.7%) (Mersiyanova et al, 2000b).…”

“…The mutation frequency in GJB1 (7.1%) in this study was considerably lower than in several European groups, i.e., Spain 21.3% (Bort et al, 1997), Finland 19.0% (Silander et al, 1998), Russia 13.0% (Mersiyanova et al, 2000b), Italy 16.7% (Mostacciuolo et al, 2001) and Germany 11.9% (Huehne et al, 2003), but similar to that of the Japanese 5.6-5.7% (Yoshihara et al, 2000;Numakura et al, 2002). It appears that mutations in GJB1 are less frequent in East Asian CMT patients than in European patients.…”

“…We first examined the CMT1A duplication by genotyping seven microsatellites within the 17p11.2-p12 region, and found 15 CMT1A duplication families among 28 CMT1 cases. The duplication frequency (53.6%) in Korean patients is slightly lower than, or similar to those of European CMT1 cases: 70.7% in an Europian collaborative study , 57.6% in Italy (Mostacciuolo et al, 2001) and 53.7% in Russia (Mersiyanova et al, 2000b). However the frequency is higher than the level of 31.2% in Japanese CMT1 patients (Ikegami et al, 1997).…”

“…However the frequency is higher than the level of 31.2% in Japanese CMT1 patients (Ikegami et al, 1997). Mersiyanova et al, 2000bHuehne et al, 2003Bort et al, 1997Silander et al, 1998Jordanova et al, 2003Mostacciuolo et al, 2001 Patients with the CMT1A duplication were excluded. b Patients neither CMT1A duplication nor causative mutation in PMP22, MPZ and GJB1.…”

“…Mutations in PMP22 (MIM# 601097), myelin protein zero (MPZ/P0) in 1q23 (MIM# 159440), early growth response 2 (EGR2/Krox-20) in 19q21.1-q22.1 (MIM# 129010), gap junction protein beta-1 (GJB1/Cx32) in Xq13.1 (MIM# 304040) and neurofilament light chain (NEFL) gene in 8p21 (MIM# 162280) frequently provide the genetic causes of hereditary peripheral neuropathies (Bird et al, 1982;Timmerman et al, 1996;Warner et al, 1998;Mersiyanova et al, 2000a). 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).…”