Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Abstract

To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.

Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing

“…Point mutations in GJB1 or MPZ , the two genes most frequently mutated in CMT1,were identified in 44% of the American patients, 60% of the Spanish patients, and only 14–22% of the patients in the other three studies. We identified a higher percentage of pathogenic CMT2 variants than the British and Japanese studies but lower than the American and Spanish studies [9, 10, 12, 13]. GJB1 , MPZ, and MFN2 variants, the most common causes of CMT2, accounted for 12% in our study and 18, 20, 28, and 34% in the British, Japanese, Spanish, and American studies.…”

“…A comparison of our results with the prevalence of identified CMT point mutations in four large clinic populations of affected individuals from Japan, Spain, United Kingdom, and USA is shown in Figure 3 [9, 10, 12, 13]. …”

“…After exclusion of the PMP22 duplication, point mutations were detected in 36% of our, Japanese, and British CMT1 patients, 66% of the American CMT1 patients, and 79% of the Spanish CMT1 patients [9, 10, 12, 13]. Point mutations in GJB1 or MPZ , the two genes most frequently mutated in CMT1,were identified in 44% of the American patients, 60% of the Spanish patients, and only 14–22% of the patients in the other three studies.…”

Severe phenotypes in a Charcot–Marie–Tooth 1A patient with PMP22 triplication

“…3 PMP22 duplication and deletion are the most frequent genetic cause of peripheral neuropathies. [4][5][6] Major genetic mechanism of CMT1A and hereditary neuropathy with liability to pressure palsies is based on recurrent nonallelelic homologous recombination. However, replication-based nonrecurrent rearrangement has been also reported in CMT1A.…”

INF2 mutations in Charcot‐Marie‐Tooth disease complicated with focal segmental glomerulosclerosis

“…To identify the common mechanism underlying CMT and FSGS, we analyzed the major causing genes of CMT in three patients, but they were negative for mutations of PMP22, MPZ , LITAF, NEFL, GJB1, GDAP1, EGR2, MFN2, RAB7, GARS, HSP27, HSP22, GJB1, and NDRG1 using methods described previously (Abe et al, 2011). Finally, we analyzed INF2 and detected the heterozygous c.206T>C mutation leading to p.L69P in cases 1 and 2, and the heterozygous c.323T>A mutation leading to p.V108D in case 3.…”