Large Study Focuses on CMT Genetic Variants and Age of Onset in Japan

Variants in the genes GJB1, MFN2 and MPZ are the predominant causes of Charcot-Marie-Tooth disease (CMT) across Japan, and the first decade of life is the most common onset period for CMT patients in the country, a large, nationwide study suggests.

Researchers also found that the CMT-related genetic profiles of patients vary depending on from where in Japan they originate.

The study with those findings, “Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan,” was published in the journal of Neurology, Neurosurgery & Psychiatry.

CMT includes a group of genetic disorders caused by defects in several genes. To date, approximately 100 genes have been linked to CMT.

The genetic basis of the disease becomes even more complex because many of the CMT-related genes also may cause inherited peripheral neuropathies other than CMT.

Given to its diversity in disease presentation and genetic diversity, “the clinical subtyping of CMT is always laborious and difficult,” researchers noted in the study.

Taking advantage of the development of next-generation sequencing (NGS), which allows the profiling of multiple genes simultaneously, researchers studied the genetic spectrum of CMT across Japan.

Researchers performed screens for CMT-related genes in 1,005 Japanese subjects with suspected CMT, linking their genetic profiles with their clinical features, including age at onset.

Included cases were grouped according to their inheritance pattern into sporadic (570), autosomal dominant or X-linked (341), autosomal recessive (72) or with unknown inheritance (22).

Based on nerve conduction exams, cases also were grouped as demyelinating CMT (282), axonal CMT (682), or of unclassified type (41).

From the 40 genes screened, the team identified disease-causing genetic variants, or ones likely to be causing disease, in 301 subjects (30% of total cases).

The most common variations were found in the genes GJB1 (21.9%) (related with X-linked CMT), MFN2 (21.9%) (linked with CMT type 2A), and MPZ (16.9%) (related with CMT type 1, type 2 and dominant-intermediate).

In demyelinating CMT, variants were detected in 45.7% cases, whereas axonal CMT had a relatively lower detection rate (22.9%).

Regarding age at onset, most often subjects started experiencing CMT symptoms during their first decade of life; and the earlier the onset of CMT, the more likely it was that the subject carried an identifiable CMT gene variant.

Additionally, researchers saw that the genetic profile varied with the geographical distribution of patients. Variants in GJB1, MFN2 and MPZ were the top three causative CMT genes over most of the country. Variants in MFN2 were predominant in northern and southern Japan, while GJB1-related CMT was more prevalent in middle Japan.

“Our results updated the genetic profile within a large-scale of Japanese CMT cases,” researchers said.

“Subsequent analyses regarding onset age and geographical distribution advanced our understanding of CMT, which would be beneficial for clinicians,” they concluded.