Intermediate CMT Rates are Higher in Southeast China, with Later Onset for Type 1A, Study Suggests

Charcot-Marie-Tooth disease (CMT) patients from southeast China have higher rates of intermediate CMT, and patients with CMT type 1A seem to have later age of onset, when compared with other patient populations, a study suggests.

The study, titled “Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease,” was published in Clinical Genetics.

CMT is a highly variable disease, both in terms of genetics and phenotype (observable disease characteristics). Next-generation sequencing (NGS) has revolutionized genomic medicine and has been successfully used to improve the diagnosis of CMT and other neurogenetic conditions.

“Consequently, nearly 90 genes associated with CMT and other inherited peripheral neuropathies [nerve diseases] have been assembled in a gene panel, and parallel sequencing can be performed to interrogate these genes,” the authors wrote.

However, thorough genetic screenings of large populations of CMT patients using state-of-the-art NGS technologies are rarely performed in Chinese people.

Therefore, a team of Chinese investigators set out to analyze the genetic spectrum and clinical profiles of CMT patients from southeast China.

They performed molecular techniques combined with NGS in 150 unrelated patients suspected of having CMT.

The results showed that the PMP22 gene, which is involved in CMT type 1A, was duplicated in 40 (76.9%) patients, causing CMT type 1A, while part of the gene was deleted in 12 (23.1%) patients, causing hereditary neuropathy with liability to pressure palsies.

The researchers then screened the remaining 98 subjects (negative for PMP22 mutations) using a panel containing 88 genes known to be implicated in CMT and other diseases associated with damage in the peripheral nervous system.

Results revealed 55 variants, including 36 known mutations and 19 novel variants, in 57 out of the 98 patients. Importantly, among these 55 variants, the researchers found 45 pathogenic (meaning “disease-related or harmful”) or likely pathogenic variants in 48 patients, and 10 variants with uncertain significance in nine cases.

Out of the study sample of 138 subjects, 88 (63.8%) were genetically diagnosed with CMT.

After excluding the 12 non-CMT subjects, the researchers classified patients based on their clinical feature: “65 were classified as CMT1 (47.1%), 41 as CMT2 (29.8%), and 25 as ICMT [intermediate CMT] (18.1%). The other seven cases were not able to be classified because they refused nerve conduction studies,” the researchers wrote.

Of note, ICMT is a rare variant, with both axonal and demyelinating characteristics. CMT is usually caused by mutations in genes which results in degeneration of either the nerve fibers or axons (axonal type), or the protective myelin layer that insulates the nerve fibers (demyelinating  type).

The majority of subtypes identified in the study were CMT1A (PMP22), CMTX1 (GJB1), and CMT2A (MFN2 ), “which accounted for 49.3% (68/138) of all CMT patients,” the authors said.

They further noted that the rate of ICMT cases was significantly higher in this study than in European studies, but similar to previous Chinese investigations. Mutations in the GJB1 gene were more often related to this type of CMT.

Mutations in PMP22 were most commonly associated with CMT1, while mutations in MFN2 were associated with CMT type 2. MPZ and NDGR1 were the second most common causative genes in CMT1.

Evidence indicates that European and American CMT1A patients experience their first symptom of disease before age 10, while in other studies, Chinese and Japanese patients reported symptoms showing up in their 20s. In this study, the median age of disease onset in CMT1A patients was 32.5 years old, which suggests that individuals from southeast China with PMP22 mutations may have milder symptoms.

“Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis,” the authors said.

They added that, given the distinct genetic and clinical characteristics of CMT patients from southeast China, further research into the genetics behind CMT is needed, which will help clinical diagnosis and development of novel therapeutic strategies.