CMT2S Patient Features, New Gene Mutations ID’d in Chinese Study

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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CMT2S | Charcot-Marie-Tooth News | illustration of DNA strand

Newly identified mutations in the IGHMBP2 gene have been associated with Charcot-Marie-Tooth disease type 2S (CMT2S), according to a study in China.

Data also suggested that missense IGHMBP2 mutations localized in the functional domains of the resulting IGHMBP2 enzyme may be linked to more severe forms of the disease. Missense mutations occur when a single nucleotide change results in an amino acid swap in the resulting protein. Nucleotides are the building blocks of DNA, while amino acids are proteins’ building blocks.

These findings expand the spectrum of CMT2S-associated IGHMBP2 mutations, and call for additional studies on the potential links between genetic and clinical features, the researchers noted.

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The study, “Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations,” was published in the journal Neuromuscular Disorders.

Charcot-Marie-Tooth disease (CMT) is a group of inherited progressive disorders of the peripheral nervous system, which controls movement and sensation in the limbs. It is mainly divided into “demyelinating CMT,” also known as CMT type 1 (CMT1), and “axonal CMT,” or CMT type 2 (CMT2).

CMT2S is caused by mutations in both copies of the IGHMBP2 gene, which provides instructions to generate an enzyme of the same name that is critical for protein production and cell division, or multiplication. When mutations need be in both gene copies to be disease-causing, the disease is considered autosomal recessive.

Since its first reported case in 2014, CMT2S has been associated with an early symptom onset with limb weakness and sensory impairment, but typically without significant respiratory involvement.

However, data are still limited on the genetic and clinical features of CMT2S, as well as potential links between these features.

A team of researchers in China analyzed the frequency of CMT2S among 178 families with CMT2 enrolled at two Chinese hospitals between 2012 and 2021.

They also described CMT2S genetic and clinical features in their patient group and worldwide, and assessed potential links between the localization of IGHMBP2 mutations and disease severity.

Results showed that 11 patients from eight families had CMT2S. A total of 15 distinct IGHMBP2 mutations were detected.

Since the features of four of these families were previously described, the researchers focused on the remaining four, who carried eight different IGHMBP2 mutations. All of these genetic variants (six newly identified) were deemed disease-causing or likely to be disease-causing.

The four girls and one boy from the four families had an age at onset that ranged from 3 months to 7 years. The most frequent initial symptoms comprised muscle weakness affecting the lower limbs. At the time of study evaluation, with ages ranging from 3 to 38 years, they showed moderate to severe muscle weakness, muscle wasting, and loss of sensory function.

These findings were consistent with those previously reported for CMT2S patients, the team noted.

With these 11 patients, a total of 25 CMT2S cases from 34 unrelated families and carrying 47 different IGHMBP2 mutations have been reported to date. Patients’ age at onset ranged from 1 month to 20 years, and the most common initial symptoms included muscle weakness (33.3%), delayed milestones (20%), and feet deformity and walking problems (17.8% each).

While most patients develop symptoms in infancy or early childhood and show moderate to severe impairment, “a tiny minority of patients were relatively late onset and [mildly] affected, which should be given more attention in genetic diagnosis and treatment,” the researchers wrote.

Given that two-thirds of identified mutations so far were missense variants, the team conducted a molecular structural model analysis on 26 of these mutations and tried to assess potential links with disease severity.

They found that, among their patients, those with one or two missense mutations in or close to the functional regions of the resulting IGHMBP2 enzyme showed more severe disease, while one patient with two mutations far away from those regions was only mildly affected.

While incomplete clinical information for other patients in the literature hindered a potential link, CMT2S patients with more severe disease “tended to carry missense mutations in the functional regions,” the researchers wrote.

Larger studies are needed to confirm a link between IGHMBP2 missense mutations in these functional regions and more severe disease.

Notably, the frequency of IGHMBP2 mutations was 4.5% in a group of 178 CMT2 patients and 7.5% in CMT2 patients without dominant inheritance. Of note, dominant inheritance, also known as autosomal dominant, means that only one mutated gene copy is sufficient to cause the disease.

“In view of the relatively higher frequency of IGHMBP2 mutation in CMT2 patients in mainland China, we recommended focusing on IGHMBP2 mutation screening in early-onset, moderately or severely affected, [autosomal recessive] or sporadic CMT2 patients,” the team wrote.