Japanese Study Describes 15 New Variants of MFN2 Gene in Group of Charcot-Marie-Tooth Patients

Charcot–Marie–Tooth (CMT) disease type 2, or axonal CMT, has long been associated with genetic variants of the MFN2 gene, which encodes a protein of the mitochondrial outer membrane. A Japanese study now finds that these mutations may also be related to demyelinating CMT subtype (type 1), which could help explain the different clinical features of these disorders.

The study, “Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study.” appeared in the Journal of the Peripheral Nervous System.

The research team, led by the Kagoshima University Graduate School of Medical and Dental Sciences, evaluated 1,334 DNA samples collected from individuals with clinically suspected CMT, referred by neurological or neuropediatric departments throughout Japan. Researchers screened the samples for variants in the MFN2 gene that could potentially be causing CMT. They identified a total of 45 mutations in 79 CMT patients. Fifteen of these 45 had never been seen before.

In this cohort, about 8 percent of the patients with MFN2 mutations — or 63 people out of 801 participants, had CMT2. This fits with previous studies for this population in Japan. However, the frequency of sporadic or de novo mutations found was 45 percent, which is much higher than the 28 to 34 percent previously reported for other countries.

“The low frequency of MFN2 mutations and high frequency of sporadic cases might indicate the influence of geographical and social distribution, although there is a possibility of an incomplete family history,” the authors wrote, adding that patients harboring MFN2 mutations had earlier disease onset than average CMT patients. In addition, those with demyelinating CMT subtype caused by MFN2 mutation presented earlier disease onset than those with CMT2.

Most patients carrying MFN2 identified variants showed CMT’s characteristic symptoms – spasticity (continuous muscle contraction), optic atrophy and vocal cord paralysis. Researchers also detected co-occurrence of MFN2 and PMP22 mutations, previously associated with CMT1A subtype, in a patient who presents early onset gait disturbances and mild mental retardation. This result suggested that presence of these two variants could lead to a severe phenotype, caused by double-dose effect or genetic burden effect, the authors said.

“Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed,” authors proposed. “Combinations of causative genes should be considered to explain the phenotypic diversity.”