New Gene Mutation Found in Five Family Members with CMTX4, Case Report Shows

José Lopes, PhD avatar

by José Lopes, PhD |

Share this article:

Share article via email
CMT genetic mutations


A new gene mutation was identified in five family members with X-linked Charcot-Marie-Tooth disease type 4 (CMTX4), a Chinese case report describes.

The study, “A Novel AIFM1 Mutation in a Chinese Family with X-linked Charcot-Marie-Tooth disease type 4,” appeared in the journal Neuromuscular Disorders.

Mutations in the AIFM1 gene have been linked to diverse disorders, including CMTX4, a rare CMT subtype associated with deafness and cognitive impairment.

Scientists described the first Chinese family with a CMTX4 diagnosis, who presented with motor and sensory nerve fibers damage (axonal neuropathy).

The family included five affected and 17 unaffected members over five generations. The first person diagnosed showed slowly progressing weakness in the lower limbs and mild loss of balance at age 10. He later developed pes cavus — high arch of the foot — and difficulty climbing stairs at 17 years old.

At age 25, neurological examinations further revealed muscle weakness and atrophy in the lower limbs, reduced pain and temperature sensation near the ankles, and absence of knee and ankle reflexes. The patient’s intellectual function was normal.

The other four patients had variable manifestations. Their initial symptom was leg weakness, followed by atrophy and sensory impairments. However, two of these patients had an earlier age of disease onset — at 7 and 5 years old — and faster progression. While one patient needed ankle-foot orthoses to walk when he was 14 years old, the other could walk unaided after ankle surgery at 35 years old.

Of the other two patients, one could walk unaided at age 49, and the other was wheelchair-bound at age 64.

All but one patient had absent deep tendon reflexes. However, all patients showed steppage gait, pes cavus, and distal muscular atrophy below the knee. Two patients demonstrated sensory and motor axonal neuropathy (nerve disease) in studies of nerve conduction, particularly in the peroneal nerve, which is a branch of the sciatic nerve innervating the lower leg and foot.

Magnetic resonance imaging in the calf of the first diagnosed family member revealed fatty infiltration, atrophy, and edema (swelling). This patient also showed reduced myelin, the protective layer of nerve fibers, as well as decreased fiber density.

Detailed analyses revealed atrophy of nerve fibers, an increased number of mitochondria, which supply energy to cells, and mitochondrial swelling. No signs of cell death, degeneration, scarring, or infiltration were found.

Genetic analyses were conducted in all family members. Results revealed a hemizygous missense gene mutation exclusively in the patients, which was classified as likely pathogenic according to the guidelines of the American College of Medical Genetics and Genomics. Hemizygous missense mutations occur when the change of a single nucleotide — the building blocks of DNA — results in the presence of only one of the two copies of a gene normally present in people.

Based on the patients’ manifestations, the scientists concluded that “this mutant variant (c.513G>A, p.Met171Ile) was mainly involved in peripheral nerves [lesions] with relatively slight muscular changes.”

“In conclusion, the identification of a novel missense AIFM1 mutation in a Chinese family in our study expands our knowledge of the genetic spectrum of AIFM1-associated diseases,” they said.

They also said that their findings indicate that abnormal mitochondrial shape and accumulation, as well as fatty infiltration and muscle atrophy, may occur in the early stages of CMTX4.