Novel Mutation Identified in Rare Form of CMT in Chinese Girl, Case Study Reports

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Researchers identified a novel mutation responsible for a rare form of Charcot-Marie-Tooth disease in a 13-year-old Chinese patient.

The case report, “A novel homozygous nonsense mutation in NEFL causes autosomal recessive Charcot-Marie-Tooth disease,” appeared in the journal Neuromuscular Disorders.

Mutations (errors) in the gene coding for the neurofilament light polypeptide (NEFL) – a key component of the structural machinery of nerve cells (or neurons) called the cytoskeleton – is the cause of a rare form of Charcot-Marie-Tooth (CMT) disease. This type of CMT is called autosomal dominant axonal Charcot-Marie-Tooth, or CMT2E, and it means that getting one copy of the mutated gene is sufficient to trigger the disease.

A pattern of what is known as autosomal recessive axonal form of Charcot-Marie-Tooth – meaning that in this case both copies of the gene need to carry the mutation for the disease to manifest – is much rarer and has only been identified, until now, in two patients.

These patients exhibited a set of common features, including disease onset during childhood with severe damage to peripheral nerves.

Now, authors describe a case of a 13-year-old Chinese girl carrying a mutation that caused autosomal recessive axonal Charcot-Marie-Tooth.

The child was born from consanguineous parents (in genetics, this means the parents are second cousins or closer and share a common ancestor). At birth she had no neuromuscular disorders and was capable of sitting at 6 months of age, but was unable to stand or walk until she was around 1 year old. She then began to develop gait disturbance and weakness in her lower extremities until she was 10 years old. At this age she had to use a tailored ankle-foot orthosis.

As in the other two cases, this girl presented “marked delay in motor milestones, distal wasting of legs and pes cavus deformities,” the authors said in the report.

A biopsy to the sural nerve in the leg showed a severe loss of large myelinated fibers.

The authors conducted additional analyses, and using targeted next-generation sequencing, identified a new mutation in the NEFL gene as the potential cause for the disease spectrum in the patient. The mutation may lead to a reduction in the levels of the NEFL protein, which may explain the absence of neurofilaments, authors stated.

Overall, “we report a novel homozygous nonsense NEFL mutation causing autosomal recessive CMT. It expands the mutation spectrum of NEFL-related CMT [Charcot-Marie-Tooth],” the case report concluded.