A mutation in the SEPT9 gene — which provides instructions for making the septin-9 protein that is involved in many cell functions, including cell division and movement — can lead to the development of Charcot-Marie-Tooth disease, according to a new case report.
Titled “Identification of a rare SEPT9 variant in a family with autosomal dominant Charcot-Marie-Tooth disease,” the case study was published in the journal BMC Medical Genetics.
Charcot-Marie-Tooth, known as CMT, comprises a group of disorders caused by genetic mutations that affect the peripheral nerves. Those nerves, found outside the central nervous system (comprised of the brain and spinal cord), control limb movement and sensation.
Up to 60–70% of demyelinating CMT, also known as CMT type 1 — the most common type of the disease — is caused by a mutation in the PMP22 gene. In addition to PMP22, mutations in the MPZ, GJB1, and MFN2 genes can explain more than 50% of all CMT cases. To date, mutations in more than 80 genes have already been reported to cause CMT.
However, there is still a significant percentage of CMT patients for whom a disease mutation has not yet been identified.
In this report, the researchers described the case of a 55-year-old German woman with CMT who was treated at the hospital for progressive muscular weakness and moderate sensory problems that started when she reached age 40.
A neurological examination revealed she had pes cavus — a foot deformity characterized by an abnormally high arch — tremor of the right upper extremity, muscle weakness, and reduced tendon reflexes. The woman also was found to have hypesthesia, or low sensitivity in her lower extremities, and severe gait ataxia, meaning she had abnormal, uncoordinated movements.
She consistently experienced forgetfulness, lack of concentration, and cognitive deficits, and felt disorientated.
Her physicians then performed nerve conduction studies, which indicated the presence of polyneuropathy, or peripheral nerve damage.
Hence, all her symptoms were consistent with a diagnosis of CMT.
The patient’s condition continued to worsen, and two years she later required walking aids to move. She also had a legal guardianship to assist her with financial affairs.
A second family member, her youngest son, had similar symptoms, including physical and cognitive issues. This led her doctors to investigate if other family members could also be experiencing the same symptoms.
Among the woman’s other three children were one daughter, who had been diagnosed with early childhood cerebral palsy, and two sons, neither of whom had no symptoms of neuropathy, or nerve damage.
However, the patient’s father and one older brother also had peripheral nerve damage, accompanied by the same foot deformity and cognitive deficits.
That led the physicians to conduct genetic sequencing on the patient. They were able to identify a mutation — c.1406 T > C — in the SEPT9 gene. This mutation had never been reported to date.
Subsequent bioinformatic analyses indicated the new mutation was likely pathogenic, or disease-causing. Mutations in SEPT9 had previously been described as a cause of hereditary neuralgic amyotrophy (HNA), which is a rare type of neuropathy similar to CMT.
“We, for the first time, present a SEPT9 variant associated to a CMT phenotype [disease] and suggest SEPT9 as new sufficient candidate gene in CMT,” the researchers said.
“Thus, SEPT9 alterations may be considered as a genetic risk-factor in CMT,” they said. “However, future clinical and functional studies are needed to elucidate the pathogenic relevance.”
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