New Mutation in PMP22 Gene Linked to CMT3 in Chinese Patient

Scientists have pinpointed a new genetic mutation in the PMP22 gene as the cause of Charcot-Marie-Tooth disease type 3 (CMT3) in a 26-year-old Chinese man.

Titled “A novel PMP22 insertion mutation causing Charcot–Marie–Tooth disease type 3,” the case report was published in the journal Medicine.

The PMP22 gene is one of the known CMT-causing genes. It contains instructions to make a protein with a role in the maintenance and development of myelin, the fatty layer that coats nerve cells and ensures proper communication between them.

Mutations that cause a duplication in the PMP22 gene’s DNA sequence are linked with CMT1A, the most common subtype of CMT. Other small mutations, including those that cause the change of a single nucleotide — the building blocks of DNA — underlie rarer forms of the disease, including CMT3.

Researchers now described the case of a man in China who was found to have a new mutation in the PMP22 gene, and was later diagnosed with CMT3.

At a hospital visit in August 2019, the patient reported a history of generalized weakness, muscle shrinkage in the lower limbs, and deformed hands and feet. He had begun walking by age 6, yet his gait — his manner of walking — was unstable. He developed arches in his feet that gradually worsened. At age 16, he underwent straightened correction of the feet, which led to a greater improvement in his right foot.

The patient now was treated for a myopathic or waddling gait. Further examination revealed muscle shrinkage and scoliosis (sideways spinal curvature), as well as deformities in both thumbs and feet, including pes cavus or high foot arch, a foot deformity associated with CMT.

Lab tests revealed abnormally elevated protein levels in the cerebrospinal fluid (CSF), which is the liquid surrounding the brain and spinal cord. The patient’s levels of creatine kinase, a marker of muscle damage, were elevated. Blood and urine analyses were normal and no self-reacting antibodies were found. Those results ruled out an autoimmune disease as the cause of the symptoms.

MRI scans revealed an abnormal accumulation of fluid around the joints of the feet, accompanied by swelling of the ankle joints and soft tissues.

Nerve conduction tests showed impairments in both motor and sensory nerves located in the extremities, suggestive of serious demyelination (myelin loss) and degeneration of axons nerve fibers, the team said.

Notably, sensory nerves are those responsible for carrying information from different types of stimuli to the central nervous system (CNS), which includes the brain and spinal cord. Motor nerves are responsible for controlling voluntary movements by passing information from the CNS to the muscles.

Although neither the patient nor his parents allowed nerve and muscle biopsies, genetic analysis unveiled a mutation in one of the two copies of the PMP22 gene, which had never been described. Computational analysis indicated that this mutation altered the structure of the PMP22 protein.

The patient was given a therapeutic regimen to lessen the symptoms of nerve damage and prescribed routine rehabilitation exercises during his hospitalization. The rehabilitation eased his muscle weakness slightly, allowing him to take care of himself. He was discharged from the hospital after two weeks and advised to continue the rehabilitation exercises at home and in the clinics on a regular basis. At one and three months of follow-up, his condition was maintained and he was still able to take care of himself.

Overall, this case report describes a new PMP22 mutation linked with CMT3, the researchers wrote.

The diagnosis was only confirmed after genome sequencing, which “deserves to be considered for the diagnosis of CMT and other similar inherited diseases,” they concluded.