Rare CMT Type F Described by Variable Clinical, MRI Findings

A small study described variable clinical and MRI findings in three Korean people with rare dominant intermediate Charcot Marie Tooth (CMT) disease type F. 

These results may be useful for the diagnosis of CMT patients with unknown genetic mutations, the scientists said.

The study, “Clinical and Neuroimaging Features in Charcot–Marie–Tooth Patients with GNB4 Mutations,” was published in the journal Life. 

Dominant intermediate CMT type F (CMTDIF) is caused by mutations in the GNB4 gene, which carries instructions for the Gb4 protein. This protein is found widely in many tissues, including nerve fibers (axons) of the peripheral nervous system — those outside the brain and spinal cord. 

Nerve biopsies in people with the condition show damage to myelin, the fatty coating surrounding nerve fibers that enhances electrical signals along axons.

The onset of CMT type F typically occurs in adolescence. It is characterized by slowly progressive muscle weakness and atrophy, which is shrinkage affecting the arms and legs and sensory loss that usually occurs in the hands and feet.

Until recently, only a small number of CMT families with GNB4 variants, including two Han Chinese and one Japanese family, have been reported. 

Now, researchers in South Korea described the cases of three Korean CMT patients with GNB4 variants. The team investigated these patients’ clinical characteristics using imaging techniques and electrophysiology, which measures the electrical signal along axons. 

One male patient, 12 years old at the time of the exam, had a disease duration of three years. He carried an A265G variant, in which A stands for adenosine and G for a guanine in the DNA sequence. The results of this change converted a lysine amino acid to glutamate (Lys89Glu) in the Gb4 protein. Notably, amino acids are the building blocks of proteins. 

This same variant was found in a 17-year-old girl with a disease duration of 12 years. In both patients, no variants were found in their unaffected parents and brothers, suggesting it arose spontaneously. This same variant was previously reported in a Han Chinese family with CMT type F.

The third patient was an adult woman, age 31. Her disease duration was six years. She carried a previously unidentified GNB4 variant known as G229A, with unaffected parents as well. The variant led to a glycine amino acid change to an arginine (Gly77Arg).

Clinical assessments found the two individuals with the Lys89Glu variant had an earlier disease onset and more severe disease, with muscle weakness and atrophy predominately in the leg but lesser in the arms. 

In contrast, muscle atrophy was not found in the patient with the Gly77Arg variant, and muscle weakness was similar in the upper and lower limbs.

Vibration sensation was reduced more than pain perception in all three patients, and all had foot deformities. Pinprick sensation was normal in the lower limbs of the older Gly77Arg patient. Tendon reflexes were absent in the younger participants but decreased in the older patient.

Only the two participants with the Lys89Glu variant had scoliosis, which is a sideways curvature of the spine. They also showed moderate to severe functional disability, as assessed by the functional disability scale and the CMT neuropathy score version 2. The Gly77Arg patient was classified with mild disabilities. 

The median motor nerve conduction velocity (MNCV), a measure of the speed of nerve signals, ranged between 3.9 and 7.1 meters per second (m/s) in the two patients with the Lys89Glu variant. Normal MNCV generally ranges from 50 to 60 m/s. The woman with the Gly77Arg mutation ranged from 37.5 to 39.7 m/s. 

Not all sensory nerve signals were evoked in the Lys89Glu patients; however, they were relatively preserved in the older Gly77Arg participant. Nerve conduction studies over five years showed the older patient had slow disease progression. 

A nerve biopsy was performed on one of the younger patients who showed severe loss of myelinated nerve fibers.

Lower limb MRI scans were taken twice within an interval of three or five years and measured fat infiltration — a measure of muscle loss. The older patient had scans at the ages of 27 and 32, while the participants with the Lys89Glu mutation had scans between 14 and 19 years. 

The woman with the Gly77Arg mutation showed minimal fat infiltration in calf and thigh muscles. No notable progression was found between scans. 

As for those with the Lys89Glu mutation, the boy showed moderate fat infiltration in the calf muscle and mild fat infiltration in the thigh muscles, while the girl had mild fat infiltration in the calf and the thigh. No significant progression of fat infiltration was seen. 

“In summary, we described the first three Korean families with a GNB4 mutation and found [variable characteristics] among intermediate and demyelinating neuropathy [nerve damage],” the scientists wrote. “Additionally, we presented lower limb MRI findings of patients with GNB4 mutations for the first time.”

“These results would be useful for differential diagnosis of CMT patients with unknown GNB4 variants and for broadening our knowledge of the spectrum of [genetic/disease characteristics] correlations,” they added.