A study in Korean patients found four previously unreported mutations causing Charcot–Marie–Tooth disease type 4C (CMT4C), which were associated with manifestations such as foot deformities, walking difficulties, and slowed nerve conduction.
The research, “Compound heterozygous mutations of SH3TC2 in Charcot–Marie–Tooth disease type 4C patients,” appeared in the Journal of Human Genetics.
The scientists assessed mutations in the SH3TC2 gene, which cause CMT4C, in Korean patients with the autosomal recessive (AR) demyelinating, or intermediate forms of this disorder. Demyelination is the loss of myelin, the protective layer of nerve fibers, that affects the transmission of messages between the brain and the muscle.
Then, the remaining 198 individuals underwent genetic analysis. Their level of physical disability was determined by the functional disability scale and the CMT neuropathy score (CMTNS).
Four patients — two males and two females — revealed two combinations of compound heterozygous mutations in SH3TC2. Heterozygous refers to having two different mutated gene copies. This corresponds to a CMT4C frequency of 2.02% in patients without PMP22 duplication, which is similar in Japan, but higher in Germany.
The age at disease onset in these four patients was 8, 10, 30, and 38 years. Their disease duration ranged from 6 to 23 years.
All had foot deformities, walking difficulties, and pes cavus, or high-arched feet. However, none had lower limb proximal weakness. Three had mild scoliosis (spine curvature), cranial nerve involvement, and hearing loss. According to the CMTNS, disease severity was mild to moderate.
Assessments of nerve conduction velocities indicated demyelinating or intermediate types of nerve damage. Also, the compound muscle action potentials — the muscle response to nerve fiber stimulation — were lower in lower limb than in upper limb muscles. No correlation was found between nerve conduction slowing and disease duration.
As assessed with magnetic resonance imaging (MRI), the distal leg muscles of a 16-year-old male had atrophy (shrinkage) and fatty infiltration, which also was found in the calf and the anterior muscle compartment of the lower leg. Both sciatic nerves showed hypertrophy, or enlargement.
In turn, a nerve biopsy of the same patient revealed characteristic myelin abnormalities, including loss of large myelinated fibers, as well as onion bulbs — structures that result from proliferating Schwann cells and deposition of collagen. The researchers noted that Schwann cells produce myelin in peripheral nerve fibers.
No patient showed abnormalities in brain MRIs.
“This study will be helpful in making molecular diagnoses of demyelinating or intermediate CMT due to SH3TC2 mutations,” the team said.