The study, “Novel GARS mutation presenting as autosomal dominant intermediate Charcot‐Marie‐Tooth disease,” was published in the Journal of the Peripheral Nervous System.
Up to 37 mutations in the GARS gene have been identified in patients with Charcot-Marie-Tooth disease type 2D (CMT2D) or in patents with distal hereditary motor neuropathy type V, a progressive disorder that, similar to CMT, affects nerve cells resulting in muscle weakness. But none have been associated with DI-CMT until now.
The GARS gene provides instructions for making glycyl-tRNA synthetase, a protein that belongs to a group of enzymes that mediate the binding of amino acids — the building blocks of proteins — to RNA in gene expression (protein production).
In this case study, researchers report on a new mutation in the GARS gene that is linked to DI-CMT, which is inherited in an autosomal dominant manner, meaning the disease develops even if the child only receives one mutated copy of the gene from either parent.
The patient, a 21-year-old male, began having problems with walking (gait disturbance) and hand weakness. He first noticed muscle weakness in both legs at 14 years old. Clinical tests revealed that some impairments in muscle function were already present.
His 58-year-old father also said that he experienced muscle weakness at 20 years old, followed by walking difficulties at 22 years old. Muscle weakness progressed slowly from that point on.
“Neurological examination at age 58 revealed abnormal walking with steppage and waddling components,” the researchers wrote, along with other parameters of muscle wasting.
Motor nerve conduction tests performed every two months in both the father and son revealed a moderate decrease in muscles responses. These tests are used to check how well electrical signals are being transmitted by the nerves to the muscles.
A biopsy performed on the left sural nerve (located at the ankle) in the father revealed loss of axons, the long slender projection of nerve cells that carries the electrical stimuli, and of the myelin sheath itself, the insulating layer protecting them.
A family history revealed that three individuals in three generations had the same symptoms, including the deceased grandfather.
“Therefore, we clinically diagnosed this family as having DI-CMT,” the researchers wrote.
Genetic testing identified a new mutation located in exon 5 of the GARS gene. The mutation was absent in the mother, sister, and aunt, all without symptoms, “indicating the mutation co-segregated with DI-CMT in this family,” they added.
“In conclusion, the present study revealed the first GARS mutation associated with DI-CMT, which broadens the current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with the [aminoacyl-tRNA synthetase] family,” the researchers concluded. “Further studies are required to better understand GARS-associated intermediate CMT.”