Their findings were published in the study, “LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2,” was published in the European Journal of Human Genetics.
Charcot-Marie-Tooth disease is a set of hereditary neuropathies (nerve diseases) that arise due to different gene mutations that lead to degeneration of the nerve fibers (axons) or the myelin sheath, the thin insulating layer essential for communication between nerve cells.
CMT is divided into several types and subtypes according to the genes that are mutated, the way the disease is inherited, whether the damage is in axons — the long, wire-like parts of nerve cells — or in the myelin sheath, among other clinical symptoms.
CMT1 is the most common subtype of the disease and is caused by genetic defects that damage the myelin sheath, while CMT2 is caused by defects in genes important for axons of the peripheral nerves, those connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound.
While mutations in genes that cause degeneration of myelin are identified in about 80% of the cases, a genetic diagnosis for the mutations linked to axon degeneration are found only in 25% of the cases.
These data support the need “to identify new genes involved in this subtype of CMT,” the researchers wrote.
Mutations in the LRSAM1 gene have been previously identified as a cause of the relatively mild and benign CMT type 2P. Patients with this type of CMT typically develop symptoms between 20 and 40 years of age, but the disease progresses slowly.
The LRSAM1 protein belongs to a group of enzymes called RING-finger E3 ubiquitin ligase, which are produced in the fetal and adult spinal cord, sensory neurons, and all developing muscles.
Researchers analyzed 72 members of eight non-related French families with adult-onset disease; their mean age of disease onset was 39 years old.
The disease was dominated by sensory impairment (80%) and neuropathic pain, affecting 38% of the patients, and a mild motor deficit confined mostly to the lower limbs.
Although clinical severity varied, most of the patients retained the ability to walk. After a median follow-up of 12 years, 86% of the patients were still able to walk without aids. Three patients used a cane to move, and another three used a wheelchair.
A genetic analysis revealed two \variants in the LRSAM1 gene that had not been previously identified: a deletion (Gln698_Gln701del) was detected in the members of seven families, while a duplication (Pro702_Gln711dup) was found in the eighth family.
“Our work increases the number of LRSAM1 variants and expands the phenotypic spectrum of CMT2P, extending from painful to predominantly sensory ataxic neuropathies,” the study concluded.