Uncovering the genetic layers of Charcot-Marie-Tooth disease

Source: Victor Swoboda, The Neuro

Ask people to describe Charcot-Marie-Tooth (CMT) disease and their answer will probably be a blank stare. CMT is an inherited, progressive neurological disorder affecting about one out of every 2,500 Canadians, which puts it in the rare disease category along with better-known diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD).

As The Neuro marks Rare Disease Day, Feb. 29, its neurologists and researchers are providing hope to some 14,000 Canadian patients who are suffering from CMT, a disease for which there is still no cure or effective treatment.

CMT is named after the three 19th century medical men who identified it – Jean-Martin Charcot, Pierre Marie and Howard Henry Tooth. The disease is a genetically inherited ailment that affects nerves in the muscles and the sensory organs. People begin to experience symptoms in their youth – weakness in the feet and lower legs, foot deformities, awkward gait – followed in later life by muscle atrophy in the hands. CMT can also cause difficulty breathing, swallowing and talking as well as mild to severe pain. CMT is not fatal, but it is a progressive disease, which means that symptoms worsen with time.

“It’s usually the case that people have mild symptoms for several years until it gets to the point that they decide to get help,” notes neurologist Dr. Rami Massie, who treats more than 200 CMT patients at The Neuro and at a neuropathy clinic at the Montreal General Hospital.

CMT is characterized according to its effect on axons, the long strands that connect nerve cells. In the most common type, CMT1, the disease affects the protective myelin sheath that surrounds the axon. In a second type, CMT2, the axon itself is affected.

Finding the cause of CMT involves examining the many mutations found in genes that produce proteins that make either the axons or the myelin. More than 100 genes have been linked to CMT, which makes it difficult to find a treatment or cure that will be effective for all CMT patients.

“One genetic mutation called PMP22 is the cause of 70 per cent of patients with CMT1,” says Dr. Massie. “In the past, when we were able to test for only a few genetic mutations at a time, it was very hard to find a genetic cause. Today, however, we can test for up to 600 genes at a time and find a specific gene mutation for a greater number of patients. In CMT1 cases, we almost always find the mutation. Still, in about half the cases that we test for inherited neuropathy, we don’t find the cause.”

Dr. Massie has collaborated with his McGill colleague, Dr. Benoit Gentil, in looking for biomarkers that can clarify genetic mutations.

“Sometimes when we screen for a mutation, we don’t know whether it’s pathogenic or not,” says Dr. Gentil. “We are providing ways to determine whether the mutations are pathogenic.”

Dr. Gentil and Dr. Massie discovered intriguing genetic links in the case of a man who first showed symptoms of CMT in adolescence and who now, at age 52, is quadriplegic. The man has a rare form of the disease called CMT4J with a mutation in a gene called FIG4. Dr. Gentil did a skin biopsy from the patient so that he could look for biomarkers of the pathology in the skin cells and make neuronal models for study. Using these cells, he also examined the role of a gene called TRPV4 that is known to cause CMT2. His investigation found that TRPV4 had a role in promoting the pathology caused by FIG4 mutations. The discovery suggests that by inhibiting TRPV4, it might be possible to develop an effective therapy for this form of CMT.

“There are so many forms of CMT that we’ll have to go for customized medicine,” predicts Dr. Gentil. “Trying to find a general cure for all these forms is probably not going to happen, and we need to tackle them one by one.”

Despite the challenges, Dr. Massie sees an exciting future for CMT research and for the possibility of finding effective treatments, especially for CMT1 patients.

“We have to develop new ways to test patients’ genetics through whole-genome sequencing for a still larger number of genes and for genes that aren’t always expressed. Other types of studies will look to find the cause of those inherited neuropathies that are still a mystery.”

In addition to CMT, The Neuro vigorously conducts research into other rare diseases. Dr. Bernard Brais, co-director of the Rare Neurological Diseases Group, is a specialist in rare diseases with founder effects in Quebec. Dr. Edward Fon, The Neuro’s scientific director, investigates genes that cause Parkinson’s disease. Dr. Eric Shoubridge, an expert on mitochondria, is investigating the function of a gene called SLC25A46 that is linked to a spectrum of neurological disorders including Leigh Syndrome. The Neuro’s director, Dr. Guy Rouleau, has been a pathfinder in uncovering genes underlying rare diseases.

Patients at The Neuro’s specialized clinics have access to the latest genetic tests and treatments. In the past year, for example, The Neuro began providing a drug called Spinraza that was newly approved in Quebec for patients with spinal muscular atrophy (SMA).

Rare Disease Facts
1. Rare diseases impact 1 in 12 Canadians

2. 80% of rare diseases are genetic diseases

3. 75% of rare diseases are neurological diseases

March 2 2020