WHAT IS CMT4J?
CMT4J is a rare, progressive neurological disease that can be quite similar to ALS. People with CMT4J can experience progressive muscle weakness, leading to difficulty walking or wheelchair dependence. They can lose the ability to use their arms. CMT4J can cause joint deformities, joint instability and dislocations. Like many neuromuscular diseases, the disease can progress to involve respiratory compromise, resulting in pneumonias, respiratory failure, and untimely death. The common cold or flu can be devastating.
CMT4J, or Charcot Marie Tooth, Type 4J, is a severe form of Charcot Marie Tooth Disease, or CMT. CMT diseases are the most common hereditary neuropathy, affecting about 1/2,500 people in the U.S. CMT is an umbrella term, encompassing many different forms of CMT with a very wide variation in onset, symptoms and nature of inheritance. CMT is also known as hereditary motor and sensory neuropathy (HMSN). CMT affects the peripheral nerves in the body–those that lie outside the brain and spinal cord, supplying muscles and sensory nerves. One of the many subsets of CMT, CMT4J is considered to be ultra-rare, known to affect approximately 30 people in the world. Several papers published on CMT4J estimate that the incidence of the more common mutation that is associate with CMT4J occurs in about 1 in a million people. Even though this is still extremely rare, it is likely that there are many more people living with CMT4J who are either misdiagnosed or as yet undiagnosed.
CMT4J is known as an autosomal recessive disease, meaning that two mutations need to be inherited in order to have the disease–one from each parent.
HOW DO PEOPLE GET CMT4J?
CMT4J is an autosomal recessive disease, caused by a mutation on the FIG4 gene, located on chromosome 6. Usually, the parents of a person with CMT4J are both carriers for the FIG4 gene. Most autosomal recessive diseases tend to have great variability, meaning that the age of onset, severity and course of disease progression can be very different from person to person.
Cytogenetic Location: 6q21, which is the long (q) arm of chromosome 6 at position 21
Molecular Location: base pairs 109,691,216 to 109,825,431 on chromosome 6 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)
Credit: Genome Decoration Page/NCBI
WHAT ARE THE SYMPTOMS OF CMT4J?
As we learn more about CMT4J, we know that the disease course and symptoms can differ significantly from person to person, making it hard to predict. People with CMT4J can begin to exhibit signs or symptoms of the disease from very early on–from infancy or toddlerhood. Often, walking is delayed and many CMT4J patients exhibit clumsiness, gait difficulties or weakness in early childhood. Sometimes CMT4J does not start until later in life.
Symptoms of CMT4J can include: mild to profound muscle weakness in either the legs or arms or both. Sometimes CMT4J can cause joint deformities and contractions in the hands and feet, which may require surgery. It can also cause looseness in the joints, making them more vulnerable to instability and dislocation. CMT4J has the capacity to cause profound, accelerating limb weakness and muscle atrophy. Patients can have difficulty walking, requiring the use of walkers, wheelchairs or other assistive devices. CMT4J can cause upper extremity weakness, making it difficult for people to use their hands or lift up their arms. As disease progresses, it can also cause weakness in the trunk, chest and neck muscles. Later, it could affect the muscles involved with breathing or the diaphragmatic nerve, making it difficult to breathe, cough or take a full breath. Upper respiratory infections–the common cold and flu–can cause severe complications with breathing because of this.
Some scientific papers compare CMT4J with ALS (Lou Gehrig’s Disease). In fact, the FIG4 gene mutation is shared in common with a percentage of people diagnosed with ALS.
At present, there is no treatment or cure for CMT4J. But there is HOPE.
WHAT HAPPENS IN THE BODY BECAUSE OF CMT4J?
The FIG4 mutation involved with CMT4J causes the malfunction of a protein involved in lysosomal function. This protein is believed to play a role in regulating a compound called PtdIns(3,5)P(2), or phosphatidylinositol-3,5 bisphosphinate. This compound is crucial in the movement of vesicles within cells. The FIG4 protein is also believed to improve survival function of nerve cells.
Credit: Genetics Home Reference/U.S. National Library of Medicine
IS THERE A TREATMENT OR CURE FOR CMT4J?
Currently there is no treatment or cure; however, many clinicians and scientists believe that Gene Therapy holds promise for a cure for CMT4J and many other rare diseases. Gene therapy has already shown success in other diseases and is currently being used in over 600 clinical trials throughout the world. We are truly on the cusp of enormous breakthroughs using gene therapy to treat and cure many diseases. Rare and diseases are ideal candidates for gene therapy, as most are monogenic (involving only one faulty gene).
CureCMT4J is on a path to test and use gene therapy to treat the devastating symptoms of CMT4J:
PRE CLINICAL WORK: CureCMT4J’s scientists from The Jackson Laboratory, University of Michigan, Wayne State University, and the University of Texas-Southwestern created the first-ever gene therapy pre-clinical trial using CMT4J mouse models. CMT4J mice treated with gene therapy showed a halting of disease progression, along with some reversal of symptoms. We can’t say for sure whether or not this science can directly translate to humans, but it is incredibly hopeful and will serve as the basis for a CMT4J Gene Therapy clinical trial in the future.
NATURAL HISTORY STUDY: CureCMT4J is working with Neurogene on a natural history study to better understand how the disease affects people. A natural history study is a research study that follows a group of people over time who have a disease or medical condition in common. By collecting the same data in CMT4J patients we can compare and contrast, giving us a better understanding of when and how the disease seems to start in people and how it progresses over time. These data points will also be used to compare pre- and post-treatment, in order to check for safety and efficacy of treatments. You can find out more about the CMT4J natural history study by visiting clinicaltrials.gov or through Neurogene’s website.
WHAT IS GENE THERAPY?
Gene therapy is an experimental treatment that involves replacing malfunctioning copies of genes in the human body with healthy copies of the genes. CureCMT4J is pursuing in-vivo gene therapy, where a person would be injected with trillions of copies of a viral vector–a healthy copy of the FIG4 gene paired with a benign virus. The virus carries the working copy of the gene into the cells, thereby taking over for the previously malfunctioning genes. Gene therapy is seeing success in treating many diseases for which there was no previous treatment, including SMA (spinal muscular atrophy) and a form of blindness.
HOW CAN A POSSIBLE TREATMENT APPLY TO OTHER RARE DISEASES?
Rare diseases are surprisingly common! 1 in 10 Americans is affected by a rare disease, with 80% of them involving a problematic gene. The model that Cure CMT4J is pursuing has shown success in on-going clinical trials with other rare diseases, such as Spinal Muscular Atrophy, San Filippo Syndrome, and blindness caused by single-gene mutations. The adaptability of gene therapy to many rare diseases is on the minds of many researchers and key players in industry—in the pharmaceutical and biotech world. The idea of using an assembly line-type approach, looking at gene therapy as a cassette that merely changes up the faulty gene needed, or the type of viral vector needed for delivery, represents a model of treating thousands of rare diseases with gene therapy. CureCMT4J represents Hope for so many other families.