Understanding CMT4J

Charcot-Marie-Tooth 4J (CMT4J) is a rare, inherited, recessive subtype of CMT caused by a variant in the FIG4 gene. This variant leads to uneven loss of myelin on motor and sensory nerves. Myelin coats the outside of nerves, enabling nerve impulses or signals to travel more quickly. The loss of myelin leads to muscle loss and muscle atrophy (weakness) and may also cause reduced sensation. Symptoms of CMT4J may appear for the first time during childhood or later in life.

The onset, severity, and the ways that CMT4J impacts the body can vary from person-to-person, ranging from mild to severe. Common signs and symptoms are typically characterized by muscle and limb weakness in early childhood that further progresses over time. Symptoms may include loss of gross motor skills such as difficulty in walking, as well as the loss of fine motor skills such as being able to feed themselves or do other activities that require arm strength. In some individuals, these signs and symptoms may eventually lead to the inability to walk, and some patients may become dependent on assistive devices to remain mobile. Both males and females may be affected.1,2

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Charcot-Marie-Tooth (CMT) history

First identified in 1886, Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder that affects both motor and sensory nerves. It currently impacts approximately 1 in 2,500 people, of all genders and ethnicities. CMT is also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy, which are a group of disorders that affect peripheral nerves and the muscles attached to the peripheral nervous system. Peripheral nerves are found outside the brain and spinal cord; their job is to supply the muscles and sensory organs in the limbs with the messages needed to operate correctly. There are many subtypes of CMT, including variants in at least 80 genes that cause the different subtypes of CMT. Symptoms and disease management for each subtype of CMT vary.

Type CMT4 history

All subtypes of CMT4 are inherited in an autosomal pattern. Autosomal recessive describes one of several ways that a disorder or disease is passed down through families. An autosomal recessive disorder occurs when two copies of an abnormal gene are passed from each parent to the child.

CMT is further classified based on the pathogenic variant involved — for instance, CMT4A, CMT4B, etc.

Type CMT4J history

CMT4J is a very rare subtype of CMT. It accounts for approximately one quarter of the 4% of CMT cases that are recessive. First described in scientific literature 100 years earlier, the gene was not identified until 2007, when it was found in patients previously diagnosed with unknown CMT variants. In 2011, a study was conducted that identified almost three times more patients living with 4J. Today, even more patients have been diagnosed with CMT4J outside of this study through the efforts of CureCMT4J, a family foundation and advocacy organization.

Reported cases of CMT4J total approximately three dozen worldwide and make up less than 1% of all CMT cases. Healthy carriers of the FIG4 gene are more common; the carrier rate of the FIG4 gene among northern Europeans is 1 in 1,000.

It is common for individuals to receive misdiagnoses prior to learning that they are living with CMT4J. People living with CMT4J are commonly misdiagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis (MS), Guillain-Barré Syndrome (GBS), and amyotrophic lateral sclerosis (ALS), as well as other CMT and neuromuscular diseases, with the primary symptom being muscle weakness due to issues with the muscle fiber (myopathies).

Sources:

  1. Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., … Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4. Brain: a journal of neurology134(Pt 7), 1959–1971. doi:10.1093/brain/awr148. Retrieved on June 26, 2019, from link.
  2. Field research conducted by Neurogene and Ten Bridge Communications, July 2019.
  3. Charcot-Marie-Tooth disease. (2018, October). Retrieved June 26, 2019, from link.
  4. Charcot-Marie-Tooth Disease Fact Sheet. (2019, May 13). Retrieved June 26, 2019, from link.
  5. Kushimura, Y., Azuma, Y., Mizuta, I., Muraoka, Y., Kyotani, A., Yoshida, H., Tokuda, T., Mizuno, T., Yamaguchi, M. (2018, July 4). Loss-of-function mutation in Hippo suppressed enlargement of lysosomes and neurodegeneration caused by dFIG4 knockdown. NeuroReport. 29(10), 856-862. doi:10.1097/WNR.0000000000001044. Retrieved September 12, 2019, from link.
  6. Lewis, R. (2017, February 23). Rare Disease Day 2017: Talia’s Story [Web log post]. Retrieved June 26, 2019, from link.
  7. Martyn, C., & Li, J. (2013, Feb.). Fig4 Deficiency: a newly emerged lysosomal storage disorder? Progress in Neurobiology. doi:10.1016/j.pneurobio.2012.11.001. Retrieved September 12, 2019, from link.
  8. Rajabelly, Y., Adams, D., Latour, P., Attarian, S. (2016, March 23). Hereditary and inflammatory neuropathies: a review of reported associations, mimics, and misdiagnoses. JNNP Online First. BMJ. doi:10.1136/jnnp-2015-310835. Retrieved September 12, 2019, from link.

How CMT4J Affects the Body

The severity and timing of when signs and symptoms of CMT4J begin to show in individuals can vary. Some patients show mild signs, while others have a more severe disability that requires more support. CMT4J mainly causes problems with motor skills, such as weakness in the limbs and muscles. Individuals with CMT4J gradually or rapidly lose both gross motor control and fine motor control.

Science Behind CMT4J

CMT4J affects both motor and sensory nerves, so understanding how the nervous system functions is essential. The nervous system consists of both motor neurons and sensory neurons. One set of nerves delivers messages from the brain to the rest of the body, and the other brings messages from the rest of the body back to the brain.

Motor neurons send messages from the brain through the spinal cord to the lower muscles of the body. Sensory neurons send messages from the sensory input to the spinal cord upward to the brain. The peripheral nervous system (the nervous system outside of the brain and spinal cord) affects both motor and sensory nerve fibers. These nerves have an inner coating, the axon core, which is wrapped with a protective insulation called the myelin sheath. The myelin sheath’s job is to protect the axon and speed transmission of signals through the nerves.

In individuals living with CMT, these nerves are damaged due to mutated genes that result in both motor symptoms (weakness and muscle wasting) and sensory symptoms (numbness).

 

 

All subtypes of CMT4 are inherited in an autosomal recessive pattern. Autosomal recessive describes one of several ways that a disorder or disease is passed down through families. An autosomal recessive disorder occurs when a child inherits two copies of an abnormal gene, one from the mother and one from the father. The biological parents often have no symptoms of disease because the one functional gene is able to compensate for the defective gene. Two healthy people, who are carriers, can have multiple children with a genetic disorder even though they do not show symptoms themselves.

In the case of CMT4J, a variant in the FIG4 gene must be inherited from both parents for a child to inherit the CMT4J disease.

Healthy FIG4 Gene

When functioning normally, FIG4 encodes a protein that aids in the survival of neurons and regulates the transport of waste within the cells.

CMT4J Gene

When there is a FIG4 variant present, the body’s ability to move waste through cells is impaired and waste builds up. This buildup of waste slows the nerves’ ability to do their job of sending messages and leads to nerve damage, classifying CMT4J as a demyelinating neuropathy. Demyelination leads to weakness and sometimes numbness or pain.

Sources:

  1. Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., … Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4. Brain: a journal of neurology134(Pt 7), 1959–1971. doi:10.1093/brain/awr148. Retrieved June 26, 2019, from link.
  2. Field research conducted by Neurogene and Ten Bridge Communications, July 2019.
  3. Novais, E. N., Bixby, S. D., Rennick, J., Carry, P. M., Kim, Y. J., & Millis, M. B. (2014). Hip dysplasia is more severe in Charcot-Marie-Tooth disease than in developmental dysplasia of the hip. Clinical orthopaedics and related research472(2), 665–673. doi:10.1007/s11999-013-3127-z. Retrieved June 26, 2019, from link.
  4. Hatakeyama, S., Suzuki, J., Murukami, T., Nagaoka, T., Suzuki, K., Sakamato, K., … Uchigata, M. (2000). [Respiratory failure due to diaphragmatic dysfunction in Charcot-Marie-Tooth disease: A case report]. Journal of the Japanese Respiratory Society, 38(8), 637-641. Retrieved June 26, 2019, from link.
  5. Bharadwaj, R., Cunningham, K. M., Zhang, K., & Lloyd, T. E. (2015). FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Human Molecular Genetics, 25(4), 681-692. doi:10.1093/hmg/ddv505. Retrieved September 24, 2019, from link.
  6. Haidar, M., & Timmerman, V. (2017). Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies. Frontiers in Molecular Neuroscience, 10. doi:10.3389/fnmol.2017.00143. Retrieved September 24, 2019, from link.
  7. Types of CMT. (n.d.). Retrieved June 26, 2019, from link.
  8. Fliesler, N. (2017, March 6). With no time to lose, parents drive CMT4J gene therapy forward. Retrieved June 26, 2019, from link.
  9. Lewis, R. (2017, February 23). Rare Disease Day 2017: Talia’s Story [Web log post]. Retrieved June 26, 2019, from link.
  10. Li, J. (1993). Charcot-Marie-Tooth Neuropathy Type 4J. Retrieved June 26, 2019, from link.
  11. About CMT4J. (n.d.). Retrieved June 26, 2019, from link.
  12. Orengo, J. P., Khemani, P., Day, J. W., Li, J., & Siskind, C. E. (2018). Charcot Marie Tooth disease type 4J with complex central nervous system features. Annals of Clinical and Translational Neurology, 5. doi:10.1002/acn3.525. Retrieved on June 26, 2019, from link.

CMT4J is a variable disease, which means that signs and symptoms can be experienced differently from individual-to-individual. Some people living with CMT4J may show signs and symptoms in early childhood years, meaning their disease becomes more apparent earlier, and may become more severe as the disease progresses over time. Others may be living with a late onset form, where their disease does not become apparent until their later years. Some people may experience only periodic muscle weakness, while others may develop rapidly progressing muscle-related difficulties. A physical trauma or an illness may cause symptoms to worsen more quickly.

Generally, CMT4J affects all muscles. It is also common for a specific muscle to be affected on one side of the body and not the other, or for only part of a leg, not the entire leg, to be affected. Sensory involvement varies from person-to-person.

Birth Through Age 5

Typically, motor signs and symptoms don’t become obvious until the toddler years and may include:

  • Balance issues
  • Struggling to crawl might occur
  • Frequent falling or tripping
  • Delayed walking
  • Difficulty climbing stairs
  • Clubfoot deformity
Birth Through Age 5

Our daughter was born healthy without indication of muscle weakness. At around 3 ½ years old, we started to notice she would fall easily, was a guarded walker, had balance issues, and started riding her tricycle later than her peers. We originally attributed these symptoms to her calm spirit and laid-back personality.

- Sabrina, mother of daughter living with CMT4J

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Adolescent years

As the disease continues to progress through the adolescent years, weakness in the muscles typically accelerates and other signs and symptoms may become apparent:

  • Overwhelming fatigue
  • Respiratory compromise or muscle weakness leading to respiratory infections
  • Grooved tongue (with deep fissures, cracks, and grooves)
  • Gradual decline in muscle effectiveness (muscle atrophy)
  • Arm and leg weakness
  • Joint instability
  • Joint dislocation
  • Numbness and tingling or pain in hands and feet
  • Diminished or lack of deep tendon reflexes (areflexia)
  • Inability to sense the orientation of body parts and balance issues (proprioception)
  • Difficulties with balance and proprioception (inability to sense)
  • Decreased response to touch below the knee
  • High arches and drop foot (difficulty lifting the front part of the foot) or flat feet
Adolescent years

Childhood Years

Mild, varied issues with motor development and muscle weakness can become more apparent in this age range. You may notice some of the following signs and symptoms:

  • Scoliosis
  • Difficulties with physical activities
  • Progression of muscle weakness and muscle loss
  • Balance issues
  • Numbness and tingling or pain in hands and feet
  • Uneven weakness in proximal muscles (upper arms, shoulders, and upper legs) and distal muscles (forearms and below the knee)
  • Diminished or lack of deep tendon reflexes (areflexia)
  • Inability to sense the orientation of body parts and balance issues (proprioception)
  • Difficulties with balance and proprioception (inability to sense)
  • Decreased response to touch below the knee
  • Joint instability or joint contractures
  • Clumsy walking (gait), frequent tripping and clumsiness
  • High arches or flat feet
Childhood Years

Our son’s disease became apparent early, progressed quickly, and he was in a wheelchair by the age of 4. Today, our son is 8. While he suffers from constant respiratory infections and has lost his motor functions, he has found a number of ways to stay social, happy, and engaged through adaptive technology.

- Daniel, father of son living with CMT4J

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Adulthood

Symptoms reported vary between late versus early-onset cases of CMT4J. Adaptive equipment is typically needed prior to adulthood. Common signs and symptoms during this time include:

  • Overwhelming fatigue
  • Speech or eating challenges
  • Respiratory compromise or muscle weakness leading to respiratory infections
  • Rapidly progressive asymmetric (uneven) paralysis of arms and legs
  • Numbness and tingling or pain in hands and feet
  • Diminished or lack of deep tendon reflexes (areflexia)
  • Inability to sense the orientation of body parts and balance issues (proprioception)
  • Difficulties with balance and proprioception (inability to sense)
  • Decreased response to touch below the knee
Adulthood

Common signs and symptoms

While the signs, symptoms, and age of onset of CMT4J may vary and can progress differently in each individual, there are common signs and symptoms that are consistent across people living with CMT4J. People living with CMT4J commonly have muscle weakness and muscle loss. In addition, they may also have a reduced ability to sense touch, pain, and vibration. In some cases, these symptoms may eventually lead to the inability to walk and some patients may become dependent on adaptive devices to remain mobile. It is important to note that motor symptoms are more common for CMT4J than sensory symptoms, which tend to be mild or nonexistent.

  • Overwhelming fatigue
  • Grooved tongue (with deep fissures, cracks, and grooves)
  • Respiratory compromise or muscle weakness leading to respiratory infections
  • Numbness and tingling or pain in hands and feet
  • Uneven weakness in proximal muscles (upper arms, shoulders, and upper legs) and distal muscles (forearms and below the knee) and muscle loss
  • Leg atrophy (weakness), which can lead to tripping and clumsiness
  • Diminished or lack of deep tendon reflexes (areflexia)
  • Inability to sense the orientation of body parts and balance issues (proprioception)
  • Difficulties with balance and proprioception (inability to sense)
  • Decreased response to touch below the knee
CMT4J Glossary of Terms

Sources:

  1. Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., … Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4. Brain: a journal of neurology134(Pt 7), 1959–1971. doi:10.1093/brain/awr148. Retrieved June 26, 2019, from link.
  2. Field research conducted by Neurogene and Ten Bridge Communications, July 2019.
  3. Li, J. (1993). Charcot-Marie-Tooth Neuropathy Type 4J. Retrieved June 26, 2019, from link.
  4. Kniffin, C. L. (2017, June 19). CHARCOT-MARIE-TOOTH DISEASE, TYPE 4J; CMT4J. Retrieved June 26, 2019, from link.
  5. Mayo Clinic. Foot drop. Retrieved August 5, 2019, from link.
  6. Orengo, J., Khemani, P., Day, J.W., Li, J, Siskind, C. (2018, January 22). Charcot Marie Tooth disease type 4J with complex central nervous system features. Retrieved August 5, 2019, from link.

Obtaining a definitive genetic diagnosis is an important first step in seeking appropriate care and treatment, learning about potential research or therapies that may become available, and preparing for the future. Patients and their families should consider discussing the implications of obtaining a diagnosis of CMT4J with their physician and a genetic counselor or other specialists who are familiar with the disease management of CMT4J.

Because of low disease awareness and the fact that neurological symptoms are among the earliest signs observed, common misdiagnoses may include chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis (MS), Guillain-Barré Syndrome (GBS), amyotrophic lateral sclerosis (ALS), and other neuromuscular disorders.

If you believe your child is showing signs or symptoms of CMT4J, tests are available for a physician or other healthcare professional to order to help confirm a diagnosis.

Testing for CMT4J may not be included in standard testing panels; however, a diagnostic genetic test including an expanded exome sequencing panel for CMT4J can be requested to confirm a diagnosis. Many academic and commercial laboratories offer genetic blood testing. Your physician can help you navigate the process or refer you to a geneticist.

A representative is available to help you by calling 1-877-237-5020 or via email at medicalinfo@neurogene.com.

A Researcher’s Perspective on Diagnosis:

“CMT4J is difficult to diagnose without genetic testing because it looks very similar to other neuromuscular illnesses. If you are noticing common symptoms related to muscle weakness and wasting affecting the feet and legs, and overwhelming fatigue, it is important to document these symptoms and discuss with your primary care doctor or request a referral to a neurologist. Your healthcare provider will be able to review your symptoms and order a saliva or blood DNA test. With a positive diagnosis, you or a family member may be eligible to participate in research that could help the community better understand CMT4J.”

Mario Saporta, M.D., Ph.D., is an Assistant Professor of Neurology and Human Genetics at the CMT Center of Excellence at the University of Miami. In addition to his role as a primary care physician, Dr. Saporta’s research and clinical work is focused on neurogenetic and neuromuscular conditions, particularly inherited peripheral neuropathies.

Sources:

  1. Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., … Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4. Brain: a journal of neurology134(Pt 7), 1959–1971. doi:10.1093/brain/awr148. Retrieved June 26, 2019, from link.
  2. Field research conducted by Neurogene and Ten Bridge Communications, July 2019.
  3. Hu, B., McCollum, M., Arpag, S., Moiseev, D., Castoro, R., Burnette, B., Siskind, C., Day, J., Yawn, R., Feely, S., Yan Q., Shy., M., Li, J. (2018). Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination. Annals of Neurology. 83(4), 756-70. Retrieved September 12, 2019, from link.
  4. Vaccari, I., Carbone, A., Previtali, S. C., Mironova, Y. A., Alberizzi, V., Noseda, R., Rivellini, C., Bianchi, F., Del Carro, U., D’Antonio, M., Lenk, G. M., Wrabetz, L., Giger, R. J., Meisler, M. H., Bolino, A. (2015, Jan. 15). Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Human Molecular Genetics. 24(2), 383-96. Retrieved September 12, 2019, from link.
  5. Martyn, C., & Li, J. (2013, Feb.). Fig4 Deficiency: a newly emerged lysosomal storage disorder? Progress in Neurobiology. doi:10.1016/j.pneurobio.2012.11.001. Retrieved September 12, 2019, from link.
  6. Rajabelly, Y., Adams, D., Latour, P., Attarian, S. (2016, March 23). Hereditary and inflammatory neuropathies: a review of reported associations, mimics, and misdiagnoses. JNNP Online First. BMJ. doi:10.1136/jnnp-2015-310835. Retrieved September 12, 2019, from link.
  7. Zhang X., Chow C. Y., Sahenk Z., Shy, M. E., Meisler, M. H., Li, J. (2008, Aug.). Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain. 131(8), 1990–2001. Retrieved September 12, 2019, from link.

While there is currently no cure or treatment for people living with CMT4J, there are therapeutic management strategies. There are also opportunities for participation in natural history studies, which can contribute to the community’s understanding of the disease. Information on the Natural History Study of CMT4J can be found here.

People living with CMT4J may require varying levels of support and assistive devices. Most likely, families will benefit from a team of healthcare professionals to help manage the progressive and, in some cases, rapidly severe impact of their disease. Useful specialists may include:

Low-intensity therapeutic management strategies may bring symptom relief. Individuals living with CMT4J could explore the following with their physical therapist:

  • Water (aquatic) therapy leverages dynamic resistance movements under water.
  • Home-based resistance programs that focus on improving strength related to daily life.
  • Stretching for maintenance and optimization of functional limb use, especially as weakness persists.
  • Pilates and yoga reinforce similar strategies; stretching and can be helpful with maintenance of muscle function.

A range of adaptive devices, equipment, and supportive interventions may become necessary for those living with CMT4J, depending on the severity of the disease.

Learn more about equipment, recreation, and support:

 

EDUCATIONAL PDF

 

The amount of supportive care an individual with CMT4J needs is typically relative to the age of onset and the severity of their disease. However, not all cases are as severe, and even severely-affected individuals can live independently with the help of adaptive devices. Home adaptations may also be helpful, and recommendations can be obtained through a physical therapist. Various levels of accessibility and support can help to cultivate independent living skills as symptoms progress.

Discover more resources

Sources:

  1. Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., … Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4. Brain: a journal of neurology134(Pt 7), 1959–1971. doi:10.1093/brain/awr148. Retrieved June 26, 2019, from link.
  2. Field research conducted by Neurogene and Ten Bridge Communications, July 2019.
  3. McCorquodale, D., Pucillo, E. M., & Johnson, N. E. (2016). Management of Charcot-Marie-Tooth disease: improving long-term care with a multidisciplinary approach. Journal of multidisciplinary healthcare9, 7–19. doi:10.2147/JMDH.S69979. Retrieved on June 26, 2019, from link.
  4. CMT. (n.d.). Retrieved June 26, 2019, from link.