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Charcot-Marie-Tooth 2A
CMT2A typically causes progressive weakness and wasting of muscles, especially in the feet, lower legs, hands, and forearms. It can also lead to sensory changes, such as numbness. The condition is often noticed in childhood or adolescence.
Overview
Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders that affect the peripheral nervous system. These nerves carry signals from the brain and spinal cord to the rest of the body, and also relay sensory information back to the brain. CMT2A is a specific subtype of CMT, characterised primarily by damage to the axons of these peripheral nerves, which are the long, slender projections that conduct electrical impulses [PMID:34731818].
Individuals with CMT2A often experience a gradual onset of symptoms, typically beginning in childhood or adolescence, though presentation can vary. The condition is progressive, meaning symptoms tend to worsen over time. It is considered a rare disease, although the exact prevalence for CMT2A specifically is not well established.
Living with CMT2A involves managing symptoms and adapting to the progressive nature of the condition. Support from healthcare professionals, including neurologists, physiotherapists, and occupational therapists, plays a key role in maintaining quality of life.
Symptoms & clinical features
The symptoms of CMT2A primarily affect the limbs, particularly the feet and lower legs, and often progress to involve the hands and forearms. Common initial signs include muscle weakness and wasting, especially in the muscles below the knee. This can lead to difficulties with walking, such as frequent tripping or a high-stepped gait (steppage gait), where individuals lift their knees high to avoid dragging their feet [PMID:33678036].
Characteristic physical features can include high-arched feet (pes cavus) or hammer toes, where toes are permanently bent downwards. As the condition progresses, individuals may experience muscle weakness in their hands, making fine motor tasks, like writing or buttoning clothes, more challenging. Sensory symptoms, such as numbness, tingling, or reduced sensation to touch, temperature, and pain, are also common, particularly in the feet and hands.
The severity and specific presentation of symptoms can differ significantly between individuals, even within the same family. Some people may experience mild symptoms that have little impact on daily life, while others may have more pronounced weakness and disability. In rare instances, individuals with CMT2A may develop optic atrophy, affecting vision, or experience hearing loss, though these are less common features.
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Affected organs
CMT2A primarily affects the peripheral nervous system. This network of nerves transmits information between the brain and spinal cord and every other part of the body, including muscles and sensory receptors in the skin. Within the peripheral nervous system, CMT2A specifically damages the axons of nerve cells. Axons are the main body of the nerve cell that transmit signals.
The muscles, particularly those in the lower legs and feet, are significantly impacted due to the disrupted nerve signals, leading to weakness and atrophy. Over time, muscles in the hands and forearms can also be affected. Sensory nerve fibres are also damaged, which can lead to altered sensation in the extremities. While primarily a peripheral neuropathy, some individuals may experience less common features affecting other systems, such as the eyes (optic nerves) or ears (auditory nerves), highlighting the broad role of the causative gene in cellular function [PMID:28790382].
Risks & severity
The severity of CMT2A symptoms can vary widely among affected individuals, even within the same family. Some people may experience mild symptoms that progress slowly, while others might have more significant muscle weakness and functional impairment. The condition is typically progressive, meaning symptoms tend to worsen gradually over time. However, the rate of progression is highly variable and difficult to predict for any individual.
Symptoms typically begin in childhood or adolescence, though onset can range from early childhood to adulthood. While CMT2A can lead to considerable disability, it is generally not considered life-threatening, and individuals usually have a normal life expectancy. Regular monitoring and supportive therapies are key to managing symptoms and maintaining mobility and independence as much as possible.
Genetic causes
Charcot-Marie-Tooth type 2A is caused by pathogenic variants (sometimes called mutations) in the *MFN2* gene. The *MFN2* gene provides instructions for making a protein called mitofusin 2. This protein is primarily located in the outer membrane of mitochondria, which are often referred to as the 'powerhouses' of the cell. Mitochondria generate the energy that cells need to function [PMID:32252194].
Mitofusin 2 plays a crucial role in mitochondrial fusion, a process where mitochondria merge to form a network. This fusion is important for maintaining healthy mitochondria, ensuring efficient energy production, and allowing mitochondria to move and distribute properly within the cell, especially in long nerve cells (neurons). Additionally, mitofusin 2 is involved in the transport of mitochondria along axons, which is vital for nerve function.
Pathogenic variants in *MFN2* lead to a dysfunctional mitofusin 2 protein or a reduced amount of functional protein. This disrupts the normal mitochondrial processes, including fusion and transport, particularly in the long axons of peripheral nerves. The resulting mitochondrial dysfunction impairs the ability of these nerve cells to generate energy and maintain their structure, ultimately leading to nerve degeneration and the characteristic symptoms of CMT2A.
- MFN2 mitofusin 2
Inheritance pattern
CMT2A is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered *MFN2* gene from one parent to develop the condition. In most cases, an affected individual has one parent who also has CMT2A. Each child of an affected parent has a 50% chance (1 in 2) of inheriting the altered gene and therefore developing the condition.
Occasionally, CMT2A can occur as a result of a new (de novo) pathogenic variant in the *MFN2* gene in an individual who has no family history of the condition. In such cases, neither parent carries the gene alteration. However, once the variant occurs, that individual can then pass it on to their children in an autosomal dominant manner. Genetic counselling is available to discuss inheritance patterns and risks for family members.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of CMT2A typically begins with a clinical evaluation by a neurologist. This involves a detailed medical history, including any family history of neurological conditions, and a physical examination to assess muscle strength, reflexes, sensation, and the presence of characteristic foot deformities. Nerve conduction studies (NCS) and electromyography (EMG) are often performed to evaluate the function of peripheral nerves and muscles. These tests can help distinguish between different types of CMT and other neuromuscular disorders.
Confirmation of CMT2A diagnosis relies on genetic testing. Blood samples are usually taken to look for pathogenic variants in the *MFN2* gene. Genetic testing for CMT, including *MFN2*-related conditions, is available through the NHS Genomic Medicine Service. The relevant NHS R-code for hereditary motor and sensory neuropathy (including CMT) is R14. Individuals suspected of having CMT2A would typically be referred to a clinical genetics service or specialist neurologist for assessment and consideration of genetic testing.
Management & lifestyle
The management of CMT2A focuses on alleviating symptoms, maintaining mobility, and improving quality of life, as there is currently no cure. A multidisciplinary team approach is often recommended, involving neurologists, physiotherapists, occupational therapists, orthotists, and genetic counsellors.
Physiotherapy is crucial for maintaining muscle strength, flexibility, and range of motion, and can help prevent contractures. Occupational therapy can provide strategies and adaptive equipment to assist with daily tasks affected by hand weakness. Orthotics, such as ankle-foot orthoses (AFOs), can help support the foot and ankle, improve walking ability, and prevent falls. Surgical interventions may be considered in some cases, for example, to correct severe foot deformities. Regular follow-up appointments with specialists allow for monitoring of disease progression and adjustment of management strategies as needed. Genetic counselling provides information about the condition, inheritance patterns, and support for families.
UK care pathway
In the UK, individuals suspected of having inherited neurological conditions like CMT2A are typically referred through their GP to specialist services. This usually involves a neurologist for clinical assessment and diagnosis. If CMT2A is suspected, referral to a clinical genetics service may follow to arrange genetic testing.
Genetic testing for Charcot-Marie-Tooth disease, including specific subtypes like CMT2A, is available through the NHS Genomic Medicine Service. The test code R14 (Hereditary motor and sensory neuropathy) covers a broad panel of genes, including *MFN2*. A clinical geneticist or genetic counsellor will discuss the testing process, results, and implications for the individual and their family. Genetic counsellors also provide essential support and information regarding inheritance patterns, family planning, and connection to patient support groups.
Frequently asked questions
What is the typical age that CMT2A symptoms start?
Symptoms of CMT2A most commonly begin during childhood or adolescence. However, the exact age of onset can vary significantly, with some individuals developing symptoms earlier in childhood and others not until adulthood. The condition is progressive, meaning symptoms tend to worsen over time.
Is CMT2A a progressive condition?
Yes, CMT2A is a progressive condition. This means that symptoms such as muscle weakness and sensory changes typically worsen gradually over many years. The rate of progression can differ greatly between individuals, even within the same family.
Can CMT2A affect more than just my legs and feet?
While CMT2A primarily affects the muscles and sensation in the feet and lower legs, it can also impact the hands and forearms as the condition progresses. In some less common instances, individuals may also experience visual problems due to optic atrophy or hearing loss.
How is CMT2A diagnosed?
Diagnosis typically involves a neurological examination, nerve conduction studies, and electromyography to assess nerve and muscle function. The definitive diagnosis is confirmed through genetic testing, which looks for specific changes in the *MFN2* gene. This testing is available through the NHS Genomic Medicine Service.
What treatments are available for CMT2A?
Currently, there is no cure for CMT2A, so treatment focuses on managing symptoms and improving quality of life. This often includes physiotherapy, occupational therapy, the use of orthotics (like ankle-foot orthoses), and sometimes surgery to correct foot deformities. A multidisciplinary team of healthcare professionals usually provides care.
References
- Zanfardino P, Longo G, Amati A. Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts. Human molecular genetics. 2023. PMID: 35994048
- Rizzo F, Ronchi D, Salani S. Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot-Marie-Tooth 2A motor neurons. Human molecular genetics. 2016. PMID: 27506976
- Lv H, Wang L, Zhang W. A cohort study of Han Chinese MFN2-related Charcot-Marie-Tooth 2A. Journal of the neurological sciences. 2015. PMID: 26382835
- Iwata K, Scorrano L. Finding a new balance to cure Charcot-Marie-Tooth 2A. The Journal of clinical investigation. 2019. PMID: 30882369
- Stergachis AB, Blue EE, Gillentine MA. Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A. Neurology. Genetics. 2023. PMID: 37560121
- Stergachis AB, Blue EE, Gillentine MA. Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A. bioRxiv : the preprint server for biology. 2023. PMID: 36798371
- Chung KW, Kim SB, Park KD. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain : a journal of neurology. 2006. PMID: 16835246
- Beręsewicz M, Charzewski Ł, Krzyśko KA. Molecular modelling of mitofusin 2 for a prediction for Charcot-Marie-Tooth 2A clinical severity. Scientific reports. 2018. PMID: 30442897