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Charcot-Marie-Tooth 1A
CMT1A causes progressive weakness and wasting of muscles, particularly in the lower legs and hands, along with sensory changes like numbness or tingling. It typically begins in childhood or adolescence and affects individuals across the UK.
Overview
Charcot-Marie-Tooth disease type 1A (CMT1A) is a form of hereditary motor and sensory neuropathy. This means it affects both the nerves that control movement (motor nerves) and those responsible for sensation (sensory nerves) in the peripheral nervous system [PMID:17006877]. The peripheral nervous system comprises all the nerves that lie outside the brain and spinal cord, extending to the limbs and organs.
CMT1A is one of the most common types of Charcot-Marie-Tooth disease, a group of inherited conditions. It leads to progressive muscle weakness, particularly in the lower legs and feet, and can also affect the hands and forearms over time. Sensory symptoms, such as reduced sensation or tingling, are also common. The condition is progressive, meaning symptoms tend to worsen gradually over many years.
It is estimated that CMT1A affects approximately 1 in 2,500 people, making it one of the more frequently encountered inherited neurological disorders in the UK. The symptoms and their severity can vary considerably among individuals, even within the same family.
Symptoms & clinical features
Individuals with CMT1A typically begin to experience symptoms during childhood or adolescence, though the exact age of onset can vary [PMID:20301323]. Initial symptoms often include weakness in the muscles of the lower legs and feet, leading to difficulties with walking and balance. This weakness can cause an altered gait, sometimes described as 'foot drop', where the front of the foot drags while walking.
Over time, muscle wasting (atrophy) can become noticeable in the lower legs, giving them a characteristic 'inverted champagne bottle' or 'stork leg' appearance. Foot deformities are also common, such as high arches (pes cavus) or hammer toes. As the condition progresses, muscle weakness and wasting can extend to the hands and forearms, impacting fine motor skills and grip strength.
Sensory symptoms are also a key feature of CMT1A. These can include numbness, tingling, or reduced sensation in the feet and hands. Some individuals may experience neuropathic pain, which is pain arising from nerve damage. Fatigue is also a common complaint, potentially contributing to the overall impact on daily life.
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Affected organs
CMT1A primarily affects the peripheral nervous system. This network of nerves extends from the brain and spinal cord to the rest of the body, including muscles, skin, and internal organs. In CMT1A, the insulating myelin sheath surrounding the peripheral nerve fibres is primarily affected. Myelin acts like insulation around an electrical wire, allowing nerve signals to travel quickly and efficiently.
The degradation of this myelin sheath, known as demyelination, disrupts the normal transmission of nerve impulses. This disruption leads to the impaired communication between the brain and muscles, causing muscle weakness and atrophy, particularly in the lower limbs and hands. It also affects the sensory nerves, leading to altered sensation. While the primary impact is on nerves to the limbs, the autonomic nervous system, which controls involuntary bodily functions, is generally not significantly affected in CMT1A.
Risks & severity
CMT1A is a progressive condition, meaning its symptoms tend to worsen gradually over many years. The severity of symptoms can differ significantly between individuals; some may experience mild weakness and sensory changes, while others might face more pronounced difficulties with mobility and fine motor tasks [PMID:20301323]. However, CMT1A is generally not considered life-threatening and typically does not affect life expectancy.
Most individuals with CMT1A maintain the ability to walk throughout their lives, although some may require assistive devices like ankle-foot orthoses (AFOs) or walking aids as the condition progresses. A small proportion of individuals may eventually require a wheelchair for longer distances. The age of symptom onset is typically in childhood or adolescence, but even within the same family, symptoms can appear earlier or later, and their progression can vary. Regular monitoring by neurological specialists helps track the progression and manage symptoms effectively.
Genetic causes
CMT1A is caused by a duplication of a region on chromosome 17, which includes the PMP22 gene. This means that instead of having two copies of the PMP22 gene (one from each parent), individuals with CMT1A have three copies. The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22.
This PMP22 protein is a crucial component of myelin, the fatty sheath that insulates nerve fibres in the peripheral nervous system. Myelin is essential for rapid and efficient transmission of nerve signals. When there are too many copies of the PMP22 gene, an excess of the PMP22 protein is produced. This overproduction disrupts the normal formation and maintenance of the myelin sheath, leading to its breakdown (demyelination) [PMID:17006877].
The impaired myelin function slows down nerve conduction and eventually leads to nerve damage. This damage underlies the muscle weakness, wasting, and sensory deficits characteristic of CMT1A. Other genetic changes in PMP22, such as point mutations or deletions, can cause different forms of CMT or related conditions.
- PMP22 peripheral myelin protein 22
Inheritance pattern
CMT1A is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered PMP22 gene duplication from either parent to develop the condition. If a parent has CMT1A, there is a 50% (1 in 2) chance with each pregnancy that their child will also inherit the condition.
This inheritance pattern applies equally to male and female children. CMT1A can also arise spontaneously in an individual with no family history, due to a new (de novo) genetic change; however, this is less common. Once an individual has the genetic duplication, they have CMT1A, although the severity and progression of symptoms can vary, even within the same family.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of CMT1A typically begins with a clinical evaluation, where a doctor will assess symptoms, perform a neurological examination, and review the family medical history. Specific signs, such as muscle weakness, foot deformities, and reduced reflexes, may suggest CMT. Nerve conduction studies (NCS) and electromyography (EMG) are often used to measure how quickly electrical signals travel through nerves and to assess muscle response, which can indicate peripheral nerve damage and demyelination [PMID:20301323].
Confirmation of CMT1A relies on genetic testing. This typically involves a blood test to analyse the PMP22 gene for the characteristic duplication on chromosome 17. Genetic testing falls under specific NHS Genomic Medicine Service (GMS) pathways, often initiated by a neurology specialist or a clinical genetics service. These tests correspond to various R-codes (e.g., R143 for CMT and related neuropathies) within the NHS GMS testing directory. Referral to a clinical geneticist or genetic counsellor is generally recommended for individuals suspected of having CMT for appropriate testing and counselling.
Management & lifestyle
While there is currently no cure for CMT1A, management focuses on alleviating symptoms, improving function, and maintaining quality of life. A multidisciplinary team often provides care, including neurologists, physiotherapists, occupational therapists, orthotists, and podiatrists. Physiotherapy is crucial for maintaining muscle strength, flexibility, and range of motion, and to help with balance and gait training. Occupational therapy can provide strategies and adaptive equipment to assist with daily tasks affected by hand weakness.
Orthotic devices, such as ankle-foot orthoses (AFOs), are commonly prescribed to help support the foot and ankle, improving gait and preventing foot drop. Custom footwear or orthotics can also help manage foot deformities and discomfort. Regular follow-up with healthcare professionals allows for monitoring of symptom progression and adjustment of management strategies. Surgical interventions may be considered for severe foot deformities to improve function or reduce pain. Lifestyle considerations, such as regular, gentle exercise and avoiding prolonged standing or walking that can exacerbate fatigue, are also part of a comprehensive management plan.
UK care pathway
In the UK, individuals with suspected or diagnosed Charcot-Marie-Tooth disease, including CMT1A, are typically managed within the NHS Genomic Medicine Service (GMS) framework. Initial assessment and referral often come from a GP to a neurologist. If CMT is suspected, the neurologist may then refer the patient to a clinical genetics service for confirmation through genetic testing.
Genetic testing for CMT and related neuropathies is available through the NHS GMS, often covered by specific R-codes such as R143. Genetic counsellors play a vital role, providing information about the inheritance pattern, implications for family members, and support regarding the diagnosis. Ongoing care involves a multidisciplinary team, usually coordinated by neurology services, to provide a holistic approach to symptom management and support.
Frequently asked questions
What does 'autosomal dominant' mean for CMT1A?
Autosomal dominant means you only need one copy of the altered gene to develop the condition. If a parent has CMT1A, each of their children has a 50% chance of inheriting the condition.
Will my CMT1A symptoms get worse over time?
CMT1A is a progressive condition, so symptoms typically worsen gradually over many years. However, the rate of progression and severity varies significantly among individuals.
Can children get CMT1A?
Yes, CMT1A typically begins in childhood or adolescence. However, the exact age when symptoms first appear can differ.
Is there a cure for CMT1A?
Currently, there is no cure for CMT1A. Management focuses on treating symptoms, improving function, and maintaining quality of life through therapies and supportive devices.
What kind of doctors treat CMT1A in the UK?
In the UK, CMT1A is typically managed by a team of specialists, including neurologists, physiotherapists, occupational therapists, and podiatrists, often coordinated through NHS neurology services and clinical genetics.
References
- Msheik Z, Durand S, Pinault E. Charcot-Marie-Tooth-1A and sciatic nerve crush rat models: insights from proteomics. Neural regeneration research. 2023. PMID: 36453423
- Soldevilla B, Cuevas-Martín C, Ibáñez C. Plasma metabolome and skin proteins in Charcot-Marie-Tooth 1A patients. PloS one. 2017. PMID: 28575008
- Tozza S, Aceto MG, Pisciotta C. Postural instability in Charcot-Marie-Tooth 1A disease. Gait & posture. 2016. PMID: 27491052
- Boutary S, Khalaf G, Landesman Y. Therapeutic potential of siRNA PMP22-SQ nanoparticles for Charcot-Marie-Tooth 1A neuropathy in rodents and non-human primates. International journal of pharmaceutics. 2025. PMID: 39855282
- Menotti F, Laudani L, Damiani A. Amount and intensity of daily living activities in Charcot-Marie-Tooth 1A patients. Brain and behavior. 2014. PMID: 24653950
- Lencioni T, Rabuffetti M, Piscosquito G. Postural stabilization and balance assessment in Charcot-Marie-Tooth 1A subjects. Gait & posture. 2014. PMID: 25082324
- Tousignant R, Trepanier A, Shy ME. Genetic testing practices for Charcot-Marie-Tooth type 1A disease. Muscle & nerve. 2014. PMID: 23963961
- McGrath MC. Charcot-Marie-Tooth 1A: A narrative review with clinical and anatomical perspectives. Clinical anatomy (New York, N.Y.). 2016. PMID: 26457477