Charcot Marie Tooth DiseaseEdit

Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders that affect the peripheral nervous system, specifically the nerves outside the brain and spinal cord. It is one of the most common inherited neurological conditions, with estimates placing its prevalence at about 1 in 2,500 to 3,000 people worldwide. The condition typically causes progressive distal muscle weakness and atrophy, foot deformities such as pes cavus, sensory loss in the feet and legs, and a distinctive high-stepped or steppage gait. Onset most often occurs in childhood or adolescence, but the course and severity can vary widely between individuals.

CMT is a genetically diverse family of neuropathies. Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked transmission. The condition is broadly categorized into demyelinating forms, in which the myelin sheath surrounding peripheral nerves is affected, and axonal forms, in which the nerve fibers themselves are primarily involved. The demyelinating form (CMT1) and the axonal form (CMT2) together account for the majority of cases, though many subtypes exist, each linked to mutations in specific genes. The most common genetic form is CMT1A, which typically arises from a duplication of the PMP22 gene. Other important genes include MPZ (encoding myelin protein zero) and GJB1 (encoding connexin 32, associated with X-linked CMT). In axonal forms, MFN2 is a major contributor, with other genes such as DNM2 also implicated. A related condition, hereditary neuropathy with liability to pressure palsies (HNPP), is usually caused by a deletion including PMP22 and shares some clinical features with CMT.

Pathophysiology and subtypes - Demyelinating CMT (CMT1 and related forms) largely involves Schwann cells, which form the myelin sheath around peripheral nerves. Mutations can disrupt myelin production or maintenance, slowing nerve signal conduction. - Axonal CMT (CMT2 and related forms) primarily affects the axon itself, leading to reduced nerve fiber integrity and slower transmission without a primary demyelinating process. - Subtypes are categorized by the responsible gene and the pattern of nerve involvement. For example, CMT1A is linked to PMP22 duplication; CMTX refers to X-linked forms (often due to GJB1 mutations); CMT2A is commonly associated with MFN2 mutations. See PMP22 and GJB1 for gene-specific details, and MFN2 for axonal forms.

Signs and symptoms - Distal weakness and wasting of muscles in the feet and lower legs, leading to a high-arched foot (pes cavus) and hammer toes, with potential progression to hands and forearms. - Sensory loss in the distal limbs, reduced or absent ankle reflexes, and problems with balance and walking. - Foot deformities may necessitate orthotic devices or surgical correction, and some individuals require mobility aids later in life. - The course is usually slow and progressive, and many people maintain a useful level of function for decades. Pain, cramps, or fatigue can occur but vary by individual and subtype.

Diagnosis and clinical assessment - Diagnosis relies on a combination of clinical examination, nerve conduction studies (to distinguish demyelinating from axonal patterns), and genetic testing to identify the causative mutation. - Genetic testing has become increasingly accessible and can confirm the subtype, inform prognosis, and guide family planning. See nerve conduction study and genetic testing for related topics. - Differential diagnosis includes other hereditary neuropathies and acquired neuropathies, which are distinguished by pattern of symptoms, conduction velocities, and genetic testing results.

Management and prognosis - There is no cure for Charcot-Marie-Tooth disease, but management focuses on maintaining mobility, independence, and quality of life. - A multidisciplinary approach is common, involving physical therapy to preserve strength and flexibility, occupational therapy, and the use of orthotic devices such as ankle-foot orthoses to improve gait. See orthosis for related equipment. - Orthopedic surgery may be considered for severe foot deformities or muscle imbalance. Pain management and symptom-specific therapies are used where appropriate. - Genetic counseling is often part of care since CMT is inherited. See genetic counseling for related topics. - Prognosis is highly variable and depends on the subtype and individual factors. Many people live independently for many years, though some may require assistance with mobility in later life.

Genetics and classification (expanded) - Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked forms. Autosomal dominant forms are the most common, while autosomal recessive and X-linked forms account for a subset of cases. - Subtypes are defined by the gene involved and the pattern of nerve involvement (demyelinating vs axonal). See PMP22, GJB1, MPZ, MFN2, and DNM2 for examples of genes associated with CMT. - HNPP (hereditary neuropathy with liability to pressure palsies) is linked to PMP22 deletions and shares some clinical features with CMT; see the entry for related context. See HNPP.

Research and future directions - Research continues into disease mechanisms, better genotype-phenotype correlations, and targeted therapies. Gene-targeted approaches, neuroprotective strategies, and therapies aimed at stabilizing myelin or axons are areas of active investigation. - Ongoing natural history studies and patient registries help define progression patterns across subtypes and inform clinical trial design. See gene therapy and neurodegenerative disease for broader context.

Controversies and debates - As with many genetic neuropathies, debates exist around the optimal use of broad genetic screening, especially in milder cases, and how results should influence management and family planning. These discussions involve considerations of cost, accessibility, and clinical utility, and they are shaped by healthcare system contexts and evolving guidelines. - Clinically, the heterogeneity of CMT means that phenotype-based classification can be imperfect; genotype-first approaches and deeper phenotyping are evolving areas of discussion in the field. See genetic testing for related topics.

See also - HNPP - PMP22 - GJB1 - MPZ - MFN2 - DNM2 - Peripheral nervous system - Nerve conduction study - Genetic testing - Orthosis - Charcot–Marie–Tooth disease