Simply Stated: Updates in Charcot-Marie-Tooth Disease (CMT)

Charcot-Marie-Tooth disease (CMT) encompasses a group of inherited disorders that affect movement and sensation in the arms, legs, hands, and feet. Common symptoms include lower leg weakness, foot deformities, reduced sensations, and sometimes impaired fine motor skills. While CMT typically progresses slowly, symptoms may spread over time and lead to secondary complications, such as scoliosis. The severity and presentation of CMT can vary greatly between different people with the disease. It is estimated that CMT affects about 1 in 2,500 people.

Causes of CMT

CMT is caused by defects (mutations) in more than 100 different genes, many of which encode proteins involved in the structure or function of peripheral nerves and/or the myelin sheath that protects the nerves. The most common defects occur in the PMP22, MPZ, GJB1, or MFN2 genes.

In CMT, peripheral nerves gradually degenerate, reducing the speed and strength of electrical signals (nerve conduction) from the spinal cord to the muscles. This impaired communication causes progressive muscle weakness and atrophy (thinning), often affecting the arms, legs, hands, and feet. Depending on the subtype, CMT is inherited in one of three patterns: autosomal dominant (caused by one defective gene copy), autosomal recessive (caused by two defective gene copies), and X-linked (caused by a defective gene on the X chromosome).

CMT subtypes

CMT is classified into subtypes based on clinical features, the type of nerve dysfunction, and inheritance patterns. These subtypes are named CMT types 1 through 4, plus an X-linked type. A letter is added after the name of the subtype to denote association with a particular gene defect.

CMT subtypes fall into three main groups based on nerve conduction speed. Demyelinating forms are caused by myelin sheath defects and exhibit the slowest nerve conduction speeds. Axonal forms are caused by damage to nerve fiber itself and exhibit mostly normal nerve conduction speeds, but with a weaker signal. Finally, intermediate forms of CMT exhibit nerve conduction speeds in between the demyelinating and axonal forms.

Select demyelinating forms of the CMT

• CMT1: Most common; onset usually in childhood
  • CMT1A: PMP22 gene duplication; progressive muscle weakness
  • Hereditary neuropathy with liability to Pressure Palsy (HNPP): PMP22 deletion; recurring episodes of nerve damage
  • CMT1B: MPZ mutations; onset varies from infancy to adulthood
• CMT3 / Dejerine-Sottas disease: Early-onset demyelinating form; peripheral nerve thickening, weakness, and sensory disturbances; can result in the inability to walk

Select axonal forms of CMT

• CMT2: Less common; there are more than 30 known subtypes of CMT2; some subtypes affect speech and breathing

Subtypes of CMT with both demyelinating and axonal forms

• CMT4 (recessive, severe): Childhood onset; many lose walking ability by teenage years; most forms are demyelinating, though some are axonal
• CMTX (X-linked): Mutations on X chromosome; boys typically more affected than girls; CMTX exhibits a combination of demyelinating and axonal pathology.

Intermediate forms of CMT

Many intermediate forms of CMT are known, some with dominant and some with recessive inheritance patterns. Intermediate forms are characterized as intermediate not based on severity, but because the nerves send signals at an intermediate speed between the axonal and demyelinating CMT forms.

In addition to the established subtypes of CMT, researchers have recently identified a new form, called recessive intermediate CMT E (CMTRIE), caused by changes in the KCTD11 gene. CMTRIE is inherited in an autosomal recessive pattern and can cause muscle weakness, sensory loss, balance issues, and foot deformities. The discovery of CMTRIE was shared at the 2025 Peripheral Nerve Society meeting.

Diagnosis and Management of CMT

Diagnosis of CMT typically involves review of medical and family history, a neurologic examination, electrodiagnostic testing (nerve conduction studies), and confirmatory genetic testing. Advances in understanding of the genetic basis of CMT subtypes have expanded genetic testing options and increased the likelihood of providing patients and families with a definitive diagnosis. No disease-modifying treatments currently exist for CMT, but multidisciplinary care can improve overall health and quality of life.

For more information about the signs and symptoms of CMT, as well an overview of diagnosis, prognosis, and care management concerns, an in-depth review can be found from T. Bird, 2024.

Evolving research and treatment landscape

Promising strategies are under active investigation for CMT, including small molecule therapy, gene therapy, stem cell therapy, and siRNA and antisense oligonucleotide (AON) gene silencing therapies. A high-level overview of ongoing research and development in CMT was presented in the previous blog post Simple Stated: Updates in Charcot-Marie-Tooth Disease (CMT).

A few notable investigational therapies currently in clinical trials for CMT include:

ABS‑0871 (Actio Biosciences) – This therapy is being studied in a phase 1 trial in healthy volunteers to evaluate safety, tolerability, and activity in the body. ABS-0871 is an oral small-molecule therapy designed to inhibit the TRPV4 ion channel, which is overactive in CMT2C.

AGT-100216 (Augustine Therapeutics) – Augustine Therapeutics is conducting a phase 1 clinical trial to assess the safety, tolerability, and pharmacokinetics of AGT-100216 in healthy volunteers. AGT-100216 is an HDAC6 inhibitor designed to target the root causes of nerve damage in CMT with fewer side effects.

EN001 (Encell) – EN001 is being studied in a phase 1b study to evaluate the safety and efficacy of higher dosing in patients with CMT1A. It is a specially designed mesenchymal stem cell therapy that works by targeting damaged nerves and secreting substances that may help regenerate the protective myelin sheath.

NMD670 (NMD Pharma) – The SYNAPSE-CMT trial is a phase 2a study evaluating the efficacy, safety, and tolerability of NMD670 in adult patients with genetically confirmed CMT1 or CMT2. NMD670 targets the skeletal muscle-specific chloride ion channel 1 (ClC-1), aiming to improve nerve-muscle communication and address skeletal muscle weakness associated with CMT.

By the end of 2025, MDA will have invested more than $44M in CMT research. Strategic investments from MDA and other advocacy organizations, combined with traditional funding sources such as the National Institute of Health (NIH), are helping to move the field of CMT forward.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about CMT, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.