Charcot-Marie-Tooth disease type 1A (CMT1A)

CMT1A typically manifests in the first to third decade of life, most commonly between ages 5 and 25 years, with symmetric, slowly progressive distal motor and sensory involvement of the legs before the hands. Affected individuals develop weak ankle dorsiflexion, depressed or absent tendon reflexes, and pes cavus foot deformity, with bilateral foot drop emerging as the disease advances. Gait is often steppage in character, and intrinsic hand-muscle wasting may follow once the lower-limb disability is well established. Sensory involvement is typically mild to moderate, with decreased
vibration sense the earliest finding; impaired sensation of pain or pinprick, temperature, and joint position may also occur. Although often described as painless, neuropathic pain is not infrequent. Inter- and intra-familial variability is well recognised; progression is gradual, fewer than 5% of individuals become wheelchair-dependent, and life span is not shortened.

The estimated prevalence of Charcot-Marie-Tooth disease overall is 1/2,500. CMT1A is the most common subtype, accounting for as much as 50% of all CMT and for 43.3% of genetically confirmed cases in a large UK referral cohort.

CMT1A is caused by a germline pathogenic variant in PMP22, specifically a 1.5-Mb tandem duplication at chromosome 17p11.2 that encompasses the gene; the duplication is heterozygous in
affected individuals. The additional copy of PMP22 leads to overexpression of peripheral myelin
protein 22, disrupting Schwann-cell myelination and producing a uniform, length-dependent demyelinating peripheral neuropathy; CMT1A is thus a disorder of excessive PMP22 gene dosage.

CMT1A is inherited in an autosomal dominant manner; offspring of an affected individual have a 50% risk of inheriting the PMP22 duplication. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Charcot-Marie-Tooth disease type 1A is diagnosed primarily by molecular genetic testing. Nerve conduction studies typically demonstrate a uniform demyelinating sensorimotor polyneuropathy with motor nerve conduction velocity below 35 m/s, consistent with the CMT1 electrophysiological pattern. The molecular diagnosis is established by detection of the causative PMP22 duplication at chromosome 17p11.2.

Main differential diagnoses include:

• : Acute, recurrent, painless
  focal sensorimotor neuropathy in a single nerve following minor compression, rather than the symmetric, slowly progressive distal pattern of CMT1A; caused by the reciprocal 1.5-Mb deletion at 17p11.2; PMP22 (deletion)
• X-linked Charcot-Marie-Tooth neuropathy type 1 (CMTX1): Family history may appear autosomal dominant because heterozygous females can be affected, but males are typically more severely affected and nerve conduction velocities tend to be in the intermediate range rather than the uniform demyelinating range; central-nervous-system myelin may be affected; GJB1
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): Acquired, treatment-responsive, often relapsing demyelinating polyneuropathy without family history; nerve-conduction findings may show non-uniform/multifocal demyelination with conduction block (EAN/PNS criteria) rather than the uniformly slowed conduction velocities seen in CMT1A; not a hereditary disorder

• Establishing the diagnosis ends a potentially long diagnostic odyssey for the affected individual and family.
• Enables specific and individualised clinical management; a confirmed molecular diagnosis is a prerequisite for targeted medical care, which is decided by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant enables predictive testing of at-risk relatives and informed family planning.

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• Record CJ, Pipis M, Skorupinska M, Blake J, Poh R, Polke JM, et al. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain. 2024;147(9):3144-56. doi:10.1093/brain/awae064. PMID:; PMCID:PMC11370804
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