Hereditary neuropathies

CMT – also termed hereditary motor and sensory neuropathy (HMSN) – and related disorders represent the most common, heritable neurologic conditions. They are classified according to clinical phenotype and nerve conduction studies into demyelinating CMT1 (MNCV < 38m/s), axonal CMT2 (MNCV >38 – 45 m/s), and intermediate CMT (CMTi) (MNCV 25-45 m/s). Additional phenotypes include hereditary sensory neuropathy (HSN), hereditary motor neuropathy (HMN), sensory ataxic neuropathy (SAN), complex neuropathies with extra-neurological manifestations, and hereditary neuropathy with liability to pressure palsies (HNPP), characterised by recurrent compression-induced mononeuropathies.

A common pathological hallmark across all forms of CMT is progressive, length-dependent axonal degeneration, resulting in a characteristic phenotype of distal motor weakness, sensory dysfunction, musculoskeletal deformities, and reduced or absent tendon reflexes. These impairments lead to substantial limitations in daily functioning and are associated with markedly reduced quality of life in both children and adults. Although considerable progress has been made in elucidating disease mechanisms and developing targeted therapeutic strategies, no disease-modifying treatment has yet entered routine clinical practice.

With an estimated prevalence of 1:2,500 globally, hereditary neuropathies are one of the most frequent inherited diseases.

More than 100 genes are associated with hereditary neuropathies. The most common genetic cause is Charcot-Marie-Tooth disease type 1A (PMP22 17p11.2 duplication, autosomal dominant). Further examples include CMT1B (MPZ, autosomal dominant) and HNPP (PMP22 17p11.2 deletion, recurrent focal mononeuropathies).

The genetic conditions associated with hereditary neuropathies follow heterogeneous inheritance patterns. Autosomal dominant, autosomal recessive, X-linked and rarely mitochondrial forms are all recognised across the spectrum.

• Where hereditary neuropathy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Bird TD. Charcot-Marie-Tooth hereditary neuropathy overview. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Müller KI, Ghelue MV, Lund I, Jonsrud C, Arntzen KA. The prevalence of hereditary neuromuscular disorders in Northern Norway. Brain Behav. 2021;11(1). PMID: .
• 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):3144-3156. PMID: .
• Burns J, Timmerman V, Laurá M, Yiu EM, D’Antonio M, Mukherjee-Clavin B, et al. Charcot-Marie-Tooth disease and related neuropathies. Nat Rev Dis Primers. 2026;12(1):3. PMID: .