Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies

Christopher J. Klein, MD, FAAN Peripheral Nerve and Motor Neuron Disorders p. 1224-1256 October 2020, Vol.26, No.5 doi: 10.1212/CON.0000000000000927
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PURPOSE OF REVIEW This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited neuropathies. These disorders encompass a broad spectrum with variable motor, sensory, autonomic, and other organ system involvement. Considerable overlap exists, both phenotypically and genetically, among these separate categories, all eventually exhibiting axonal injury and neurologic impairment. Depending on the specific neural and non-neural localizations, patients experience varying morbidity and mortality. Neurologic evaluations, including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis is often complex, especially when genetic and acquired components overlap.

RECENT FINDINGS Next-generation sequencing has greatly improved genetic diagnosis, with many third-party reimbursement parties now embracing phenotype-based panel evaluations. Through the advent of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients improved care and counsel. The new classification scheme for inherited neuropathies emphasizes the causal gene names. A specific genetic diagnosis is important as considerable advances are being made in gene-specific therapeutics. Emerging therapeutic approaches include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry disease are discussed.

SUMMARY Comprehensive genetic testing through a next-generation sequencing approach is simplifying diagnostic algorithms and affords significantly improved decision-making processes in neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for most inherited neuropathy categories, specific symptomatic management and family counseling remain the mainstays of therapy.

Address correspondence to Dr Christopher J. Klein, Mayo Clinic, 200 First St SW, Rochester, MN 55905, [email protected].

RELATIONSHIP DISCLOSURE: Dr Klein serves on the clinical expert and therapy boards of the Charcot-Marie-Tooth Association. Dr Klein has received personal compensation for speaking engagements at the Neuropathic Pain Symposium and research/grant support from the Mayo Clinic Center for Individualized Medicine.


© 2020 American Academy of Neurology.