Scientific Background
Charcto-Marie-Tooth (CMT) neuropathies are the most common hereditary peripheral neuropathies with clinical and genetic heterogeneity (prevalence approximately 1:3,300). The mode of inheritance is predominantly autosomal dominant, but can also be autosomal recessive or X-linked. The age of onset is the 1st to 3rd decade. Affected individuals typically show slowly progressive distal muscle (arms and legs) weakness and atrophy, often accompanied by mild to moderate sensory loss. In addition, decreased tendon reflexes and high arches can be observed.
CMT neuropathies are classified according to genetic, electrophysiological, and neuropathological criteria. The most common form is the autosomal dominant inherited CMT1 which accounts for 40-50% of all CMT neuropathies. It is divided into several subtypes depending on the affected gene and type of pathogenic variant, and 70%-85% of all CMT1 involve the CMT1A subtype. The genetic cause is a 1.5 MB tandem duplication on chromosome 17p11.2 (CMT1A duplication), that includes the PMP22 gene. In about one third of patients, it is a de novo duplication.
CMT1 is a predominantly motor, demyelinating peripheral polyneuropathy with distal paresis, especially of the lower limbs. Motor nerve conduction velocity is severely reduced (<38m/s). Approximately 20% of all patients with unclassified chronic peripheral neuropathy have CMT1A. A large study of German patients with the CMT1 phenotype found that CMT1A accounted for 51%, CMTX1 for 9%, and CMT1B for 5%. Molecular genetic testing of genes for these and other subtypes cantake place following exclusion of the typical CMT1A duplication (see also Hereditary Neuropathies).
References
Wu et al. 2017, Biomed Res Int 2017:6481367 / McGarth 2016, Clin Anat 29:547 / Gess et al. 2013, Nervenarzt 84:157 / Rautenstrauss et al. 2009, medgen 21:543 / Juarez et al. 2012, Neural Plast 2012:171636