CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A (CMT1)

PMP22

Description

Scientific Background

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 manifestation affects the first to third decade. Affected individuals typically show slowly progressive weakness and atrophy of distal muscles (arms and legs), often accompanied by mild to moderate sensory loss. In addition, decreased tendon reflexes and a hollow foot can be observed.

 

Classification of CMT neuropathies is based on genetic, electrophysiologic, and neuropathologic criteria. The most common form is the autosomal dominant inherited CMT1 which accounts for 40-50% of all CMT neuropathies, and is divided into several subtypes depending on the affected gene and type of pathogenic variant. 70%-85% of all CMT1 involve the CMT1A subtype. The genetic basis is a 1.5 MB tandem duplication on chromosome 17p11.2 (CMT1A duplication), which includes the PMP22 gene. In about one third of patients, this duplication arises de novo.

 

CMT1 is a predominantly motor, primarily peripherally demyelinating polyneuropathy with distal paresis, especially of the lower extremities. Motor nerve conduction velocity is severely reduced (<38m/s). Approximately 20% of all patients with unclassified chronic peripheral neuropathy have CMT1A. In a recent large study of German patients with CMT1 phenotype, the following percentages were elicited: CMT1A (51%), CMTX1 (9%), and CMT1B (5%). Molecular genetic testing of these and other genes can be followed after exclusion of the typical CMT1A duplication (see Hereditary Neuropathies).

 

References

Wu et al. 2017, Biomed Res Int.: 6481367 / McGarth 2016, Clin. Anat. 29:547 / Gess et al. 2013, Nervenarzt 84:157 / Rautenstrauss et al. 2009, medgen 21:543-554 / Juarez et al. 2012, Neural Plasticity Article ID 171636, 11 pages

GENES

PMP22

ASSOCIATED TESTS

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