Charcot-marie-tooth disease and related neuropathies: molecular basis for distinction and diagnosis.
Great advances have been made in understanding the molecular basis of Charcot-Marie-Tooth disease (CMT) and related neuropathies, namely Dejerine-Sottas disease (DSD), hereditary neuropathy with liability to pressure palsies (HNPP) and congenital hypomyelination (CH). The number of newly uncovered mutations and identified genetic loci is rapidly increasing, and, as a consequence, the classification of these disorders is becoming more complicated. Molecular genetics, animal models, and transfected cell studies are shedding light on function and dysfunction of proteins involved in hereditary myelinopathies-peripheral myelin protein 22 (PMP22), myelin protein zero (PO), connexin 32 (Cx32), and early growth response 2 (EGR2). Gene dosage effect, loss of function, gain of toxic function, and dominant negative effect are possible mechanisms whereby different gene mutations may exert their detrimental action on peripheral nerves. A tentative rational approach to clinical and molecular diagnosis based on genotype-phenotype correlation analysis is described.
Pareyson
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Department of Neurology, Istituto Nazionale Neurologico "C.Besta," Via Celoria 11, 20133 Milan, Italy. dpareys@tin.it
D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D015417:Hereditary Sensory and Motor Neuropathy / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D017354:Point Mutation