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Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.

Bolest Charcot Marie Tooth (CMT) je najčešća nasljedna periferna neuropatija. Elektrofiziološki se razlikuju demijelinizirajući (CMT1) i aksonalni tip (CMT2).Klinički pregled i elektromioneurografija (EMNG) učinjeni su u 15-ero djece, a biopsija perifernog živca u 12/15 djece s CMT u dobi od 1 do 15 godina. Djeca su praćena klinički i neurografski u razdoblju od 1-13 godina u 1-4 navrata. Molekularno-genetska analiza CMT mutacija učinjena je u sve djece i članova njihovih obitelji. Ekskavirano stopalo i kontrakture su najčešće kliničke karakteristike u djece s CMT u dobi do 10 godina, dok se hipotrofija mišića i skolioza razvijaju u drugom desetljeću života. U djece s CMT1A, CMT1X i CMT4A otkrivene su usporene brzine provodljivosti (7-39 m/s) i produljene krajnje latencije (KL) na prvom pregledu, te redukcija amplituda složenih mišićnih akcijskih potencijala (SMAP) tijekom drugog desetljeća života (0, 1-1, 25 mV). Molekularno-genetskom analizom u 10/15 djece otkrivena je duplikacija PMP22 (CMT1A), u 2/15 djece nađena je delecija PMP22 (HNPP), u 1/15 mutacija koneksina (CMT1X) te u 2/15 djece mutacija GDAP1 (CMT4A). Izrazite neurografske abnormalnosti i blagi klinički simptomi registrirani su u djece s CMT1A u prvom desetljeću života. U djece s HNPP te CMT4A brzine motorne i senzorne provodljivosti su blago usporene u odnosu na vrijednosti u djece sa CMT1A na prvom i kontrolnim neurografskim pretragama. Znakovi lezije aksona i mijelina registrirani su u prvom i drugom desetljeću života u djece s CMT4A. Značajna progresivna redukcija SMAP, do potpune inekscitabilnosti perifernog živca, registrirana je u razdoblju 1-5 godina praćenja u djece s CMT1A te nakon 10 godina u djece s CMT4A.

Background Mutations in P0, the major protein of the myelin sheath in peripheral nerves, cause the inherited peripheral neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B), Dejerine-Sottas syndrome (DSS) and congenital hypomyelination (CH). We reported earlier a de novo insertional mutation c.662_663GC (Ala221fs) in a DSS patient. The c.662_663GC insertion results in a frame shift mutation Ala221fs altering the C-terminal amino acid sequence. The adhesion-relevant intracellular RSTK domain is replaced by a sequence similar to Na+/K+ ATPase. To further clarify the molecular disease mechanisms in this sporadic patient we constructed wild type P0 and the c.662_663GC mutant expression cassettes by site-specific mutagenesis and transfected the constructs into insect cells (S2, High5). To trace the effects in live cells, green fluorescent protein (GFP) has been added to the carboxyterminus of the wild type and mutated P0 protein. Results In contrast to the membrane-localized wild type P0-GFP the Ala221fs P0-GFP protein was detectable almost only in the cytoplasm of the cells, and a complete loss of adhesion function was observed. Conclusions The present study provides evidence that GFP is a versatile tool to trace in vivo effects of P0 and its mutations. Not only a loss of adhesion function as a result of the loss of the RSTK domain, but also altered intracellular trafficking indicated by a loss of membrane insertion are possible consequences of the Ala221fs mutation.

Dejerine-Sottas syndrome (DSS), or hereditary motor and sensory neuropathy (HMSN) type III, is a severe hypertrophic demyelinating neuropathy with infantile onset. The clinical symptoms are similar to those found in Charcot-Marie-Tooth disease type 1 (CMT1) or HMSN type I patients, but they are more severe. DSS is genetically heterogeneous, Dominant mutations in two major peripheral myelin protein genes, PMP22 and P-0, are associated with a DSS phenotype. Mutations in the same genes are also responsible for the CMT1 phenotype. A 1.5 Mb duplication in 17p11.2 is the major mutation found in familial and sporadic CMT1 patients. We studied two genetically sporadic DSS patients. The presence of a de novo duplication in one patient was revealed by Southern blot analysis, using polymorphic markers located in the duplicated area. The 17p11.2 allele segregation in this patient and in her parents suggests that the duplication is of maternal origin, In the other patient, single strand conformation polymorphism (SSCP) analysis of the 6 exons of the P-0 gene revealed two additional bands in exon 3. Sequencing of this exon identified a novel dominant mutation replacing a sequence of 8 bp by a mutated sequence of 5 bp, The mutation apparently leads to the replacement of 4 amino acids at positions 86-89 by three different amino acids, in an area that is part of a predicted beta-strand. Our findings support the suggestion that DSS and CMT1 disease should not be considered as two different clinical entities. (C) 1996 Wiley-Liss, Inc.