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Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin., Objective: To identify mutations in the SH3TC2 gene., Methods: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis., Results: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (

In some countries with a high prevalence of consanguineous marriages, autosomal recessive inheritance is likely to account for the great majority of all forms of Charcot-Marie-Tooth (CMT) disease. As with the dominant forms, it is usual to differentiate the demyelinating forms (autosomal recessive -CMT1 or AR-CMT4) from the axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has proved to be an efficient mean of discovering novel CMT genotypes (eg, the genes GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin, and lamin). Because of the clinical, electrophysiologic, and histologic heterogeneity of these patients, it is likely that there are numerous genes that remain to be discovered, which will probably make classification even more complex. Clinical, and especially histologic, phenotypes often lead to a suspicion that a specific gene is implicated. There is, therefore, an indication for nerve biopsy to orient diagnostic research in molecular biology, which is presently very time consuming and can only be performed in highly specialized laboratories.

Autosomal recessive forms of axonal Charcot-Marie-Tooth (ARCMT2) disease are frequent in some areas, such as North Africa and the Middle East, since consanguineous marriages are still common there. Recently, a unique homozygous mutation in LMNA, which encodes lamin A/C, a component of the nuclear envelope, was identified in members of three Algerian families with ARCMT2 linked to chromosome 1q21.2-q21.3. In the present study we describe a group of 21 ARCMT2 patients from seven unrelated Algerian families with the same R298C mutation in the lamin A/C gene and marked variability of the clinical phenotype. There is a wide range of age of onset, from 6 to 27 years, with a mean of 14.4 +/- 4.6 years. The course of the disease varies considerably from one patient to another. Twelve patients with a disease duration of 10-15 years had a severe CMT phenotype with distal wasting and weakness of all four limbs and areflexia associated with involvement of the proximal lower limb muscles. In contrast, nine patients had the classical CMT phenotype with mild functional disability without proximal lower limb involvement after a disease duration of 5-18 years. Electrophysiological studies showed a median motor nerve conduction velocity (MNCV) in the normal range in almost all the patients. MNCV and compound muscle action potential (CMAP) values were inversely correlated with the disease duration and the MNCV was strictly related to the CMAP, strongly supporting a pure axonal process without a demyelinating component. Six patients had a nerve biopsy, which revealed severe rarefaction of myelinated fibres in all cases and an increased density of unmyelinated fibres in the majority of cases. In conclusion, the ARCMT2 associated with the R298C mutation differs from other types of ARCMT2. The variability among patients in the age of onset and the course of the disease strongly suggests the action of modifying genes, which remain to be identified.

Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.

Mutations in the connexin 32 gene (Cx 32) are associated with the x-linked form of Charcot-Marie-Tooth disease (CMTX) and segregate with a CMT 1 phenotype. The gap junction protein Cx 32 is expressed in myelinating Schwann cells and has been localized to regions of non-compacted cytoplasm in paranodes and in Schmidt-Lanterman incisures. Mutant Cx 32 myelin proteins are predicted to impair Schwann cell functions. We have studied the resulting pathology in motor and sensory nerves from the probands of 13 CMTX kindreds with precisely defined genotype. This report provides a detailed descriptive and morphometric analysis of 14 CMTX nerve biopsy samples, taken at various stages in the development of the neuropathy and studied by light and electron microscopic examination. Findings indicated unusually prominent changes in paranodal myelin with resulting widened nodes of Ranvier, but with segmental demyelination being less common. In parallel early axonal cytoskeletal abnormalities were noted, which were followed later by axonal atrophy, degeneration and loss of myelinated nerve fibers, occurring in a length-dependent fashion. Regenerative sprouting was also unusually prominent. Ultrastructural abnormalities included a frequent dilatation of the adaxonal spaces, prominence of the adaxonal Schwann cell cytoplasm and widening of the Schmidt-Lanterman incisures. We conclude that mutations in Cx 32 gap junction protein lead to a compromise of Schwann cell functions and to impaired Schwann cell-axon interactions with subsequent pathology in both myelin and axons.

Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a peripheral neuropathy and features of central nervous system involvement. We describe four patients belonging to a consanguineous Algerian family with late onset (6-10 years) slowly progressive autosomal recessive giant axonal neuropathy. The propositus presented with a Charcot-Marie-Tooth 2-like phenotype with foot deformity, distal amyotrophy of lower limbs, areflexia and distal lower limb hypoesthesia. Central nervous system involvement occurred 10 years later with mild cerebellar dysarthria and nystagmus in the propositus and 16 years after onset, a spastic paraplegia in the oldest patient. The two youngest patients (13 and 8 years old) do not present any signs of central nervous involvement. Magnetic resonance imaging showed cerebellar atrophy in the two older. Nerve biopsy showed moderate axonal loss with several giant axons filled with neurofilaments. Genetic study established a linkage to chromosome 16q locus. This clinical presentation differs from the classical form of giant axonal neuropathy.

X-linked Charcot-Marie-Tooth disease (CMT-X) is caused by mutations of connexin-32 (Cx-32), which encodes a gap-junction protein. Whether the neuropathy is primarily demyelinative or axonal remains to be established. We report findings of prominent demyelination in a 71-year-old woman with late-onset disease. Electrophysiological studies revealed a nonuniform slowing of motor conduction velocities and dispersion of compound action potentials indicative of a demyelinating process which was confirmed by nerve biopsy. Such electrophysiological features are unusual in hereditary neuropathies and are more commonly found with acquired chronic demyelinating neuropathies. A systematic search confirmed the molecular genomic diagnosis of CMT-X, illustrating the value of such tests in sporadic cases. Severity of clinical symptoms and signs may vary with age and sex of the patient. The pathology of CMT-X in other reported cases has been variably interpreted as axonal, demyelinating, or showing both features. Our observations emphasize the demyelinative nature., (Copyright 1999 John Wiley & Sons, Inc.)

Hereditary sensorimotor neuropathies form a heterogeneous group of genetically determined diseases, of which Charcot-Marie-Tooth (CMT) disease is the most common. In order to establish relations between genotype and the expression of peripheral myelin proteins, we carried out a quantitative study by ultrastructural immunocytochemistry of several myelin proteins (PMP22, P0, MBP) on sural nerve biopsy samples from 12 unrelated CMT patients. The diagnosis of CMT was based on the clinical, electrophysiological, and histological findings along with those of molecular biological studies. CMT X diagnoses were not included in this study. The expression of myelin proteins was well correlated with the molecular biological findings in these patients. The results also provided evidence for interference between different myelin proteins. Our findings are in line with the results from animal studies (trembler and knock-out mice), which may provide insights into the pathogenesis of these human conditions.

The Trembler mouse (Tr) suffers from a dominantly inherited autosomal mutation (glycine to aspartic acid. G150D) affecting the PMP22 gene, which results in an abnormal myelination of the peripheral nervous system. The Tr mouse represents an animal model for the human hereditary neuropathy, Charcot-Marie-Tooth disease. We compared the expression of PMP22, P0, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in nerve biopsies from a 1-year-old heterozygous Tr mouse (Tr/+) with that of a control mouse of the same age. Quantitative and qualitative ultrastructural immunocytochemical analysis showed a significant decrease in PMP22, P0 and MBP and an abnormal location of the MAG in the sciatic nerve of the Tr/+ mouse. We also noted a marked reduction in number of myelinated fibers associated with the presence of two types of myelinated axons: a population of abnormally thin myelin sheaths with lower PMP22 labeling than that observed in myelinated fibers from the control mouse, and some others fibers with normal sheaths for axons of comparable diameter to those of normal mouse with no difference in the PMP22 immunolabeling. This pointed to an involvement of PMP22 in the structure of myelin sheaths.

Hereditary sensoro-motor neuropathies such as Charcot-Marie-Tooth disease (CMT) form a heterogeneous group including some genetic conditions whose clinical manifestations differ in severity within a group or even within a sub-group. Diagnosis is based on the clinical, electrophysiological and pathological findings along with a genetic analysis. The current classification of CMT encompasses the clinical signs, mode of transmission, genomic localization and identification of the proteins actually involved. Several authors have identified the mutations on genes coding for proteins of peripheral myelin in CMT patients. Recent advances in molecular genetics have thrown more light on the differences between phenotypes within a sub-group, and have established genotype-phenotype relationships. It has been shown recently that the severity of the clinical signs depends on the nature and site of various mutations affecting the genes coding for certain myelin proteins. These mutations give rise to "dominant negative effects" or "mutations with loss of function of the allele". These observations may be extended to other proteins as many of them belong to the super family of immunoglobulins and have similar structures. In this study, we present a review of the literature focussing on the principal myelin proteins and the genomic modifications observed in patients with CMT.

Charcot-Marie-Tooth type 1B (CMT 1B) disease, an inherited demyelinating peripheral neuropathy, results from different point mutations located in the P0 gene on chromosome 1 q21-23. We have quantified, at the ultrastructural level, the immunocytochemical expression of the P0 protein in two unrelated CMT 1B patients with mutations (Ser 78 to Leu and Asn 122 to Ser) located in two different exons in the extracellular domain of the protein. A twofold decrease in P0 expression was observed in compact myelin in each case, compared with age-matched controls. The severity of the phenotypes showed no direct relationship to the levels of P0 protein expression in these 2 patients.

The present study reports eight additional mutations in the connexin32 gene associated with the X-linked form of Charcot-Marie-Tooth disease. One of these mutations was found twice in two apparently unrelated families. This form of the disease is demyelinating and dominant. However, patient selection for mutational screening should not be limited to these criteria since presentation can either be familial or sporadic, and some patients may be incorrectly classified as suffering from an 'axonal' form. These new mutations complete our previously published work on 12 other mutations and enable meaningful observation in a representative sample of the French population. Mutations are found in all regions of the gene. The most frequently observed mutations were those affecting arginines and mainly involved CpG sequences. Compared with other sources, some of the mutations were present at a higher frequency in the French population.

Charcot-Marie-Tooth disease can be inherited either autosomal dominantly or recessively or linked to the X chromosome. X-linked dominant Charcot-Marie-Tooth disease (CMTX) is a sensorimotor peripheral neuropathy in which males have usually more severe clinical symptoms and decreased nerve conduction velocities than do females. CMTX is usually associated with mutations in exon 2 of the connexin 32 (Cx32) gene. DNA from 35 unrelated CMT patients, without the 17p11.2 duplication, but with median nerve conduction between 30 and 40 m/s, were tested for the presence of Cx32 mutations. The entire coding sequence of the Cx32 gene was explored using a rapid nonradioactive technique to detect single-strand conformation polymorphisms (SSCP) on large PCR fragments. Thirteen abnormal SSCP profiles were detected and characterized by sequencing. In addition, systematic sequencing of the entire Cx32 coding region in the remaining index cases revealed another mutation that was not detected by SSCP. A total of 14 mutations were found, five of which were not previously reported. These results demonstrate the high frequency (40%) of mutations in the coding region of the Cx32 gene in CMT patients with intermediate MNCV, without 17p11.2 duplications. Most of these mutations (93%) can be detected by SSCP.

Charcot-Marie-Tooth type 1A (CMT-1A) disease results from a duplication of the PMP22 gene on chromosome 17p11.2. A deletion of the same region causes hereditary neuropathy with liability to pressure palsies (HNPP). We examined the expression of PMP22 in sural nerve biopsies from 2 unrelated patients with CMT-1A, 2 unrelated patients with HNPP, and control patients. The ultrastructural immunocytochemical quantitative analysis of cases of CMT-1A and HNPP showed, respectively, an elevated and reduced expression of PMP22 level compared with controls.