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PubMed2001

Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity.

Charcot-Marie-Tooth disease type 1 (CMT1) is a demyelinating peripheral neuropathy most commonly caused by a DNA duplication on chromosome 17p11.2 including the peripheral myelin protein 22 (PMP22). Point mutations in the myelin protein zero gene (MPZ) and gap junction protein, beta-1 gene (GJB1) are also found in association with CMT1 or the subclass of CMT type X (CMTX), respectively. Recently point mutations in these genes have been found in patients showing the axonal variant of CMT, CMT type 2 (CMT2). We here describe the clinical and electro-physiological findings caused by two novel and two recently described MPZ mutations and six GJB1 mutations. Different MPZ and GJB1 mutations were associated with different grades of severity in CMT1 and CMTX. The novel MPZ Glu141st op mutation was associated with the axonal CMT2. We conclude that the clinical and electrophysiological heterogeneity among CMT patients carrying point mutations in MPZ and GJB1 is similar. Thus for clinical purposes CMT1 and CMT2 patients should be screened for mutations in these two genes after duplication on chromosome 17p11.2 has been excluded as the disease causing mutation.

Adolescent↗

PubMed1996

The pathology of charcot-marie-tooth disease and related disorders.

Approximately a quarter of a century ago, the disorders originally designated as Charcot-Marie-Tooth disease and Dejerine-Sottas disease were shown by combined clinical, electrophysiological and nerve biopsy studies to be genetically complex. In pathological terms they could be broadly classified into demyelinating neuropathies and axonopathies. Advances in the molecular genetics of these disorders, particularly for those with a demyelinating basis, have recently produced substantial new insights. The identification of mutations in genes for myelin proteins has provided the opportunity for investigating the precise mechanisms of these neuropathies, including the use of spontaneous and genetically engineered animal models.

Animals↗

PubMed2004

[Molecular diagnosis of hereditary neuropathies such as Charcot-Marie-Tooth disease].

During the last decade, molecular biology has demonstrated the extraordinary heterogeneity of genetic abnormalities in Charcot-Marie-Tooth disease (CMT). The main phenotypes are either of the demyelinating or axonal type, transmitted with dominant or recessive autosomal inheritance. X-linked CMT is less rare than it was initially described and is often misdiagnosed as autosomal dominant type. Linked phenotypes are Dejerine-Sottas disease, congenital hypomyelinization and hereditary neuropathy with susceptibility to pressure palsies. Each phenotype can be due to different genotypes and concerned genes are numerous. Conversely, each genotype can express different phenotypes. Molecular diagnostic strategy of CMT is mainly baised on three elements: - phenotypic expertise which is based on the analysis of the inheritance mode and on electrophysiological data, which are peculiar in CMTX - knowledge of respective occurrence of the different genotypes and phenotypes which is increasing - technical feasibility of molecular biology methods which is important to consider, even though progress are fastly coming. According to these considerations, a strategy is proposed for molecular diagnosis of CMT.

Algorithms↗

PubMed2004

Charcot-Marie-Tooth disease (hereditary motor sensory neuropathies) and hereditary sensory and autonomic neuropathies.

BACKGROUND: Since the description of Charcot-Marie-Tooth disease over a century ago. it has now been recognized that these conditions are not caused by generalized metabolic defects but rather have various discrete genetic origins. These disorders can also have variable phenotypes due to dysfunction of peripheral nerve axons or their myelin due to the genetic defects that affect the formation of specific nerve proteins. REVIEW SUMMARY: This article summarizes the clinical presentation of various phenotypes of the hereditary motor sensory neuropathies and the hereditary sensory and autonomic neuropathies, genetic mutations, and their relevant protein products. Proper identification of the genetic defects provides the opportunity for better genetic counseling and hopefully therapies in the future.

Charcot-Marie-Tooth Disease↗

PubMed1997

Connexin32 and X-linked Charcot-Marie-Tooth disease.

Mutations in the gap junction gene connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. More than 130 different mutations have been described, affecting all portions of the Cx32 protein. In transfected cells, the mutant Cx32 proteins encoded by some Cx32 mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, Cx32 is localized to incisures and paranodes, regions of noncompact myelin within the myelin sheath. This localization suggests that Cx32 forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the myelin sheath, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. Cx32 mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons.

Animals↗

PubMed1990

Benign autosomal dominant syndrome of neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and dementia.

We present a kindred with a previously undescribed combination of neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and mild dementia. The propositus, a 72-year-old man, had pes cavus, peripheral neuropathy, ptosis, parkinsonism, hyperreflexia, orthostatic hypotension, central hypoventilation, and mild dementia. Peripheral electrophysiologic studies showed features of an axonal neuropathy. The electroencephalogram showed intermittent 2 to 4 Hz activity symmetrically in the hemispheres. Several family members in 3 generations had pes cavus, neuropathy, ptosis, parkinsonism, and dementia although not all of the features were consistently present. Survival past the 7th decade was common. Autopsy in 2 affected members revealed the neuropathy to be axonal in type and showed mild to moderate loss of anterior horn cells in the spinal cord and pigmentary loss with gliosis in the substantia nigra. This is a unique, benign, autosomal dominant syndrome which shows complete penetrance, variable expression, and both central and peripheral nervous system involvement.

Adult↗

PubMed2003

Axonal Guillain-Barré syndrome associated with axonal Charcot-Marie-Tooth disease.

We report the first case of axonal Guillain-Barré syndrome (GBS) associated with axonal Charcot-Marie-Tooth disease (CMT). A 30-year-old Japanese man, who had suffered leg atrophy and foot deformity since childhood, developed acute weakness in his four limbs following an upper respiratory tract infection. Nerve conduction studies showed low compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes in all the nerves tested. Serial studies showed a rapid increase in CMAP amplitude, but no significant change in SNAP, which indicates that the acute event selectively involved motor axons and was superimposed on a baseline motor-sensory axonal neuropathy, probably CMT Type 2. Elevated serum IgG antibodies against GM1 and GM1b, an increase in CSF protein, and rapid clinical and electrophysiological recovery after plasma exchange support the diagnosis of a pure motor axonal form of GBS, acute motor axonal neuropathy. The association may be coincidental, but a particular susceptibility to axonal damage of CMT2 cannot be excluded.

Adult↗

PubMed1997

Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases.

A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 duplication. Onset of the first functional manifestations was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. The predominant clinical signs were muscle weakness and wasting in the lower limbs. None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients. Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss. Needle electromyography recruitment was reduced in distal muscles for all patients. MNCV slowing was fully consistent with the presence of duplication even in clinically asymptomatic individuals or in children, confirming the complete electrophysiological penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional disability was mild. Ninety-six percent of patients were autonomous; 25% were asymptomatic and diagnosed by systematic family investigation especially on the basis of median nerve MNCV reduction. Early age at onset and greatly reduced median nerve MNCV were predictive of a more severe disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be after an equivalent disease duration. Cross-sectional analysis of neurological deficit, functional deficit and MNCV according to disease duration showed that, regardless of age at onset, CMT1A disease with 17p11.2 duplication is a clinically progressive disorder. Neurological deficit and functional disability increased, whereas median nerve MNCV and compound muscle action potential (CMAP) amplitude did not change with disease course. Intrafamilial phenotype variation between parents and children and between siblings was studied in large families. Functional disability and neurological deficit differed widely and the highest range of median nerve MNCV within a family reached 23 m/s. Clinical and electrophysiological data were compared with those of CMT1B patients with peripheral myelin P0 protein point mutation. CMT1A patients were found to be more severely affected with more prolonged distal motor latency and more reduced CMAP amplitude, whereas MNCV did not significantly differ, indicating that peripheral myelin P0 protein point mutation is not always associated with a severe phenotype. The same genetic defect (17p11.2 duplication) results in variable expression within the phenotype, even in siblings with variations in age at onset, clinical severity and MNCV slowing. This phenotypic variation could be due to additional genetic factors related to peripheral myelin protein 22 expression as well as to other endogenous or environmental factors.

Adolescent↗

PubMedDate not supplied

Charcot-Marie-Tooth disease type 1A: molecular mechanisms of gene dosage and point mutation underlying a common inherited peripheral neuropathy.

Charcot-Marie-Tooth disease type 1A is a demyelinating, inherited peripheral neuropathy which is associated with a DNA duplication in chromosome 17p11.2-p12 in over 70% of patients with CMT1A. The CMT1A duplication is not detected cytogenetically, and constitutes a tandem duplication of a 1.5-Mb region of DNA flanked by homologous sequences designated as CMT1A-REP. Detection of the CMT1A duplication by molecular methods is a valuable diagnostic test for the majority of CMT1A cases. This duplication mutation shows stable inheritance through multiple generations, and may also arise as a new mutation in sporadic patients. The CMT1A duplication leads to the disease phenotype apparently through increased dosage of a gene(s) within the duplicated segment. A disease gene associated with CMT1A has been identified in the form of PMP22, which maps within the CMT1A duplication region, and encodes a myelin protein of the peripheral nerve. Point mutations in the PMP22 gene have been identified in CMT1A patients, including one case of a new mutation in PMP22 which coincided with the onset of the disease. Thus, two alternative molecular mechanisms are responsible for CMT1A: DNA duplication leading to increased gene dosage, and point mutation of the PMP22 gene.

Charcot-Marie-Tooth Disease↗

PubMed2002

Proliferation of Schwann cells and regulation of cyclin D1 expression in an animal model of Charcot-Marie-Tooth disease type 1A.

Overexpression of PMP22 is responsible for the most common form of inherited neuropathy, Charcot-Marie-Tooth disease (CMT) type 1A. The PMP22-transgenic rat (CMT rat) is an animal model of CMT1A, and its peripheral nerves show the characteristic features of ongoing demyelination and remyelination that is also seen in CMT1A patients. Since Schwann cell proliferation is a prominent feature of peripheral nerves in inherited peripheral neuropathies, we examined proliferation and the expression of cyclin D1 in CMT rats. D-type cyclins are required for the initial steps in cell division and nuclear import is crucial for the function of cyclin D1 in promoting cell proliferation. Like normal myelinating Schwann cells in wild-type rats, remyelinating Schwann cells in CMT rats show perinuclear cyclin D1 expression. Schwann cells with nuclear cyclin D1 expression, as well as proliferating Schwann cells, were both associated with demyelinated axonal segments. Supernumerary onion bulb Schwann cells, however, do not express cyclin D1 and were not proliferating. Thus, cyclin D1 expression and its subcellular localization correlate directly with distinct physiological states of Schwann cells in this animal model of CMT1A.

Animals↗

PubMed2002

Novel mutation in X-linked Charcot-Marie-Tooth disease associated with CNS impairment.

The authors describe a 16-year-old boy with severe muscular atrophy and signs of peripheral neuropathy compatible with Charcot-Marie-Tooth disease. Abnormalities in the cerebellum and central somatosensory pathway were also noted. Gene analysis revealed a novel gross insertion mutation in exon 2 of the connexin32 gene along with a 21-base pair duplication resulting in a seven-amino acid insertion in the first extracellular loop of the protein.

Adolescent↗

PubMed1993

Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A by multicolor in situ hybridization.

Genetic heterogeneity within the most common genetic neuropathy, Charcot-Marie-Tooth disease (CMT) results in about 70% slow nerve conduction CMT1 and 30% normal nerve conduction CMT2. Autosomal dominant CMT1A on chromosome 17p11.2 represents about 70% of CMT1 cases and about 50% of all CMT cases. Three different size CMT1A duplications with variable flanking breakpoints were characterized by multicolor in situ hybridization and confirmed by pulsed field gel electrophoresis and quantitative polymerase chain reaction (PCR) amplification. These different size duplications result in the same CMT1A phenotype confirming that trisomy of a normal gene region results in CMT1A. The smallest duplication does not include the 409 locus used previously to screen for CMT1A duplications. Direct analysis of interphase nuclei from fetuses and at-risk patients by multicolor in situ hybridization to a commonly duplicated CMT1A probe is informative more often than polymorphic PCR analysis, faster than pulsed field gel electrophoresis (PFGE), and faster, more informative, and more reliable than restriction enzyme analysis. CMT1B restriction enzyme analysis of CMT pedigrees without CMT1A is expected to diagnose another 8% of at-risk CMT1 patients (total: 78%).

Amniocentesis↗

PubMed2004

Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease.

To investigate the pathogenic role of connexin-32 (Cx32) mutation in X-linked dominant Charcot-Marie-Tooth disease (CMTX), dual whole-cell voltage-clamp recordings and tracer coupling were performed to investigate functional properties of wild-type and 22 CMTX mutant Cx32 proteins expressed in N2A cells. Ten mutant Cx32 proteins either formed defective junctional channels (Y65C, V95M, R107W, L156R, R164W and G199R) or failed to form gap junctions (G12S, S182T, E208K and Y211stop). Except (G12S) and (E208K) mutants, other mutant Cx32 proteins were localized in the cell membrane despite their impaired ability to form functional gap junctions. Twelve CMTX mutations (V13L, R15Q, R22Q, I30N, V35M, V63I, R75Q, Q80R, W133R, P158A, P172S and N205S) did not affect the ability of Cx32 to form homotypic gap junctions in N2A cells. Our results indicate that 10 of 22 CMTX Cx32 mutations studied in the present investigation could lead to the assembly of defective Cx32 gap junctions, which in turn may result in peripheral neuropathy. However, further studies are required to elucidate the exact mechanism by which CMTX mutant Cx32 proteins, which retain the ability to form homotypic junctional channels, damage Schwann cells and cause demyelinating neuropathy.

Amino Acid Substitution↗

PubMed1998

Response to atracurium and mivacurium in a patient with Charcot-Marie-Tooth disease.

PURPOSE: We studied the neuromuscular effects of both atracurium and mivacurium in a patient with Charcot-Marie-Tooth disease (CMTD) during nitrous oxide-oxygen-alfentanil-propofol anaesthesia. Neuromuscular blockade was monitored electromyographically. Train-of-four stimulation (2 Hz @ 20 sec intervals) was delivered to the ulnar nerve throughout the period of observation. CLINICAL FEATURES: A 17-yr-old man with the diagnosis of CMTD was presented twice for two different orthopaedic surgical procedures. The CMTD had been diagnosed since childhood. Neurological examination revealed distal wasting of the upper and lower limbs, generalised absence of reflexes and decreased sensation in a stocking distribution. In both anaesthetics, induction was carried out with alfentanil and propofol, and anaesthesia was maintained with nitrous oxide in oxygen, alfentanil and propofol infusion. The patient demonstrated a normal response to both atracurium and mivacurium. Onset time and the maximum block attained after atracurium and mivacurium were 240 and 210 sec, and 97% and 99% inhibition of T1 (the first twitch of TOF stimulation), respectively. Recovery of T1 to 10% of the control value occurred 30 and 11.5 min after the administration of atracurium and mivacurium, respectively. The patient made uneventful recoveries after both anaesthetics. CONCLUSION: There was no evidence of prolonged response to atracurium and mivacurium in our patient with CMTD.

Adolescent↗

PubMed2005

Charcot-Marie-Tooth disease type 1A: clinicopathological correlations in 24 patients.

We examined nerve biopsies from 24 patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and proven 17p11.2-12 duplication. There were seven males and 17 females with a mean age of 27.85 +/- 18.95 years at the time of nerve biopsy. A family history consistent with dominant inheritance was present in 17 patients. Clinical features were classical in 16 patients and were atypical in the other eight: one had calf hypertrophy; two had Roussy-Levy syndrome; one had had a subacute inflammatory demyelinating polyneuropathy 11 years earlier and presented a relapse on the form of a chronic inflammatory demyelinating polyneuropathy; one had carpal tunnel syndrome; one had a recent painful neuropathy in both legs; and two had chronic inflammatory demyelinating polyneuropathy. Onion bulb formations (OMFs) were present in every case and most of them were characteristic, whereas burnt-out or cluster-associated OMFs were less common. Depletion of myelinated fibers was severe in 20 cases (169-2927/mm2) and varied from 5187 to 3725/mm2 in three children (4-9 years old). In addition, features of macrophage-associated demyelination were observed in the last four atypical cases. Known for more than 20 years, inflammatory demyelination superimposed in the course of CMT1A has been reported in a few cases in the past few years, mainly concerning asymptomatic or atypical patients. Such an association deserves to be better known because corticotherapy improves weakness in most of these patients.

Adolescent↗

PubMed2005

Mutation screening of Cx32 in Han Chinese patients with Charcot-Marie-Tooth disease.

OBJECTIVE: To investigate the Cx32 mutation features and the clinical manifestations of Chinese patients with Charcot-Marie-Tooth disease(CMT). METHODS: Twenty-four of 65 unrelated CMT patients were selected for Cx32 mutation screening after the exclusion of the CMT1A 1.5 Mb duplication and male-to-male transmission. The motor and sensory nerve conduction studies were performed in all probands and most of their affected family members to establish the clinical CMT1 ,CMT2 or CMT intermediate diagnosis. The presence of mutations in the coding region of Cx32 was detected by single-strand conformation polymorphism analysis combined with direct sequencing. RESULTS: We found 7 different point mutations in the coding region of Cx32 in a total of 7 families. All the patients were mildly to moderately affected with a clinical CMT1 or CMT intermediate diagnosis. The mutation Arg15Gln was inherited with X-linked recessive trait in family 1 involved in our study. The Arg75Trp mutation was detected in a family with X-linked dominant CMT and autosomal recessive nonsydromic hearing loss. The clinical phenotype of the Thr188Ala mutation was firstly reported. CONCLUSION: Seven different Cx32 point mutations were detected and the percentage of Chinese CMT families with Cx32 mutation is about 10% in our study. The inheritance model of CMT secondary to Cx32 mutation could be X-linked dominant, X-linked recessive or sporadic. Male patients are usually more severely affected than females with slower nerve conduction velocities. Cx32 mutation screening should be firstly performed in those CMT families without male-to-male transmission and CMT1A duplication.

Charcot-Marie-Tooth Disease↗

PubMed1992

Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A.

We have investigated the peripheral myelin protein gene, PMP-22, in a family with Charcot-Marie-Tooth disease type 1A (CMT1A). The DNA duplication commonly found in CMT1A was absent in this family, but strong linkage existed between the disease and the CMT1A marker VAW409R3 on chromosome 17p11.2. We found a point mutation in PMP-22 which was completely linked with the disease. The mutation, a proline for leucine substitution in the first putative transmembrane domain, is identical to that recently found in the Trembler-J mouse. The presence of this PMP-22 defect in this CMT1A family and the location of PMP-22 within the DNA duplication associated with CMT1A suggest that both structural alteration and overexpression of PMP-22 may lead to the disease.

Amino Acid Sequence↗

PubMed1995

Clinical variability in two pairs of identical twins with the Charcot-Marie-Tooth disease type 1A duplication.

We report two pairs of male homozygotic twins in two unrelated families with the Charcot-Marie-Tooth disease type 1A duplication. Homozygosity was supported by DNA analysis. There was remarkable congruity of conduction velocities between the left and right side of each twin and between twin brothers. The similarity and symmetry of the electrophysiologic deficit contrast with the variable and asymmetric clinical presentations. Variability of clinical expression in these patients with identical mutations suggests the action of stochastic factors or environmental modulation of disease severity.

Adult↗