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PubMed2003

Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C.

BACKGROUND: Charcot-Marie-Tooth (CMT) neuropathy is a heterogeneous group of inherited disorders of the peripheral nervous system. The authors recently mapped an autosomal dominant demyelinating form of CMT type 1 (CMT1C) to chromosome 16p13.1-p12.3. OBJECTIVE: To find the gene mutations underlying CMT1C. METHODS: The authors used a combination of standard positional cloning and candidate gene approaches to identify the causal gene for CMT1C. Western blot analysis was used to determine relative protein levels in patient and control lymphocyte extracts. Northern blotting was used to characterize gene expression in 1) multiple tissues; 2) developing sciatic nerve; and 3) nerve-crush and nerve-transection experiments. RESULTS: The authors identified missense mutations (G112S, T115N, W116G) in the LITAFgene (lipopolysaccharide-induced tumor necrosis factor-alpha factor) in three CMT1C pedigrees. LITAF, which is also referred to as SIMPLE, is a widely expressed gene encoding a 161-amino acid protein that may play a role in protein degradation pathways. The mutations associated with CMT1C were found to cluster, defining a domain of the LITAF protein having a critical role in peripheral nerve function. Western blot analysis suggested that the T115N and W116G mutations do not alter the level of LITAF protein in peripheral blood lymphocytes. The LITAF transcript is expressed in sciatic nerve, but its level of expression is not altered during development or in response to nerve injury. This finding is in stark contrast to that seen for other known genes that cause CMT1. CONCLUSIONS: Mutations in LITAF may account for a significant proportion of CMT1 patients with previously unknown molecular diagnosis and may define a new mechanism of peripheral nerve perturbation leading to demyelinating neuropathy.

Amino Acid Sequence↗

PubMed2003

Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.

Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.

Action Potentials↗

PubMed1992

Localization of PMP-22 gene (candidate gene for the Charcot-Marie-Tooth disease 1A) to band 17p11.2 by direct R-banding fluorescence in situ hybridization.

We mapped PMP-22 gene, candidate gene for the Charcot-Marie-Tooth disease (CMT) 1A, by direct R-banding fluorescence in situ hybridization. The signals of PMP-22 probe were localized to chromosome band 17p11.2. The present result was within the map position of the CMT 1A gene by genetic linkage analysis, and strongly indicated that PMP-22 gene is a candidate gene for the CMT 1A.

Charcot-Marie-Tooth Disease↗

PubMed2001

Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.

X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this study we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age at onset was 15.4 +/- 9.6 years in males (range 1-40 years) and 18.7 +/- 13.1 years in females (range 1-56 years) (P = 0.22) and the duration of disease at the time of examination was 18.3 +/- 14.6 years in males and 23.9 +/- 13.7 years in females (P = 0.11). Males were more severely affected than females, with significantly more frequent muscle weakness, amyotrophy, proprioception loss, upper limb areflexia and pes cavus. Females were more frequently asymptomatic, whereas high functional disability scores were more frequently encountered in males. The electrophysiological studies showed that motor nerve conduction velocities in CMTX females, but not males, were heterogeneous between nerves compared with Charcot-Marie-Tooth type 1A (CMT1A) patients and controls. The terminal latency index (TLI) for the median nerve was 0.37 +/- 0.08; it was similar in men and in women and a little higher than those observed in CMT1A and controls. The range of values for median TLI was wider in both male and female CMTX patients than in controls, but was similar to that of CMT1A patients, suggesting that motor conduction was relatively homogeneous within a given nerve. Twenty-seven different CX32 mutations, including missense (n = 23), nonsense (n = 2) and frameshift mutations (n = 1) and one entire deletion of the CX32 coding sequence, were observed in the 37 families. Four of these mutations are described for the first time. The phenotype of the patients, especially age at onset, is discussed in relation to the functional consequences of CX32 mutations, analysed in vitro in Xenopus oocytes and mammalian cells. CMTX patients with age at onset in the first decade mostly presented non-functional mutations, suggesting that the physiological consequences of the mutations affect age at onset in CMTX.

Adolescent↗

PubMed1994

Charcot-Marie-Tooth disease in northern Sweden: pedigree analysis and the presence of the duplication in chromosome 17p11.2.

Sixty-seven patients in 29 families with the diagnosis of Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy in northern Sweden were examined by pedigree and DNA analysis for the CMT1a duplication within chromosome 17p11.2. There were 39 patients in nine families with Charcot-Marie-Tooth type 1 and autosomal dominant inheritance and in all these cases the duplication was seen. In six patients in three families with Charcot-Marie-Tooth type 1 the pedigrees strongly suggested autosomal recessive inheritance. In two patients DNA analysis was not informative but in the others no duplication was shown. There were also 11 "sporadic" patients and one pair of sibs classified as Charcot-Marie-Tooth type 1, but there was no duplication shown although in four patients DNA analysis was not informative. In nine patients with Charcot-Marie-Tooth type 2 from five families and in 13 unaffected relatives of Charcot-Marie-Tooth patients the CMT1a duplication was not found.

Adolescent↗

PubMed2004

A novel mutation of myelin protein zero associated with an axonal form of Charcot-Marie-Tooth disease.

OBJECTIVE: To report a new mutation in the MPZ gene which encodes myelin protein zero (P0), associated with an axonal form of Charcot-Marie-Tooth disease (CMT). METHODS: Three patients from an Italian family with a mild, late onset axonal peripheral neuropathy are described clinically and electrophysiologically. To detect point mutation in MPZ gene the whole coding sequence was examined. The structure of the mutated protein was investigated using the three dimensional model of P0. RESULTS: All patients showed a relatively mild CMT phenotype characterised by late onset and heterogeneity of the clinical and electrophysiological features. Molecular analysis demonstrated a novel heterozygous T/A transversion in the exon 3 of MPZ gene that predicts an Asp109Glu amino acid substitution in the extracellular domain of the P0. Asp109 is found at the protein surface, on beta strand E, in the interior of the P0 tetramer. CONCLUSIONS: The identification of Asp109Glu mutation confirms the pivotal role of P0 in axonal neuropathies and stresses the phenotypic heterogeneity associated with MPZ mutations. This study suggests the value of screening for MPZ mutations in CMT family members with minor clinical and electrophysiological signs of peripheral neuropathy.

Aged↗

PubMed2001

Clinical phenotype in X-linked Charcot-Marie-Tooth disease with an entire deletion of the connexin 32 coding sequence.

To clarify the clinical phenotype and molecular mechanism in X-linked Charcot-Marie-Tooth disease (CMTX) patients with a deletion of the whole connexin 32 (Cx32) coding sequence, we studied a family with this deletion by electrophysiology, Southern blotting and quantitative PCR analyses. Two brothers with no copy of Cx32, 27 and 25 years old, showed steppage gait, moderate muscle atrophy and weakness, and mild sensory disturbance in the distal parts of the legs. The clinical phenotypes in these brothers were not different from those in patients with other types of severe Cx32 mutations. Their mother, with one copy of Cx32, showed very mild muscle weakness and sensory disturbance. An electrophysiological study showed a nonuniform demyelinating neuropathy with some aspects of an axonal-loss neuropathy. Sural nerve biopsy showed loss of myelinated fibers, many relatively thin myelin sheaths, clusters of small myelinated fibers, and some onion bulb formations. The present findings suggest that both a demyelinating process and an axonal involvement were present in the patients with total defect of Cx32 probably due to loss of the function mechanism of Cx32 as the underlying molecular mechanism, because a dominant negative effect theory is not applicable in these patients.

Adult↗

PubMed2000

[Two families of Charcot-Marie-Tooth disease with Adie's pupil, axonal neuropahy and the Thr124Met mutation in the peripheral myelin protein zero gene].

We reported two families of Charcot-Marie-Tooth disease (CMT) with Thr124Met mutation in the peripheral myelin protein zero (MPZ). The clinical features of the proband patients of both families showed Adie's pupil, severe sensory dominant neuropathy in lower extremities, and axonal changes in sural nerve biopsies and nerve conduction studies. Muscle atrophy and weakness was mild in the lower legs, while sensory impairment was marked. The proband patient of family 1 had four symptomatic siblings and one of them showed Adie's pupil. The elderly daughter of the proband of family 2 showed Adie's pupil and younger daughter showed photophobia. The biopsied sural nerves of both proband patients revealed prominent axonal sprouting, and sub-perineurial edema and mild fascicular enlargement. Segmental demyelination was not frequent in teased fiber assessment. The present two family cases strongly suggest that this MPZ gene mutation (Thr124Met) could be present among the patients with CMT type 2, axonal form. Furthermore, the patients showing sensory neuropathy and Adie's pupil may need to be reexamined with this mutation. It is also necessary to reassess genotype-phenotype correlation in CMT patients particularly in reference to type 1 and type 2.

Adie Syndrome↗

PubMed2001

Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis.

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.

Adolescent↗

PubMed1997

Schwann cell differentiation in Charcot-Marie-Tooth disease type 1A (CMT1A): normal number of myelinating Schwann cells in young CMT1A patients and neural cell adhesion molecule expression in onion bulbs.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common hereditary demyelinating neuropathy caused by a duplication of the gene for the myelin protein PMP22, resulting in overexpression of PMP22 in young patients. Although genetically well defined, the pathogenesis of the hereditary demyelinating neuropathy CMT1A is still unclear. Homology of PMP22 cDNA to the growth arrest-specific gene gas3 and experiments in vitro showing decreased proliferation in PMP22-overexpressing Schwann cells suggest a role of PMP22 in Schwann cell differentiation. Furthermore, overexpression of PMP22 in fibroblasts induces programmed cell death. In this report we applied morphometrical methods using electron micrographs and immunohistochemistry to further characterise Schwann cells in CMT1A nerve biopsy samples from CMT1A patients. We show that the total number of PMP22-expressing Schwann cells, i.e. Schwann cells that are in a 1:1 relationship with axons, was not reduced in sural nerve biopsy samples from six young CMT1A patients. We excluded non-specific secondary Schwann cell proliferation. Thus, in young CMT1A patients with increased PMP22 overexpression there seems to be no evidence for altered initial Schwann cell proliferation in achieving a 1:1 relationship to axons prior to the process of de- and remyelination. Further, using electron microscopy we found no evidence for apoptosis of Schwann cells in CMT1A. However, we provide additional support for an abnormal Schwann cell phenotype in CMT1A by showing the expression of neural cell adhesion molecule immunoreactivity in onion bulbs. Thus, the role of PMP22 in cell growth and differentiation does not lead to an altered number of myelinating Schwann cells but to altered Schwann cell differentiation in CMT1A.

Cell Differentiation↗

PubMed2006

Effects of exercise and creatine on myosin heavy chain isoform composition in patients with Charcot-Marie-Tooth disease.

It is not known whether myosin heavy chain (MHC) content changes in response to exercise training or creatine supplementation in subjects with Charcot-Marie-Tooth disease (CMT). Based on previous data, we hypothesized that resistance exercise and creatine would increase the percentage of type I MHC composition in the vastus lateralis muscle and that myosin isoform changes would correlate with improved chair rise-time in CMT subjects. To test this hypothesis, 18 CMT subjects were randomly assigned to either a placebo or creatine group. All subjects performed a 12-week, home-based, moderate-intensity resistance training program. Chair rise-time was measured before and after the training program. Muscle biopsies were obtained from the vastus lateralis before and after the 12-week program. Gel electrophoresis showed a significant decrease (approximately 30%) in MHC type I in CMT subjects given creatine supplementation when compared with placebo. There was a nonsignificant increase in both MHC type IIa (approximately 23%) and MHC type IIx (approximately 7%) in CMT subjects given creatine. Reduced MHC type I content and increased MHC type IIa content correlated with faster chair rise-times (i.e., improved muscle performance). The training-induced change in MHC IIa content was inversely correlated with chair rise-time in CMT subjects given creatine. When the two subject groups were combined, there was a linear, negative relationship between the change in MHC type IIa content and chair rise-time after training and a positive relationship between the training-induced change in MHC type I content and chair rise-time. These data suggest that improved function (chair rise-time) was associated with a lower level of MHC type I and increased MHC type IIa composition. Furthermore, the data are consistent with the hypothesis that creatine supplementation alters MHC composition in CMT patients undergoing resistance training and that MHC changes associated with creatine supplementation can improve muscle function.

Adult↗

PubMed2004

Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management.

Over the past decade there has been a huge increase in the understanding of the molecular basis of Charcot-Marie-Tooth disease (CMT). Additionally there has been a better delineation of the neurophysiological deficits and clinical problems associated with CMT. This paper reviews the current molecular basis of CMT and the electrophysiological, clinical and phenotypical characteristics of the various subtypes, followed by a discussion of novel and promising therapeutic interventions that potentially could be used as part of a treatment regimen for CMT. These interventions may involve attempts to slow down or stop neurodegenerative processes through nerve growth factors, limiting oxidative stress by using antioxidants, or normalizing gene expression through genetic manipulation. Other potential therapeutic target areas include the progesterone receptor on myelin-forming Schwann cells, the immune system via modulation of nerve inflammation, and enhancing glutathione transferase activity. While ongoing molecular research continues to identify more of the mutant genes and proteins that cause the various disease subtypes, the focus of clinical research should continue to be on developing pharmaceutical and rehabilitative therapies to reverse nerve degeneration and ultimately improve the functioning of people with CMT.

Animals↗

PubMed1984

Pathogenesis of Charcot-Marie-Tooth disease. Gait analysis and electrophysiologic, genetic, histopathologic, and enzyme studies in a kinship.

Little has been written about the pathogenesis of pes cavus in Charcot-Marie-Tooth disease (CMT). In 12 of 22 patients in a family with known autosomal dominant CMT, a predictable pattern of progression was related to a centrifugal pattern of innervation of the extremity. The gait pattern had greater complexity than the steppage gait. Pelvic shift and elevation on the swing side were used to clear the "drop foot" from the floor. Lateral flexion of the trunk to the opposite direction was used for balance. Previous descriptions of the etiology of pes cavus did not apply to this family. The mode of development of pes cavus in CMT is not known and requires further investigation.

Adolescent↗

PubMed1997

Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population.

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.

Adolescent↗

PubMed2003

Electrodiagnostic evidence of phrenic nerve demyelination in Charcot-Marie-Tooth disease 1A.

OBJECTIVE: To determine whether neurophysiologic findings correlate to clinical respiratory signs or spirometric abnormalities in patients with hereditary motor and sensory neuropathy type 1 (Charcot-Marie-Tooth disease). DESIGN: A total of 11 patients with hereditary motor and sensory neuropathy type 1A, genetically identified, (age range, 10-58 yr) were included and studied by physical pulmonary examination, chest radiography, respiratory function tests, and bilateral transcutaneous phrenic nerve conduction. RESULTS: No patient complained of respiratory symptoms or revealed abnormal spirometric or maximal respiratory pressure data, despite a phrenic nerve conduction significantly slower (P < 0.0001; median conduction time, 18.6 msec; 95th percentile, 31.97 msec) than that recorded in the control group of healthy subjects (median, 6.05 msec; 95th percentile, 8.82 msec); the amplitudes of compound muscle action potentials were not statistically different from the controls. CONCLUSIONS: Our study confirms a dramatic phrenic nerve involvement in absence of clinical and laboratory evidence of diaphragmatic weakness; further studies and an adequate follow-up are necessary to discover whether the disease progress might encompass respiratory dysfunction at later stages.

Action Potentials↗

PubMed1995

Mutations in the myelin protein zero gene associated with Charcot-Marie-Tooth disease type 1B.

Charcot-Marie-Tooth type 1 (CMT1) disease is an autosomal dominant neuropathy of the peripheral nerve. The majority of CMT 1 cases are due to a duplication of an 1.5-Mb DNA fragment on chromosome 17p11.2 (CMT 1a). Micromutations were found in the gene for peripheral myelin protein 22 (PMP22) located in the duplicated region of CMT 1a, and in the peripheral myelin protein zero (PO) located on chromosome 1q21-q23 (CMT 1b). We have characterized two new mutations in the PO gene in two french families presenting CMT disease. Both mutations occur in the extracellular domain of the PO protein. One mutation is a de novo mutation and is from paternal origin.

Base Sequence↗

PubMed2002

[A case of Charcot-Marie-Tooth disease (CMT) type 1 complicated by diabetes mellitus (DM) showing bilateral phrenic nerve palsy].

We here report a 44-year-old woman with Charcot-Marie-Tooth disease (CMT) type 1 who showed severe bilateral phrenic nerve palsy (PNP). She had chronic progressive distal dominant muscle weakness and atrophy since early in her second decade and had been unable to walk by herself due to weakness of the legs since she was 40-years old. At that time, she was diagnosed with diabetes mellitus (DM). She also had difficulty breathing when she was in a supine position. On admission, sural nerve biopsy showed a marked decrease of large and small myelinated fibers and numerous onion bulb formations, which are compatible with CMT type 1. Chest X-ray showed bilateral elevation of the diaphragm, which was more marked on the right side, indicating bilateral PNP. Since it is reported that CMT patients show demyelination of the phrenic nerve subclinically, and DM itself may facilitate the development of PNP, periodic evaluations of respiratory function may thus be useful for preventing respiratory failure in patients with CMT, especially when it is complicated with DM.

Adult↗

PubMed2003

Charcot-Marie-Tooth disease: a novel Tyr145Ser mutation in the myelin protein zero (MPZ, P0) gene causes different phenotypes in homozygous and heterozygous carriers within one family.

Charcot-Marie-Tooth disease type 1B (CMT 1B) is caused by mutations in the gene coding for peripheral myelin protein zero (MPZ, P0) that plays a fundamental role in adhesion and compaction of peripheral myelin. Here we report a Costa Rican family with a hereditary peripheral neuropathy due to a novel Tyr145Ser MPZ mutation. Four family members were heterozygously affected; two siblings of two heterozygous carriers were homozygous for this mutation. On neurological examination the heterozygous parents and their homozygous children both showed distal sensory deficits. The mother and the siblings displayed impaired deep tendon reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with an earlier age of onset, distal motor weakness, and pupillary abnormalities. Electrophysiological studies revealed both signs of demyelination and axonal nerve degeneration. The sural nerve biopsy of one sibling showed thinly myelinated nerve fibers, onion bulb formation, and clusters of regenerating fibers. On electron microscopy axonal degeneration and decompaction of inner myelin layers were found. This Costa Rican family shows phenotypic variability depending on the homozygous or heterozygous state of the Tyr145Ser mutation carriers.

Charcot-Marie-Tooth Disease↗