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PubMed1992

Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy in humans, characterized electrophysiologically by decreased nerve conduction velocities (NCVs). CMT1A is associated with a large submicroscopic DNA duplication in proximal 17p. In this report we demonstrate that a patient with a cytogenetically visible duplication, dup(17)(p11.2p12), has decreased NCV. Molecular analysis demonstrated this patient was duplicated for all the DNA markers duplicated in CMT1A as well as markers both proximal and distal to the CMT1A duplication. These data support the hypothesis that the CMT1A phenotype can result from a gene dosage effect.

Charcot-Marie-Tooth Disease↗

PubMed1997

De novo mutation of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT 1A) is an autosomal dominant demyelinating polyneuropathy associated with a 1.5-Mb duplication of the p11.2-p12 region of chromosome 17, including the peripheral myelin protein-22 (PMP-22) gene (CMT 1A duplication). We report a male patient with a de novo CMT 1A diagnosed on clinical, electrophysiologic, and molecular grounds. Motor nerve conduction velocity (MCV) of the patient was 10.9 m/s in the ulnar nerve. The MCV of both his parents was within the normal range. Southern blot analysis of BamHI digestion showed reduced intensity rate of SF85/PMP-22, indicating CMT 1A duplication. Haplotype analysis with pVAW4093a, demonstrated that the de novo CMT 1A duplication was of paternal origin.

Blotting, Southern↗

PubMed1995

Frequency of duplication at 17p11.2 in families of northeast Italy with Charcot-Marie-Tooth disease type 1.

Charcot-Marie-Tooth disease type 1 (CMT 1) is the most common form of the hereditary motor sensory neuropathies (HMSN) with a prevalence in the Italian population of 9.4/100,000 inhabitants. CMT 1 is a genetically heterogeneous disorder. Forty CMT 1 families (35 with recurrence of cases and 5 sporadic cases) living in northeastern Italy were analyzed with the probe pVAW409R3 to reveal the presence of 17p11.2 duplication. The duplication frequency that resulted was about 82% and not significantly different in familial and in sporadic cases (p = 0.801). This kind of molecular analysis can be very useful for the differential diagnosis of CMT 1 and for the early diagnosis in the absence of a clear clinical manifestation.

Alleles↗

PubMed1993

Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B.

Charcot-Marie-Tooth disease type 1B (CMT1B) is genetically linked to chromosome 1q21-23. The major peripheral myelin protein gene, P0, has been cloned and localized to the same chromosomal region. P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content. We checked whether P0 is altered in CMT1B, and show here that a 3 basepair deletion in exon 2 of the P0 gene is present in all affected individuals of a CMT1B family. The mutation results in the deletion of serine 34 in the extracellular domain of P0, suggesting that alterations of P0 cause CMT1B.

Amino Acid Sequence↗

PubMed1994

Altered neurofilament phosphorylation and beta tubulin isotypes in Charcot-Marie-Tooth disease type 1.

Charcot-Marie-Tooth disease type 1 (CMT1) is associated with atrophy and degeneration of peripheral nerve axons in addition to prominent changes in the structure of Schwann cells. We have investigated the composition of the axonal cytoskeleton in sural nerve biopsies from patients with CMT1. Compared to controls, CMT1 nerves exhibited marked hypophosphorylation of neurofilament proteins and an increased relative abundance of beta tubulin isotypes 2 and 3. Biopsies from patients with other causes of neuropathy, matched to the CMT1 group for severity of axonal atrophy, exhibited an intermediate degree of neurofilament hypophosphorylation and no abnormality of tubulin isotypes. The axonal cytoskeleton in CMT1 resembles that of immature nerve fibers. A failure of normal Schwann cell-axon interaction in CMT1 may prevent full differentiation of the axonal cytoskeleton of myelinated nerve fibers.

Adolescent↗

PubMed1992

The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a DNA duplication at chromosome 17p11.2. In view of the point mutation in the gene for peripheral myelin protein pmp-22/gas-3 in Trembler mice, a murine model for CMT1A, we have analysed whether this gene is altered in CMT1A. Here we show that the human homologue of the murine pmp-22 gene is located within the CMT1A DNA duplication, which is a direct repeat and does not interrupt the coding region of PMP-22. Expression of PMP-22 in CMT1A fibroblasts is similar to expression in control fibroblasts. Increased gene dosage or altered PMP-22 expression in the peripheral nervous system are therefore possible mechanisms by which PMP-22 is involved in CMT1A.

Base Sequence↗

PubMed1998

The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease.

X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Using the SSCP technique and direct sequencing of PCR amplified genomic DNA fragments of the Cx32 gene from a Moroccan patient and her relatives, we identified the first de novo mutation of the Cx32 gene, consisting of a deletion of a G residue at position 499 in the Cx32 open reading frame. This previously unreported mutation produces a frameshift at position 147 in the protein and introduces a premature stop codon (TAG) at nucleotide 643, which results in the production of a truncated Cx32 molecule. This mutation illustrates the risk of an erroneous diagnosis of autosomal recessive CMT, especially in populations where consanguineous unions are frequent, and its consequences for genetic counselling, which can be avoided by molecular analysis.

Adolescent↗

PubMed1993

Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant neuropathy that can be caused by dominant point mutations in PMP22 which encodes a peripheral nerve myelin protein. Usually, CMT1A is caused by the duplication of a 1.5-megabase (Mb) region on chromosome 17p11.2-p12 containing PMP22. Deletion of a similar 1.5-Mb region is associated with hereditary neuropathy with liability to pressure palsies (HNPP), a clinically distinct neuropathy. We have identified a severely affected CMT1 patient who is a compound heterozygote for a recessive PMP22 point mutation, and a 1.5 Mb deletion in 17p11.2-p12. A son heterozygous for the PMP22 point mutation had no signs of neuropathy, while two others heterozygous for the deletion had HNPP, suggesting that point mutations in PMP22 can result in dominant and recessive alleles contributing to CMT1A.

Aged↗

PubMed1992

The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a large DNA duplication on the short arm of human chromosome 17. The trembler (Tr) mouse serves as a model for CMT1A because of phenotypic similarities and because the Tr locus maps to mouse chromosome 11 in a region of conserved synteny with human chromosome 17. Recently, the peripheral myelin gene Pmp-22 was found to carry a point mutation in Tr mice. We have isolated cDNA and genomic clones for human PMP-22. The gene maps to human chromosome 17p11.2-17p12, is expressed at high levels in peripheral nervous tissue and is duplicated, but not disrupted, in CMT1A patients. Thus, we suggest that a gene dosage effect involving PMP-22 is at least partially responsible for the demyelinating neuropathy seen in CMT1A.

Amino Acid Sequence↗

PubMed2003

Screening of the early growth response 2 gene in Japanese patients with Charcot-Marie-Tooth disease type 1.

Charcot-Marie-Tooth disease type 1 (CMT1) is a heterogeneous disorder. Most CMT1 patients are associated with a duplication of 17p11.2-p12 (CMT1A duplication), but a small number of patients have mutations of peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), connexin 32 (Cx32) and early growth response 2 (EGR2) genes. In our previous study, we identified the responsible mutations in 72 of 128 Japanese CMT1 patients as CMT1A duplication in 40, PMP22 mutation in 6, MPZ mutation in 12 and Cx32 mutation in 14 patients. A total of 56 Japanese CMT1 patients with no identified mutations were screened for EGR2 mutation by denaturing gradient gel electrophoresis (DGGE). We detected a heterozygous Asp383Tyr mutation of EGR2 in one patient with severe CMT1, Dejerine-Sottas syndrome. EGR2 mutation is rare cause of CMT1 in Japan as in other nations. We were unable to identify the responsible mutation in 55 of 128 CMT1 patients and need further analysis to identify their candidate genes.

Adult↗

PubMed1998

PCR-based strategy for the diagnosis of hereditary neuropathy with liability to pressure palsies and Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are inherited peripheral neuropathies. In most cases these disorders are caused by either the duplication (in CMT1A) or the deletion (in HNPP) of a 1.5-megabase DNA fragment on chromosome 17p11.2, which contains the peripheral myelin protein 22 gene (PMP22). We developed a rapid and simple quantitative PCR assay for the detection of the CMT1A duplication or the HNPP deletion. The assay is based on the quantitative determination of the copy number of a 240-base pair DNA fragment from exon 4 of the PMP22 gene. Quantification was done on an automated fluorescence sequencer. Using this method we analyzed four families with the HNPP phenotype. In these families we identified the deletion in all affected individuals. To test the validity of the method, we compared the quantitative PCR results from 50 DNA samples, including 15 samples from individuals with HNPP, 15 samples from CMT1A patients, and 20 from normal controls, with the results obtained by Southern blot analysis. Concordant results were obtained in 49 of the 50 cases.

Blotting, Southern↗

PubMed1993

Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a.

Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.

Autoradiography↗

PubMed2000

Prenatal detection of a 17p11.2 duplication resulting from a rare recombination event and novel PCR-based strategy for molecular identification of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease, type 1A (CMT1A) is caused in most cases by a 1.5 Mb duplication on chromosome 17p11.2 arising after unequal crossing-over between repeated sequences called CMT1A-REPs, flanking the 1.5 Mb unit. A 3.2 kb recombination hot spot has been defined, resulting in a junction fragment between EcoRI (distal CMT1A-REP) and SacI (proximal CMT1A-REP). This was further reduced to a 1.7kb EcoRI-NsiI fragment, and recently to a 731 bp hot spot region within this fragment. We describe the CMT1A-REPs-based PCR method used to identify CMT1A duplications and report on a family case in which a 29-year-old pregnant woman requested prenatal diagnosis for two successive pregnancies because her husband was affected with CMT1A. Our method enabled us to characterise the duplication in both foetuses and demonstrate that it arose from a rare recombination event taking place outside the 1.7 kb region. Since our approach is simple and enables the entire set of duplications occurring after recombination in the enlarged 3.2kb region including the hot spot to be detected, we suggest it might be considered for use in primary screening for pre- and postnatal diagnosis of CMT1A.

Charcot-Marie-Tooth Disease↗

PubMed2001

Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A, a hereditary demyelinating neuropathy, is usually caused by overexpression of peripheral myelin protein 22 (PMP22) due to a genomic duplication. We have generated a transgenic mouse model in which mouse pmp22 overexpression can be regulated. In this mouse model, overexpression of pmp22 occurs specifically in Schwann cells of the peripheral nerve and is switched off when the mice are fed tetracycline. Overexpression of pmp22 throughout life (in the absence of tetracycline) causes demyelination. In contrast, myelination is nearly normal when pmp22 overexpression is switched off throughout life by feeding the mice tetracycline. When overexpression of pmp22 is switched off in adult mice, correction begins within 1 week and myelination is well advanced by 3 months (although the myelin sheaths are still thinner than normal), indicating that the Schwann cells are poised to start myelination. Upregulation of the gene in adult mice (which had previously had normal pmp22 expression) is followed by active demyelination within 1 week, which had plateaued by 8 weeks. This indicates that Schwann cells with mature myelin are sensitive to increased amounts of pmp22 such that they rapidly demyelinate. Thus, demyelination can largely be corrected within a few months, but the correction will be sensitive to subsequent upregulation of pmp22.

Animals↗

PubMed1999

A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness.

Charcot-Marie-Tooth disease (CMT) with deafness is clinically distinct among the genetically heterogeneous group of CMT disorders. Molecular studies in a large family with autosomal dominant CMT and deafness have not been reported. The present molecular study involves a family with progressive features of CMT and deafness, originally reported by Kousseff et al. Genetic analysis of 70 individuals (31 affected, 28 unaffected, and 11 spouses) revealed linkage to markers on chromosome 17p11.2-p12, with a maximum LOD score of 9.01 for marker D17S1357 at a recombination fraction of .03. Haplotype analysis placed the CMT-deafness locus between markers D17S839 and D17S122, a approximately 0.6-Mb interval. This critical region lies within the CMT type 1A duplication region and excludes MYO15, a gene coding an unconventional myosin that causes a form of autosomal recessive deafness called DFNB3. Affected individuals from this family do not have the common 1.5-Mb duplication of CMT type 1A. Direct sequencing of the candidate peripheral myelin protein 22 (PMP22) gene detected a unique G-->C transversion in the heterozygous state in all affected individuals, at position 248 in coding exon 3, predicted to result in an Ala67Pro substitution in the second transmembrane domain of PMP22.

Amino Acid Sequence↗

PubMed2001

Regulation of Schwann cell proliferation and apoptosis in PMP22-deficient mice and mouse models of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by an increased dosage of the peripheral myelin protein 22 (PMP22) gene or by point mutations affecting the same gene. Based on in vitro data, PMP22 might be involved, besides in its proven role in the regulation of myelination and myelin maintenance, in the control of Schwann cell proliferation and programmed cell death. In this report, we have used mice lacking PMP22 and mouse models for CMT1A to analyse Schwann cell proliferation and apoptosis in vivo during postnatal sciatic nerve development. Our results show that there is no significant change in the number of Schwann cells at postnatal day 1 in the analysed PMP22 mutants compared with the corresponding wild-type animals. Furthermore, the rate of proliferation also was not changed at this early developmental time point. In contrast, cell density and proliferation rates were increased, albeit with different kinetics, in all PMP22 mutants later in development. The increase in proliferation is paralleled by a higher number of apoptotic Schwann cells found in the nerves. Thus, increased Schwann cell proliferation and apoptosis, but only in later development and in adults, are hallmarks of PMP22 mutant mice, regardless of whether increased or decreased PMP22 gene dosage or point mutations affecting the PMP22 gene are responsible for the resulting demyelinating, dysmyelinating or amyelinating phenotypes.

Animals↗

PubMed2003

Nerve excitability properties in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the in vivo assessment of multiple axonal excitability properties at the median nerve in nine CMT1A patients with PMP22 (peripheral myelin protein 22) gene duplication and 53 controls. The thresholds of CMT1A patients were much higher than normal, and threshold electrotonus (TE) exhibited a consistent pattern of abnormalities: early steep changes (fanning out) of both hyperpolarizing and depolarizing responses were followed by increased inward rectification to hyperpolarizing currents and unusually fast accommodation to depolarizing currents. Strength-duration time constants and the shapes of recovery cycles were normal, although refractoriness and superexcitability were reduced relative to controls. The high thresholds and early fanning out of electrotonus indicated altered cable properties, such that a greater proportion than normal of applied currents reached internodal rather than nodal axolemma. The rapid accommodation to depolarizing currents suggested activation of fast K+ channels, which are normally sequestered from the nodal membrane. The excitability abnormalities are therefore consistent with a demyelinating pathology and exposure or spread of K+ channels from under the myelin. It remains to be seen whether the TE abnormalities in CMT1A, which resemble previous recordings from normal immature rats, can be distinguished from those in acquired demyelinating neuropathies.

Action Potentials↗

PubMedDate not supplied

Lower limb manual muscle testing in the early stages of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous disorder that affects approximately one in 2,500 individuals. CMT 1A, which is due to a duplication in the area containing the PMP-22 gene on chromosome 17, is the most frequent CMT subtype. To date, there is no consensus among authors about which muscles are weakened in the early stages of CMT, even though this knowledge would be crucial for deciding the most appropriate interventions to restore balance between muscles and prevent the development of deformities. The aim of this study was to evaluate the strength of several lower limb muscles in the early stages of CMT 1A. In a series of 45 patients (age 10-72 years; 21 males, 24 females) affected by CMT 1A, we evaluated 83 non-operated lower limbs that corresponded to the two milder stages of a five-level functional classification. The strength of two foot muscles, seven leg muscles, two thigh muscles, and three pelvic girdle muscles was graded using the manual muscle testing techniques of Daniels and Worthingham; the power of the triceps surae was graded, in the prone position, using a 4-level scale of ability to raise the heel from the floor. Muscle strength was determined on the basis of interobserver agreement estimated by kappa statistics between two observers. The flexor hallucis brevis and lumbricals were very weak in all the limbs; the leg muscles were strong in more than 90% of limbs, except the peronei (strong in 83.13%); all the triceps surae were strong in the prone test, but 16.87% were weak in the standing test; all the proximal muscles were strong. In the large majority of patients in the early stages of CMT 1A, the intrinsic foot muscles are very weak and the leg and proximal muscles are strong.

Adolescent↗