Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy in humans and has been associated with a partial duplication of chromosome 17 (CMT type 1A). We have generated a transgenic rat model of this disease and provide experimental evidence that CMT1A is caused by increased expression of the gene for peripheral myelin protein-22 (PMP22, gas-3). PMP22-transgenic rats develop gait abnormalities caused by a peripheral hypomyelination, Schwann cell hypertrophy (onion bulb formation), and muscle weakness. Reduced nerve conduction velocities closely resemble recordings in human patients with CMT1A. When bred to homozygosity, transgenic animals completely fail to elaborate myelin. We anticipate that the CMT rat model will facilitate the identification of a cellular disease mechanism and serve in the evaluation of potential treatment strategies.
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PMID:A transgenic rat model of Charcot-Marie-Tooth disease. 863 Feb 43

Autosomal dominant Charcot-Marie-Tooth type-1A neuropathy (CMT1A) is a demyelinating peripheral nerve disorder that is commonly associated with a submicroscopic tandem DNA duplication of a 1.5-Mb region of 17p11.2p12 that contains the peripheral myelin gene PMP22. Clinical features of CMT1A include progressive distal muscle atrophy and weakness, foot and hand deformities, gait abnormalities, absent reflexes, and the completely penetrant electrophysiologic phenotype of symmetric reductions in motor nerve conduction velocities (NCVs). Molecular and fluorescense in situ hybridization (FISH) analyses were performed to determine the duplication status of the PMP22 gene in four patients with rare cytogenetic duplications of 17p. Neuropathologic features of CMT1A were seen in two of these four patients, in addition to the complex phenotype asociated with 17p partial trisomy. Our findings show that the CMT1A phenotype of reduced NCV is specifically associated with PMP22 gene duplications, thus providing further support for the PMP22 gene dosage mechanism for CMT1A.
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PMID:Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1 neuropathy. 865 46

Construction of animal models of human inherited diseases is particularly important for testing gene therapy approaches. Towards this end, we constructed a mouse model for Charcot-Marie-Tooth disease type 1A by pronuclear injection of a YAC containing the human PMP22 gene. In one transgenic line, the YAC DNA is integrated in about eight copies and the PMP22 gene is strongly expressed to give a peripheral neuropathy closely resembling the human pathology. The disorder is dominant, causes progressive weakness of the hind legs, and there is severe demyelination in the peripheral nervous system including the presence of onion bulb formations. This approach will be valuable for pathologies produced by over-expression of a gene including trisomy and amplification in cancer. Such models will be particularly useful for testing gene therapy approaches if the transgene is human.
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PMID:Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. 873 21

Charcot-Marie-Tooth (CMT) disease type 1A is an inherited peripheral neuropathy characterized by slowly progressive distal muscle wasting and weakness, decreased nerve conduction velocities, and genetic linkage to 17p12. Most (> 98%) CMT1A cases are caused by a DNA duplication of a 1.5-Mb region in 17p12 containing the PMP22 gene. The reciprocal product of the CMT1A duplication is a 1.5-Mb deletion which causes hereditary neuropathy with liability to pressure palsies (HNPP). The most informative current diagnostic testing requires pulsed-field gel electrophoresis to detect DNA rearrangement-specific junction fragments. We investigated the use of interphase FISH for the detection of duplications and deletions for these disorders in the clinical molecular cytogenetics laboratory. Established cell lines or blood specimens from 23 individuals with known molecular diagnoses and 10 controls were obtained and scored using a two-color FISH assay. At least 70% of CMT1A cells displayed three signals consistent with duplications. Using this minimum expected percentile to make a CMT1A duplication diagnosis, all patients with CMT1A showed a range of 71-92% of cells displaying at least three signals. Of the HNPP cases, 88% of cells displayed only one hybridization signal, consistent with deletions. The PMP22 locus from normal control individuals displayed a duplication pattern in approximately 9% of cells, interpreted as replication of this locus. The percentage of cells showing replication was significantly lower than in those cells displaying true duplications. We conclude that FISH can be reliably used to diagnose CMT1A and HNPP in the clinical cytogenetics laboratory and to readily distinguish the DNA rearrangements associated with these disorders from individuals without duplication or deletion of the PMP22 locus.
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PMID:Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. 909 65

The crossover breakpoints for CMT1A are located in the CMT1A-REP repeat flanking a 1.5 Mb region of chromosome 17p11.2-12. We analysed the relationship between the breakpoint locations and clinical phenotypes in 21 Japanese patients with CMT1A duplication. The CMT1A-REP region was divided in 5 regions, A, B, C, D and E, based on restriction site differences between the proximal and distal CMT1A-REP repeats (Kiyosawa et al., HMG, 1995). The breakpoint location within the CMT1A-REP was heterogeneous, the frequency distribution of which was hightest in the B/C region and similar to that in Caucasian patients. The clinical phenotypes, such as foot deformity, muscular weakness and atrophy, sensory impairment and electrophysiologic finding, were extensively variable among the CMT1A patients with PMP22 gene duplication. The location of breakpoints was not related to the clinical phenotypes, suggesting that there is a factor other than the location of the crossover breakpoint, which influences phenotypic manifestation of CMT1A.
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PMID:[Heterogeneity in breakpoint location of duplication in Japanese Charcot-Marie-Tooth disease type 1A]. 914 75

A 27-year-old man with negative family history and both parents with normal neurological evaluation and motor nerve conduction velocities (MNCVs) showed onset of severe weakness of feet at 4 years of age. Subsequently he developed left equinovarus deformity, thoracic scoliosis, ulnar nerve enlargement, areflexia, distal hypesthesia and slowing of MNCVs for median and ulnar nerves (15-25 m/sec). Molecular genetic studies showed deletion of one nucleotide (G330) (codon 94) in exon 3 of the PMP22 gene associated with frameshift mutation.
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PMID:Severe Charcot-Marie-Tooth neuropathy type 1A with 1-base pair deletion and frameshift mutation in the peripheral myelin protein 22 gene. 932 88

The peripheral neuropathy, hereditary sensory neuropathy type I (HSN-I) is an autosomal dominant degenerative disorder of sensory and motor neurons. The disease leads to distal sensory loss, distal muscle wasting and weakness, and variable neural deafness. The HSN-I locus was recently mapped to a large genetic interval on chromosome 9q22 that includes the candidate genes GAS1 and XPA. XPA mutations have been shown to cause peripheral neuropathy, and GAS1 is related to the PMP22 gene, which is critical in the pathogenesis of two other peripheral neuropathies. By undertaking extensive genetic linkage analysis within the candidate region, we have refined the HSN-I locus to a critical interval of 3-4 cM. GAS1, XPA, and several other genes that map within the interval initially identified for the disease locus have been investigated and excluded from playing a pathogenic role in HSN-I.
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PMID:Fine mapping of the hereditary sensory neuropathy type I locus on chromosome 9q22.1-->q22.3: exclusion of GAS1 and XPA. 937 9

Charcot-Marie-Tooth (CMT) disease type 1A is an autosomal dominant peripheral neuropathy characterized by slow progressive distal muscle wasting and weakness, and decreased nerve conduction velocities. Most CMT1A cases (>98%) are caused by a duplication of a 1.5 Mb region on the short arm of chromosome 17 containing the PMP22 gene. A couple with a previous history of CMT followed by termination of pregnancy was referred to our centre for preimplantation genetic diagnosis (PGD). The husband carries the CMT1A duplication which can be detected by polymerase chain reaction (PCR) analysis using polymorphic (CA)n markers localized within the duplication. PCR amplification of genomic DNA of the parents-to-be with one of the two primers labelled with fluorescein, followed by automated laser fluorescence (ALF) gel electrophoresis of the amplified fragments allows the distinction between both genotypes. Embryos obtained after intracytoplasmic sperm injection (ICSI) were evaluated for the presence of the normal allele of the father. PCR with single Epstein-Barr virus-transformed lymphoblasts and blastomeres resulted in 91.4 and 93.5% amplification efficiency respectively, whereas none of the blank controls gave a positive signal. Allele drop-out (ADO) was observed in eight out of 32 lymphoblasts (25%) or in five out of 21 blastomeres (23.8%). However, within this set-up ADO will never lead to transfer of an affected embryo. A first ICSI-PGD cycle did not result in embryo transfer for the patient. A second cycle involved 10 mature oocytes of which eight were fertilized, resulting in five embryos for biopsy. Two unaffected embryos were available for transfer and resulted in a singleton pregnancy. The genotype of the fetus has been confirmed healthy by chorionic villus sampling.
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PMID:Pregnancy after preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A. 980 80

A female patient was 12 years old when she presented with hemiatrophy and muscle weakness on the right side of her body. Then a stepwise worsening occurred, and at 19 years of age sensory symptoms were also noticed, as well as a mild involvement of the left part of her body. The cerebrospinal fluid (CSF) protein level was elevated without cells. The main electrophysiological abnormality was a marked temporal dispersion of the compound muscle action potentials (CMAPs). Motor nerve conduction velocities were moderately reduced. A superficial peroneal nerve biopsy revealed well-demarcated areas of demyelination with prominent Schwann cell hyperplasia. Neither deletion nor duplication of the PMP22 gene nor mutation of the P0 or connexin 32 genes was found by molecular genetic investigations. Immunotherapy was administered, and over the next 6 years the symptomatology fluctuated. This unusual disorder seems to be a variant of chronic acquired demyelinating polyneuropathy and may be immunologically mediated.
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PMID:Asymmetrical polyneuropathy with a stepwise progressive course and well-demarcated areas of demyelination. 1041 1

Hereditary neuropathy with liability to recurrent pressure-sensitive palsies (HNPP; also called tomaculous neuropathy) is an autosomal dominant disorder that produces an episodic, recurrent demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal-tunnel syndrome, and other entrapment neuropathies are frequent manifestations of this disorder. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. Pathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Because of mild overlap of clinical features with CMT1, HNPP patients may be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies; however, their clinical, pathological, and electrophysiological features are quite distinct. The HNPP locus maps to chromosome 17p11.2-12 and is associated with a 1.5-Mb deletion. DNA markers known to map to the region in 17p11.2-12 associated with the CMT1A duplication, including the PMP22 gene, are deleted in HNPP. The deletion breakpoints in HNPP map to the same intervals in which the CMT1A duplication breakpoints map. In one pedigree, de novo deletion of paternal origin was detected as a basis for sporadic HNPP. HNPP results from deletion of the PMP22 gene and underexpression of this locus, which is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Further support for this hypothesis was provided by the identification of a nondeleted HNPP kindred in which a two base pair deletion and early termination codon within exon 1 of PMP22 was present. The possibility of genetic heterogeneity in HNPP was raised by the identification of an HNPP pedigree that did not demonstrate linkage to the region of 17p11.2-12. Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder causing painful, recurrent brachial plexopathies and maps to chromosome 17q25.
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PMID:Overview of hereditary neuropathy with liability to pressure palsies. 1058 25


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