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 (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 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.
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PMID:Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. 918 52

Concurrence of myasthenia gravis (MG) and Charcot-Marie-Tooth type 1 (CMT1A) neuropathy is rare. We describe a 60-year-old woman with MG and genetically proved CMT1A. The fluctuating ocular symptoms and proximal limb weakness were markedly improved by pyridostigmine treatment. Recognition of the possible association of MG and CMT1A in the same patient is important because the therapeutic result is rewarding.
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PMID:Myasthenia gravis and Charcot-Marie-Tooth disease type 1A: an unusual combination of diseases. 934 65

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

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

The proband was a 38 year old mother, who had begun to walk abnormally at one year old. She developed weakness and wasting in the intrinsic hand muscles in the third decades. On neurological examinations, she showed weakness with atrophy in the distal muscles of the upper and lower limbs, mild impairment of deep sensation in the feet, and severe spastic gait with scissoring. Deep tendon reflexes were hypoactive in the arms and at the ankles, and brisk at the knees. Babinski sign was present bilaterally. Nerve conduction studies revealed mild slowing of conduction velocities and reduction of muscle and sensory action potential amplitudes. Sural nerve biopsy showed a prominent decrease in myelinated fiber density, especially in the large fibers. Neither demyelination nor typical onion-bulb was found. Results of gene analysis of PMP-22 was negative. Her two daughters, 14- and 11-year-old, respectively, also presented with gait disturbance from the beginning of walking at one year old and had almost the same clinical manifestations as their mother, indicating autosomal dominant inheritance. This family of the hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V) was distinctive in having phenotypic uniformity including onset in early childhood.
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PMID:[A family of hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V) presenting with phenotypic uniformity including onset in early childhood]. 1058 15

Charcot-Marie-Tooth disease (CMT) is characterized by distal muscle weakness and wasting, often resulting in foot deformities and gait disturbances, distal sensory impairment and by more or less typical changes in sural nerve biopsy. CMT type 1 is also characterized by reduced nerve conduction velocities. For these demyelinating subtypes, most frequently a 1.5 Mb tandem duplication in chromosome 17p11.2-12 comprising the gene for the peripheral myelin protein 22 (PMP22) is observed (CMT1A), but point mutations in PMP22 have also rarely been reported. X-linked, dominant CMTX1 disease is the second most common type of these hereditary motor and sensory neuropathies (HMSN). Mutations in the X chromosomal gene Connexin32 (Cx32) synonymous gap junction beta-1 (GJB1) are detectable in most X-linked CMT families. We report a novel missense mutation--Tyr65His--in the first extracelullar domain of the Cx32 gene in a Czech CMTX1 family. The mutation was not detectable in 50 healthy controls. The clinical phenotype in both the male proband and his mother was moderate with pronounced peroneal weakness and foot drop. Nerve conduction velocities were intermediately decreased (31-38 m/s) in both patients and slowing of central acoustic conduction (BAEP) was found in both the son and the mother whereas visual central conduction slowing (VEP) was detectable only in the son.
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PMID:Charcot-Marie-Tooth type X: A novel mutation in the Cx32 gene with central conduction slowing. 1156 88

Charcot-Marie-Tooth disease type 1A is a dominantly inherited demyelinating disorder of the peripheral nervous system. It is most frequently caused by overexpression of peripheral myelin protein 22 (PMP22), but is also caused by point mutations in the PMP22 gene. We describe a new transgenic mouse model (My41) carrying the mouse, rather than the human, pmp22 gene. The My41 strain has a severe phenotype consisting of unstable gait and weakness of the hind limbs that becomes obvious during the first 3 weeks of life. My41 mice have a shortened life span and breed poorly. Pathologically, My41 mice have a demyelinating peripheral neuropathy in which 75% of axons do not have a measurable amount of myelin. We compare the peripheral nerve pathology seen in My41 mice, which carry the mouse pmp22 gene, with previously described transgenic mice over-expressing the human PMP22 protein and Trembler-J (TrJ) mice which have a P16L substitution. We also look at the differences between CMT1A duplication patients, patients with the P16L mutation and their appropriate mouse models.
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PMID:Comparison of a new pmp22 transgenic mouse line with other mouse models and human patients with CMT1A. 1209 Apr 4

Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with pressure palsies (HNPP) are two frequent hereditary motor and sensory neuropathies. CMT is characterized by slowly progressive weakness and atrophy, primarily in peroneal and distal leg muscles. The most frequent form, CMT1A, is due, in most cases, to the duplication of a 1.5 Mb region on chromosome 17p11.2 containing the peripheral myelin protein 22 gene (PMP22). The phenotype seems to result from dosage of the PMP22 gene. This hypothesis is reinforced by the existence of HNPP, which is clinically characterized by various recurrent truncular palsies or sensory loss precipitated by minor trauma, which is caused by deletion of the same 1.5 Mb region in 17p11.2. In clinical practice, the detection of the duplication or the deletion in 17p11.2, which permits a positive diagnosis, is still performed by time consuming methods (Southern blot or various combinations of molecular tools). We developed a method for the rapid detection of 17p11.2 rearrangements, using "direct FISH" and PRINS analyses, which does not require cell culture. In a prospective study of 92 patients with CMT and 38 with suspected HNPP, we compared this new technique to classical strategies like Southern blot. The results demonstrate the high sensitivity and specificity of the new FISH technique for the diagnosis of CMT1A and HNPP. Moreover, because of its simplicity and rapidity, this technique provides a useful alternative to the molecular approaches that have been used to diagnose segmental aneusomies, especially in the case of duplications that often go undetected.
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PMID:Rapid detection of 17p11.2 rearrangements by FISH without cell culture (direct FISH, DFISH): a prospective study of 130 patients with inherited peripheral neuropathies. 1260 39


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