Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0031117 (peripheral neuropathy)
10,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a previous report, we demonstrated that a first generation (E1- and E3-deleted) recombinant adenovirus can transduce expression of the E. coli lacZ gene into Schwann cells, both in vitro and in vivo, suggesting that this method might be useful for future therapy of peripheral neuropathy, including CMT1. Adenoviral-mediated gene transfer was limited, however, by demyelination and Wallerian degeneration at the site of virus injection, as well as by attenuation of viral gene expression over time. In our current work we have optimized adenoviral-mediated gene expression after intraneural injection into sciatic nerve. Using an improved injection protocol, peak expression of lacZ occurs between 10 and 14 days after injection of 2-week-old animals, decreases thereafter, and there is minimal associated tissue injury. In contrast, very few adenoviral-infected Schwann cells are found in nerves of adult animals 10 days after injection, probably due to immune clearance of viral-infected cells. Consistent with this notion, high levels of lacZ are found in sciatic nerve 30 days after injection of adult SCOD mice, which have a genetic defect in both cellular and humoral immunity, of adult beta 2 microglobulin-deficient mice (beta 2 M-/-), which have a genetic defect in cellular immunity, or of adult mice treated with the immunosuppressing agent FK506. In addition, adenoviral-infected Schwann cells co-cultured with axons in vitro, in the absence of a host immune response, ensheath axons and express lacZ for at least 8 weeks. These data thus demonstrate that expression of first generation recombinant adenovirus in sciatic nerve in adult mice, as in other tissues, is limited mainly by the host cellular immune response to the virus, which can be overcome by attenuation of host cell-mediated immunity. Adenoviral vectors might thus be used to modulate Schwann cell gene expression in patients with peripheral neuropathy after appropriate immunosuppression.
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PMID:Overcoming cellular immunity to prolong adenoviral-mediated gene expression in sciatic nerve. 1058 64

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.
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PMID:Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. 1183 75

The Thr(118)Met substitution in the peripheral myelin protein 22 (PMP22) gene has been detected in a number of families with demyelinating Charcot-Marie-Tooth (CMT1) neuropathy or with the hereditary neuropathy with liability to pressure palsy, but in none of them has it consistently segregated with the peripheral neuropathy. We describe here a CMT1 family (a 63-year-old man, his brother and his niece) in which two mutations on different chromosomes were found in the PMP22 gene, the 17p duplication, detected by fluorescent semiquantitative polymerase chain reaction (PCR) of microsatellite markers localized within the duplicated region on chromosome 17p11.2-p12, and the Thr(118)Met substitution, detected by direct sequencing the four coding exons of the PMP22 gene. A genotype/phenotype correlation study showed that the neuropathy segregates with the duplication and that the amino acid substitution does not seem to modify the clinical characteristics or the severity of the peripheral neuropathy. We did not find any evidence to characterize this substitution as a polymorphism in the population studied and we propose that the high frequency reported for this point mutation in the literature suggests that the Thr(118)Met substitution may be a hotspot for mutations in the PMP22 gene.
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PMID:Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication. 1450 74

Charcot-Marie-Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.
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PMID:SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve. 1512 12

The myelin protein 0 (MPZ or P0) is a transmembrane glycoprotein that represents the most abundant myelin component. Mutations in the P0 gene are associated with one form of autosomal dominant demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (CMT1B). Because CMT1 may be associated with renal involvement, mostly focal segmental glomerulosclerosis, we hypothesized that P0 could be expressed in the kidney. P0 mRNA was detected by reverse transcriptase-PCR in the human and mouse renal cortex. P0 transcripts were identified by in situ hybridization at different stages of the mouse kidney development, especially in embryonic structures that give rise to the glomerulus. P0 protein was also detected by Western blot in human and rat glomerular extracts and in a human podocyte cell line using a monoclonal anti-P0 antibody. Immunofluorescence studies on human kidney sections showed that the podocytes were intensely labeled. Immunogold electron microscopy disclosed a predominant staining of the membranes of intracellular vesicles in podocytes. P0 was also detected in the podocyte cell membrane, including at the foot processes. P0(-/-) mice exhibited mild growth retardation and demyelinating neuropathy similar to the one observed in patients with CMT1B. They also presented mild albuminuria, without significant ultrastructural change of the glomerular basement membrane or the podocytes. These results demonstrate that P0, the major myelin protein, is also expressed during nephrogenesis and in mature kidney, mostly in podocytes. They suggest that P0 gene mutations might be involved in renal diseases.
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PMID:Glomerular permeability is altered by loss of P0, a myelin protein expressed in glomerular epithelial cells. 1616 11

Peripheral neuropathies often result in abnormalities in the structure of internodal myelin, including changes in period and membrane packing, as observed by electron microscopy (EM). Mutations in the gene that encodes the major adhesive structural protein of internodal myelin in the peripheral nervous system of humans and mice--P0 glycoprotein--correlate with these defects. The mechanisms by which P0 mutations interfere with myelin packing and stability are not well understood and cannot be provided by EM studies that give static and qualitative information on fixed material. To gain insights into the pathogenesis of mutant P0, we used x-ray diffraction, which can detect more subtle and dynamic changes in native myelin, to investigate myelin structure in sciatic nerves from murine models of hereditary neuropathies. We used mice with disruption of one or both copies of the P0 gene (models of Charcot-Marie-Tooth-like neuropathy [CMT1B] or Dejerine-Sottas-like neuropathy) and mice with a CMT1B resulting from a transgene encoding P0 with an amino terminal myc-tag. To directly test the structural role of P0, we also examined a mouse that expresses P0 instead of proteolipid protein in central nervous system myelin. To link our findings on unfixed nerves with EM results, we analyzed x-ray patterns from unembedded, aldehyde-fixed nerves and from plastic-embedded nerves. From the x-ray patterns recorded from whole nerves, we assessed the amount of myelin and its quality (i.e. relative thickness and regularity). Among sciatic nerves having different levels of P0, we found that unfixed nerves and, to a lesser extent, fixed but unembedded nerves gave diffraction patterns of sufficient quality to distinguish periods, sometimes differing by a few Angstroms. Certain packing abnormalities were preserved qualitatively by aldehyde fixation, and the relative amount and structural integrity of myelin among nerves could be distinguished. Measurements from the same nerve over time showed that the amount of P0 affected myelin's stability against swelling, thus directly supporting the hypothesis that packing defects underlie instability in "live" or intact myelin. Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies.
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PMID:Structure and stability of internodal myelin in mouse models of hereditary neuropathy. 1625 92

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of disorders and is the most common inherited neuromuscular disorder, with an estimated overall prevalence of 17-40/10,000. Although there has been major advances in the understanding of the genetic basis of CMT in recent years, the most useful classification is still a neurophysiological classification that divides CMT into type 1 (demyelinating; median motor conduction velocity < 38 m/s) and type 2 (axonal; median motor conduction velocity > 38 m/s). An intermediate type is also increasingly being described. Inheritance can be autosomal-dominant (AD), X-linked, or autosomal-recessive (AR). AD CMT1 is the most common type of CMT and was the first form of CMT in which a causative gene was described. This review provides an up-to-date overview of AD CMT1 concentrating on the molecular genetics as the clinical, neurophysiological, and pathological features have been covered elsewhere. Four genes (PMP22, MPZ, LITAF, and EGR2) have been described in the last 15 yr associated with AD CMTI and a further gene (NEFL), originally described as causing AD CMT2 can also cause AD CMT1 (by neurophysiological criteria). Studies have shown many of these genes, when mutated, can cause a wide range of CMT phenotypes from the relatively mild CMT1 to the more severe Dejerine-Sottas disease and congenital hypomyelinating neuropathy, and even in some cases axonal CMT2. This review discusses what is known about these genes and in particular how they cause a peripheral neuropathy, when mutated.
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PMID:Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. 1677 66

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy. Administration of vinca alkaloids is considered contraindicated in CMT because of the risk of life threatening acute neuropathy. We describe a 5-year-old patient with a family history of X-linked CMT1 who presented with Wilms tumour. Despite confirmation of a connexin 32 point mutation, the patient was treated with 40.5 mg/m(2) of vincristine with no clinical evidence of drug-related neuropathy. This case describes vincristine being safely administered to a patient with molecularly proven type CMT 1X, but in type 1A CMT vincristine is still contraindicated. An extensive literature review revealed no other series of cases in which vincristine administration in molecularly proven CMT 1X had been described. CMT should be excluded in any patient who develops a profound, acute neuropathy following vincristine, as many patients in the cases reviewed were asymptomatic prior to treatment.
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PMID:Uneventful administration of vincristine in Charcot-Marie-Tooth disease type 1X. 1751 37

Charcot-Marie-Tooth (CMT) is a common inherited peripheral neuropathy with a prevalence of 1 in 2,500. CMT has two distinct forms (CMT1 and CMT2) that can be identified electrophysiologically. A 1.5 Mb tandem microduplication including peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2-12 causes CMT1A. The increased gene dosage effect of PMP22 is thought to be responsible for the pathogenesis of CMT1A. In this study, 39 Turkish CMT1A patients and 60 unrelated control samples had been examined for the duplication using polymorphic short tandem repeat (STR) markers. Seven STR marker sites (AC005838-4A-, AC0013248-9A-, AC0013248-9B-, D17S2218, D17S2220, D17S2227, and D17S2229) on the duplicated region were amplified via polymerase chain reaction, electrophoresed through 8% polyacrilamide gel and evaluated for the duplication. The rate of duplication was 92.3' (36/39) in the patients whereas it was zero in the control samples. Allele distributions, number of alleles and heterozygosity values of more informative markers (D17S2218, D17S2220, D17S2227, and D17S2229) were assessed. It is found that approximately 85% of duplications in Turkish CMT1A patients were depicted by using D17S2220 and D17S2229 markers together.
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PMID:Duplication analysis in Turkish Charcot-Marie-Tooth type 1A patients using short tandem repeat markers. 1791 30

X-linked Charcot-Marie-Tooth disease (CMT1X) is a peripheral neuropathy transmitted in a dominant manner and caused by mutations in the Connexin 32 (Cx32) gene (GJB1, gap junction beta 1). Here we report the mutation analysis of the GJB1 gene in 76 subjects with possible CMT1 and absence of 17p11.2 duplication, and in 38 CMT2 patients without mutations in CMT2-associated-genes, selected from a cohort of 684 patients with peripheral sensory-motor neuropathy. The analysis was performed by direct sequencing of the coding sequence and exon/intron boundaries of the GJB1 gene. The mutation screening identified 22 mutations in GJB1, eight of which have not been previously published: six point mutations (c.50C > G, c.107T > A, c.545C > T, c.545C > G, c.548G > C, c.791G > T) and two deletions (c.84delC, c.573_581delCGTCTTCAT). The GJB1 mutation frequency (19.3%) and the clinical heterogeneity of our patients suggest searching for GJB1 mutations in all CMT cases without the 17p11.2 duplication, regardless of the gender of the proband, as well as in CMT2 patients with possible X-linked inheritance.
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PMID:Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease. 1837 23


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