1,721,007 research outputs found
Reply: Novel peripheral myelin protein 22 (PMP22) micromutations associated with variable phenotypes in Greek patients with Charcot–Marie–Tooth disease
No full text[no abstract available
Axonal neuropathy due to myelin protein zero mutation misdiagnosed as amyloid neuropathy
No full textIn up to 50% of chronic idiopathic axonal neuropathies, an underlying diagnosis may be identified, including hereditary neuropathy. Charcot-Marie-Tooth disease (CMT) is clinically and genetically heterogeneous. Several mutations in the myelin protein zero (MPZ) gene have been associated with different CMT phenotypes, including classical demyelinating CMT1B and the axonal form of the disease. Primary amyloidosis, a rare disease where the amyloid is formed by the N-terminal portion of a monoclonal immunoglobulin light chain, may be complicated by polyneuropathy. We report a patient who was incorrectly diagnosed with amyloid neuropathy, but was found to have axonal CMT1B only after sural nerve biopsy ruled out an acquired amyloid neuropathy
Expression and regulation of glial-cell-line-derived neurotrophic factor (GDNF) mRNA in human astrocytes in vitro
No full textThe expression and modulation of mRNA for glial-cell-line-derived neurotrophic factor (GDNF) in human glial cells was investigated. Astrocyte cell cultures were isolated from human fetal brains, characterized by immunocytochemistry and maintained in vitro in conditions of high purity; sister cultures were exposed to protein kinase C (PKC) inhibitors for 20 min. Total RNA was extracted from the cell pellets, reverse-transcribed into cDNA and amplified by the polymerase chain reaction (PCR) with primers specific for GDNF. A reverse-transcription/PCR procedure was also performed on mRNA extracted from human fibroblast and lymphocyte cell lines. Human astrocytes grown in the absence of neurons expressed detectable amounts of mRNA for GDNF but no amplification products were observed in fibroblasts and lymphocytes, thus confirming that GDNF production was cell-type specific. After exposure to PKC inhibitors, a dramatic down-regulation of GDNF mRNA was observed in astrocyte cell cultures. Thus, human astrocytes are constitutively capable of producing GDNF, such trophic activity is restricted to neural cells, and PKC plays key roles in signal pathways that regulate the gene activation and production of GDNF
Gonosomal mosaicism of a novel heterozygous mutation of P0 causes Charcot-Marie-Tooth neuropathy type 1B with apparent autosomal recessive inheritance
No full textCharcot-Marie-Tooth neuropathy type 1 (CMT1) is the most common inherited demyelinating neuropathy. It has autosomal dominant inheritance associated with heterozygous mutations in the genes coding the peripheral myelin protein 22 (PMP22), the myelin protein zero (P0) and the early growth response 2 (EGR2) transcription factor. More severe, usually sporadic de-hypomyelinating neuropathies of infancy are classified as Dejerine-Sottas syndrome (DSS). Since the original description by Dejerine and Sottas of two affected siblings born of unaffected parents, DSS has long been considered to be autosomal recessive, but it is now known that DSS is also caused by heterozygous mutations that originate de novo in the forementioned genes. True autosomal recessive, usually severe, demyelinating neuropathies are rare and associated with still unknown genes. Two sisters born of unaffected parents suffered from a severe de-remyelinating neuropathy of infancy consistent with CMT1. Both patients carried a novel heterozygous G308→A transition of P0 without any additional mutation of PMP22 and EGR. The mutation is predicted to cause a Gly74→Glu substitution in the extracellular domain of P0 (P0ex). Gly74Glu is pathogenic because: it was absent in healthy controls; it changes a phylogenetically conserved residue; it is functionally non-conservative; based on the P0ex crystal, it is predicted to be structurally incompatible with the normal β-sheet conformation of P0ex. The healthy mother carried a minor proportion of the G308→A transition in white blood cells (=20 %), fibroblasts, buccal smear and hairs (=30%). We concluded that she is actually a gonosomal mosaic harboring clones of mutant somatic and germline cells. The Gly74→Glu substitution originated early in the embryogenesis of the mother, before the commitment to germ cells
X-linked dominant Charcot-Marie Tooth neuropathy: analysis of a pedigree with a novel mutation of connexin32
No full textAdult onset charcot-marie-tooth disease type 1D with an Arg381Cys mutation of EGR2.
No full textno abstract availabl
Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22
No full textBACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0
Malattia di Charco-Marie-Tooth. Guida alla diagnosi molecolare.
No full textLa malattia di Charcot-Marie-Tooth (CMT) è la patologia genetica più frequente del sistema nervoso periferico. La diagnosi molecolare è essenziale per il counselling genetico, per la diagnosi differenziale con neuropatie acquisite fenotipicamente convergenti, nonché un prerequisito per terapie sperimentali mirate ai meccanismi patogenetici. Gli ultimi anni hanno registrato il moltiplicarsi dei fenotipi CMT e dei geni associati. Gli autori passano in rassegna le recenti acquisizioni della genetica ed illustrano i possibili percorsi clinici che orientino i tests molecolari
Deoxysphingolipids as candidate biomarkers for a novel SPTLC1 mutation associated with HSAN-I
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