Biomedical subjects

A Spinazzola

Publications and source records attributed to A Spinazzola.

At least 19 recordsLinked to original sources

PubMed2001

MNGIE: from nuclear DNA to mitochondrial DNA.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a unique autosomal recessive disorder with mitochondrial DNA alterations. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Muscle biopsies typically reveal mitochondrial abnormalities including ragged-red fibers and focal cytochrome c oxidase deficiency. Analysis of mitochondrial DNA in skeletal muscle shows partial depletion, multiple deletions, or both. To identify the cause of MNGIE, we mapped the disease locus to chromosome 22q13.32-qter. Within this region, we identified the gene encoding thymidine phosphorylase as the MNGIE gene. We have identified homozygous or compound-heterozygous thymidine phosphorylase gene mutations in 35 MNGIE patients (21 families) from diverse ethnic groups, including: Ashkenazi Jewish, Western European, Jamaican, Hispanic, and Japanese. We confirmed pathogenicity of the mutations by a spectrophotometric assay of thymidine phosphorylase activity with peripheral leukocytes of 15 MNGIE patients. Thymidine phosphorylase enzymatic activity was severely reduced, thus enabling us to conclude that the loss-of-function mutations in thymidine phosphorylase gene cause MNGIE. Thymidine phosphorylase catabolizes thymidine to thymine. In agreement with this notion, we noted that plasma thymidine level is increased more than 20-fold in MNGIE patients compared to controls. Therefore, we have hypothesized that increased thymidine causes mitochondrial nucleotide pool imbalance which, in turn, leads to motochondrial DNA alterations, via a mitochondria-specific thymidine salvage pathway. The identification of the MNGIE gene has allowed us to classify MNGIE as a disease of nucleoside dysmetabolism. We may be entering a new era of research on mitochondrial nucleoside metabolism.

Chromosomes, Human, Pair 22↗

PubMed2000

Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo-obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26-58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 +/- 0.021 micromol/hr/mg (mean +/- SD; n = 16), compared with controls, 0.67 +/- 0.21 micromol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both.

Adult↗

PubMed1999

A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13.

OBJECTIVE: To characterize a kindred with a distinctive autosomal dominant neuromuscular disorder. BACKGROUND: The authors studied a large Italian family affected by a progressive neuromyopathy. Ten individuals over three generations were affected. The disease was characterized by onset from the late teens to early 50s with distal leg weakness and atrophy, development of generalized muscle weakness with distal-to-proximal progression sparing facial and ocular muscles, dysphonia and dysphagia, pes cavus and areflexia, variable clinical expression ranging from subclinical myopathy to severely disabling weakness, and mixed neurogenic and myopathic abnormalities on electromyography. METHODS: Morphologic, immunocytochemical, and ultrastructural studies were performed in muscle biopsies from three affected patients. A genomewide linkage analysis through the genotyping of 292 microsatellite markers spanning the 22 autosomes was undertaken to map the disorder segregating in this family. RESULTS: All muscle biopsies showed variation of fiber size, panesterase-positive angular fibers, mild to severe fibrosis, and numerous "rimmed vacuoles." Electron microscopy failed to demonstrate the nuclear or cytoplasmic filamentous inclusions specific of inclusion-body myopathies and, accordingly, immunohistochemistry did not show any positivity with SMI-31 antibodies detecting hyperphosphorylated tau. Preliminary analysis of 292 microsatellite markers provided evidence for linkage to chromosome 19p13. CONCLUSIONS: This distinctive autosomal dominant disorder is characterized by a vacuolar neuromyopathy. Localization to chromosome 19p13 will allow the genetic relationship between this disease and inherited myopathies with rimmed vacuoles, in particular autosomal dominant inclusion-body myopathies, to be defined.

Adult↗

PubMed1999

Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene.

A T --> G mutation at position 8993 in human mitochondrial DNA is associated with the syndrome neuropathy, ataxia, and retinitis pigmentosa and with a maternally inherited form of Leigh's syndrome. The mutation substitutes an arginine for a leucine at amino acid position 156 in ATPase 6, a component of the F0 portion of the mitochondrial ATP synthase complex. Fibroblasts harboring high levels of the T8993G mutation have decreased ATP synthesis activity, but do not display any growth defect under standard culture conditions. Combining the notions that cells with respiratory chain defects grow poorly in medium containing galactose as the major carbon source, and that resistance to oligomycin, a mitochondrial inhibitor, is associated with mutations in the ATPase 6 gene in the same transmembrane domain where the T8993G amino acid substitution is located, we created selective culture conditions using galactose and oligomycin that elicited a pathological phenotype in T8993G cells and that allowed for the rapid selection of wild-type over T8993G mutant cells. We then generated cytoplasmic hybrid clones containing heteroplasmic levels of the T8993G mutation, and showed that selection in galactose-oligomycin caused a significant increase in the fraction of wild-type molecules (from 16 to 28%) in these cells.

Adenosine Triphosphatases↗

PubMed1999

Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease associated with multiple deletions of skeletal muscle mitochondrial DNA (mtDNA), which have been ascribed to a defect in communication between the nuclear and mitochondrial genomes. Examination of 12 MNGIE probands revealed homozygous or compound-heterozygous mutations in the gene specifying thymidine phosphorylase (TP), located on chromosome 22q13.32-qter. TP activity in leukocytes from MNGIE patients was less than 5 percent of controls, indicating that loss-of-function mutations in TP cause the disease. The pathogenic mechanism may be related to aberrant thymidine metabolism, leading to impaired replication or maintenance of mtDNA, or both.

Amino Acid Sequence↗

PubMed1996

A novel mitochondrial DNA point mutation in the tRNA(Ile) gene is associated with progressive external ophtalmoplegia.

We report a new mutation, a T-->C transition at nt.4285 in the mitochondrial tRNA(Ile) gene, in a sporadic case of progressive external ophtalmoplegia (PEO) and ragged-red fibers (RRF). The mutation, involving a highly conserved base-pair in the anticodon stem, was detected in high percentages (91%) in muscle, but not in blood. It has never been reported in literature in normal subjects and it was not found in any of 80 controls studied in our laboratory. The absence of the mutation in leukocytes in this case with pure muscle involvement confirms the importance of performing mtDNA studies in PEO patients preferentially on muscle rather than blood, which could give false negative results. Other mutations in the tRNA(Ile) gene associated with different phenotypes have been previously reported. Thus, tRNA(Ile) gene is confirmed to be another "hot spot" region for mtDNA mutations.

Adolescent↗

PubMed1979

Axillofemoral bypass: intrapleural method.

A new procedure for intrapleural axillary-bilateral femoral bypass is described. This method is proposed as an alternative procedure for bypassing aortoiliac occlusive disease in the high-risk patient.

Aged↗

PubMed1977

[Environmental dust in a plant for the production of polyvinyl chloride].

The results of an investigation on environmental dust concentration and individual dust exposure in a drying and sacking section of an "emulsion" and "suspension" PVC plant are reported; data on environmental concentration and individual dust exposure have been obtained by gravimetric techniques using similar personal and static dust samplers. Morphology and particle size distribution have been studied by electron microscopy on airborne dust specimens. Morphological analysis showed remarkable differences concerning shape and size between particles sampled in the "suspension" polymer and "emulsion" polymer sacking sections. Remarkably high mean values concerning dustness have been observed: 1.30 mg/m3 (min. 0.15; max. 18.4 mg/m3) for environmental concentration and 5.39 mg/m3 (min. 0.28; max. 45.6 mg/m3) for individual exposure.

Air Pollutants↗

PubMed1974