Percorrer por autor "Meschini, M.C."
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- Identification of maternal uniparental isodisomy of chromosome 10 in a patient with mitochondrial DNA depletion syndromePublication . Nogueira, Célia; Marques, J.S.; Nesti, C.; Azevedo, A.; Di Lullo, M.; Meschini, M.C.; Orlacchio, A.; Videira, A.; Santorelli, F.M.; Vilarinho, L.Introduction: Twinkle, the mitochondrial helicase encoded by C10orf2, serves a key function in mtDNA replication and its mutations associated with a broad spectrum of clinical conditions characterized by qualitative or quantitative defects of mtDNA, including infantile-onset spinocerebellar ataxia (IOSCA), progressive external ophthalmoplegia, and the hepatocerebral mtDNA depletion syndrome (MDS). The signs in IOSCA demonstrate a fairly distinct pattern. Among these, peripheral neuropathy seems to be the most common presenting feature in C10orf2 defects.
- A Novel SUCLA2 Mutation in a Portuguese Child Associated With "Mild" Methylmalonic AciduriaPublication . Nogueira, Célia; Meschini, M.C.; Nesti, C.; Garcia, P.; Diogo, L.; Valongo, C.; Costa, R.; Videira, A.; Vilarinho, L.; Santorelli, F.M.Succinyl-coenzyme A synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and adenosine triphosphate (ATP) from succinyl-coenzyme A and adenosine diphosphate (ADP) in the tricarboxylic acid cycle. This enzyme is made up of α and β subunits encoded by SUCLG1 and SUCLA2, respectively. We present a child with severe muscular hypotonia, dystonia, failure to thrive, sensorineural deafness, and dysmorphism. Metabolic investigations disclosed hyperlactacidemia, moderate urinary excretion of methylmalonic acid, and elevated levels of C4-dicarboxylic carnitine in blood. We identified a novel homozygous p.M329V in SUCLA2. In cultured cells, the p.M329V resulted in a reduced amount of the SUCLA2 protein, impaired production of mitochondrial ATP, and enhanced production of reactive oxygen species, which was partially reduced by using 5-aminoimidazole-4-carboxamide ribonucleotide in the culture medium. Expanding the array of SUCLA2 mutations, we suggested that reactive oxygen species scavengers are likely to impact on disease prognosis.
- Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiencyPublication . Nogueira, C.; Barros, J.; Sá, M.J.; Azevedo L, L.; Taipa, R.; Torraco, A.; Meschini, M.C.; Verrigni, D.; Nesti, C.; Rizza, T.; Teixeira, João Paulo; Carrozzo, R.; Pires, M.M.; Vilarinho, L.; Santorelli, F.M.Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo-ponto-cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.
- Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1Publication . Ferreira, M.; Torraco, A.; Rizza, T.; Fattori, F.; Meschini, M.C.; Castana, C.; Go, N.E.; Nargang, F.E.; Duarte, M.; Piemonte, F.; Dionisi-Vici, C.; Videira, A.; Vilarinho, L.; Santorelli, F.M.; Carrozzo, R.; Bertini, E.We present clinical, neuroimaging, and molecular data on the identification of a new homozygous c.1783A>G (p.Thr595Ala) mutation in NDUFS1 in two inbred siblings with isolated complex I deficiency associated to a progressive cavitating leukoencephalopathy, a clinical and neuroradiolog- ical entity originally related to unknown defects of the mitochondrial energy metabolism. In both sibs, the muscle biopsy showed severe reduction of complex I enzyme activity, which was not obvious in fibroblasts. We also observed complex I dysfunction in a Neurospora crassa model of the disease, obtained by insertional mutagenesis, and in patient fibroblasts grown in galactose. Altogether, these results indicate that the NDUFS1 mutation is responsible for the disease and complex I deficiency. Clinical presentation of complex I defect is heterogeneous and includes an ample array of clinical phenotypes. Expanding the number of allelic variants in NDUFS1, our findings also contribute to a better understanding on the function of complex I