Browsing by Author "Azevedo, Luisa"
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- Autosomal Recessive Cerebellar Ataxia and Low Mitocondrial Complex III in a Portuguese FamilyPublication . Nogueira, Célia; Nesti, Claudia; Meschini, Maria Chiara; Carrozzo, Rosalba; Barros, Jose; Sá, Maria José; Azevedo, Luisa; Vilarinho, Laura; Santorelli, FilippoIntroduction: Defects of mitochondrial complex III (CIII) are a relatively rare cause of mitochondrial dysfunction. The complex catalyzes the electron transfer from reduced coenzyme Q to cytochrome c and is composed of 11 subunits, one of which (MT-CYB) is mtDNA encoded. Mutations in MT-CYB and in assembly factor BCS1L account for the vast majority of cases with low CIII, and are associated with a wide range of neurological disorders. The gene coding for human tetratricopeptide 19 (TTC19) produces a poorly characterized protein thought to be involved in the correct assembly of CIII. Recently, mutations in TTC19 have been described in three unrelated Italian kindred in association with a severe neurodegenerative disease. Objectives: We studied a consanguineous Portuguese family where a severe neurometabolic disorder occurred in four siblings (three men and one woman) in association with a slowly progressive disorder characterized by dystonia of hands and feet, ataxic gait, severe olivo-ponto-cerebellar atrophy documented at brain MRI, and relentless psychiatric manifestations. Variability in age at onset and disease course was observed. Methods: The enzymatic activity of CIII was determined in muscle using a reported spectrophotometric method. Sequence analysis of genomic DNA was performed to identify disease-causing mutations in TTC19. Immunodetection analysis in muscle homogenate and skin fibroblasts allowed the detection of the amount TTC19 protein using a commercially available anti-TTC19 antibody. Results: In this family, we identified a novel homozygous TTC19 mutation predicting frameshift and early protein truncation. The mutation was heterozygous in parents and healthy siblings, and it was absent in ethnically-matched controls. The protein was undetectable in tissues by Western blot analyses. Conclusion: This is the fourth kindred presenting mutations in TTC19. The clinical phenotype of such condition is severe, embraces neurological and psychiatric symptoms, and represents a further example of autosomal recessive ataxia of metabolic origin.
- Complex III deficiency in a Portuguese family: expanding the clinical phenotypePublication . Nogueira, Célia; Nesti, Claudia; Meschini, M. Clara; Carrozzo, Rosalba; Barros, José; Sá, Maria José; Azevedo, Luisa; Santorelli, Filippo; Vilarinho, Laura
- Identification of a novel TTC19 mutation in a Portuguese family with complex III deficiencyPublication . Nogueira, Célia; Barros, José; Sá, Maria José; Azevedo, Luisa; Santorelli, Filippo; Vilarinho, LauraDefects of mitochondrial complex III (CIII) are a relatively rare cause of mitochondrial dysfunction. CIII or ubiquinol-cytochrome c reductase is the third component of the mitochondrial respiratory chain and catalyzes the electrons transfer from reduced coenzyme Q to cytochrome c and is composed of 11 subunits; one encoded by mitochondrial DNA (MT-CYB) and the remaining by nuclear genes. BCS1L gene is a CIII assembly factor. Mutations in MT-CYB and BCS1L genes account for the vast majority of mutations leading to CIII deficiency, and are associated with a wide range of neuromuscular disorders. The human tetratricopeptide 19 (TTC19), encodes a poorly understood member of tetratricopeptide repeat domain 19 located on chromosome 17 and appears to be involved in the correct assembly of CIII. Recently, mutations in TTC19 have been described in three unrelated Italian kindred in association with a severe neurodegenerative disease. Here we present a consanguineous Portuguese family where a severe biochemical deficiency of complex III enzyme activity occurred in four siblings in association with neurological manifestations suggestive of cerebellar ataxia combined with relentless psychiatric manifestations. Variability in age at onset and disease course was associated with a novel homozygous mutation in TTC19. We had first detected a biochemically deficient enzyme activity in the family, we had analyzed all structural genes part of CIII as well as BCS1L. Only the recent description of mutations in TTC19 raised high the suspect of a similar condition in the present family. The novel TTC19 mutation identified in this family, was homozygous in the four patients, heterozygous in their parents and in two healthy relatives, and it was absent in ethnically-matched controls. The mutation predicts a frameshift, resulting in a truncated protein by the insertion of a premature stop codon. In summary, we are describing the 4th family identified in the world carrying a novel TTC19 mutation. Our data corroborate the genotype and phenotype variability presented by the affected family members and hopefully will contribute to a deeper understanding of the CIII-related disorders.
- Identification of maternal uniparental isodisomy of chromosome 10 in a patient with mitochondrial DNA depletion syndromePublication . Nogueira, Célia; Sales Marques, Jorge; Nesti, Claudia; Azevedo, Luisa; Di Lullo, Martina; Meschini, M. Clara; Santorelli, Filippo; Vilarinho, Laura
- Identification of novel L2HGDH gene mutations and update of the pathological spectrumPublication . Vilarinho, Laura; Tafulo, Sandra; Sibilio, Michelina; Kok, Fernando; Fontana, Federica; Diogo, Luisa; Venâncio, Margarida; Ferreira, Mariana; Nogueira, Celia; Valongo, Carla; Parenti, Giancarlo; Amorim, António; Azevedo, LuisaL-2-hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a neurometabolic disorder caused by the toxic accumulation of high concentration of L-2-hydroxyglutaric acid in plasma and cerebrospinal fluid. Distinct mutations on the L2HGDH gene have been associated with the clinical and biochemical phenotype. Here we present three novel mutations (Gln197X, Gly211Val and c.540+1 G4A), which increase the present deleterious collection of L2HGDH gene up to 35 mutations that we have compiled in this study. In addition, we used the haplotypic information based on polymorphic markers to demonstrate the common origin of Gly57Arg harboring chromosomes.