Browsing by Author "Santorelli, Filippo"
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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.
- Biochemical data as important clues for diagnosis of SUCLA2 defectsPublication . Nogueira, Célia; Garcia, Paula; Diogo, Luisa; Valongo, Carla; Santorelli, Filippo; Vilarinho, Laura
- 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
- Infantile-Onset Disorders of Mitochondrial Replication and Protein SynthesisPublication . Nogueira, Célia; Carrozzo, Rosalba; Vilarinho, Laura; Santorelli, FilippoMost inherited mitochondrial diseases in infants result from mutations in nuclear genes encoding proteins with specific functions targeted to the mitochondria rather than primary mutations in the mitochondrial DNA (mtDNA) itself. In the past decade, a growing number of syndromes associated with dysfunction resulting from tissue-specific depletion of mtDNA have been reported in infants. MtDNA depletion syndrome is transmitted as an autosomal recessive trait and causes respiratory chain dysfunction with prominent neurological, muscular, and hepatic involvement. Mendelian diseases characterized by defective mitochondrial protein synthesis and combined respiratory chain defects have also been described in infants and are associated with mutations in nuclear genes that encode components of the translational machinery. In the present work, we reviewed current knowledge of clinical phenotypes, their relative frequency, spectrum of mutations, and possible pathogenic mechanisms responsible for infantile disorders of oxidative metabolism involved in correct mtDNA maintenance and protein production.
- Molecular investigation of pediatric Portuguese patients with sensorineural hearing lossPublication . Nogueira, Célia; Coutinho, Miguel; Pereira, Cristina; Tessa, Alessandra; Santorelli, Filippo; Vilarinho, LauraIntroduction Sensorineural hearing loss (SNHL) is one of the most common disabilities in human, and genetics is an important aspect in research and clinical practice for SNHL. One in 1000 children is born with bilateral SNHL, and 50-70% of them have monogenic causes for their deafness. Hereditary hearing loss can be classified into syndromic and nonsyndromic depending on the associated features. Whilst over 400 genetic syndromes have been described in association with mono- or bilateral deafness, syndromic conditions account for about 30% of hereditary congenital hearing loss whereas the relative contribution to all deaf people is much higher (>70%) for nonsyndromic subtypes. The understanding of the molecular genetics in SNHL has advanced rapidly during the last decade but the molecular etiology of hearing impairment in the Portuguese population has not been investigated thoroughly. Methods We analyzed the whole mitochondrial genome in 95 unrelated children with SNHL (53 non-syndromic and 42 syndromic) and searched for variations in two frequent mutated genes, GJB2 and GJB6, in the non-syndromic patients. Results Mutations in mtDNA were detected in 4.2% of the cases, including a hitherto undescribed change in the mtDNA-tRNATrp gene (namely, m.5558A>G). We also identified mono- or bi-allelic GJB2 mutations in 20 of 53 non-syndromic cases and also detected two novel mutations (p.P70R and p.R127QfsX84). Discussion Our data suggest that analysis of the GJB2 gene may have clinical implications in the diagnosis of deaf Portuguese children. Also, it would make feasible early rehabilitation and prevention in affected families. The relatively higher incidence of mtDNA mutation also suggests that screening for variations in the mitochondrial genome should always be considered unless mitochondrial inheritance can be excluded for certain. The molecular diagnosis will permit more accurate genetic counseling for family members, monitor possible multisystem complications, and avoid usage of aminoglycosides if infections occur.
- MPV17: fatal hepatocerebral presentationPublication . Nogueira, Célia; Souza, Carolina; Husny, Antonette; Derks, Terry; Santorelli, Filippo; Vilarinho, Laura
- MPV17: fatal hepatocerebral presentation in a Brazilian infantPublication . Nogueira, Célia; Souza, Carolina; Husny, A.; Derks, Terry; Santorelli, Filippo; Vilarinho, Laura
- A novel missense mutation in SUCLA2 associated with mild methylmalonic aciduriaPublication . Nogueira, Célia; Garcia, Paula; Diogo, Luisa; Valongo, Carla; Santorelli, Filippo; Vilarinho, LauraIntroduction Succinyl CoA synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and ATP or GTP from succinyl-CoA and ADP in the tricarboxylic acid cycle (TCA). This enzyme is made up of two subunits, α and β, encoded by SUCLG1 and SUCLA2, respectively. The clinical features of patients with mutations in SUCLA2 include early childhood hypotonia, developmental delay, and almost invariably, progressive dystonia and sensorineural deafness. Mutations in SUCLA2 and SUCLG1 cause an encephalomyopathic form of infantile mtDNA depletion syndrome. A useful diagnostic clue in succinyl CoA synthase disorders is a ‘‘mildly’’ elevated urinary methylmalonic acid (MMA), and presence of TCA intermediates. To date, two patients with SUCLG1 mutations have been reported, whereas mutations in SUCLA2 have been reported in 17 patients. We here present an additional patient with a novel SUCLA2 mutation. Methods We report a 17-month-old-boy, who presented severe muscular hypotonia, failure to thrive, developmental delay, weight loss during a gastroenteritis crises, dysmorphisms and muscular atrophy. A clinical investigation disclosed hyperlactacidemia together with moderate excretion of MMA and elevated C4-dicarboxylic carnitine. Sequencing analysis of SUCLA2 and SUCLG1 was performed using standard methods. Results Mutation analysis of SUCLA2 revealed a homozygous c.985A>G mutation in exon 8 (p.M329V). This missense mutation affects an amino acid that is highly conserved in different species and was not found in controls. The analysis by bioinformatics tools also confirmed a pathogenic mutation. Discussion The clinical and biochemical phenotype of our patient is strikingly similar to other reported patients with SUCLA2 mutations. In addition, the mildly elevated levels of methylmalonate and lactate raised the suspicion of this disease. Our study contributed to expand the spectrum of patients with SUCLA2 mutations, and will be important for an accurate genetic counseling and a prenatal diagnosis to the affected family.