Browsing by Author "Nogueira, C."
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- "Double trouble” or digenic disorder in Complex I deficiencyPublication . Almeida, L.S.; Ferreira, M.; Nogueira, C.; Furtado, F.; Evangelista, T.; Santorelli, F.M.; Vilarinho, L.Complex I (CI) deficiency is a defect of OXPHOS caused by mutations in the mitochondrial or nuclear genomes. To date disease-causing mutations have been reported in all mitochondrial-encoded subunits and 22 nuclear genes. In about 50% of the patients no mutations are found, suggesting that undiscovered factors are an important cause of disease. In this study we report a consanguineous family from Southern Portugal with three affected children presenting with CI deficiency and 3-methylglutaconic aciduria type IV.
- LPIN1 deficiency: A novel mutation associated with different phenotypes in the same familyPublication . Nunes, D.; Nogueira, C.; Lopes, A.; Chaves, P.; Rodrigues, E.; Cardoso, T.; Leão Teles, E.; Vilarinho, L.Rhabdomyolysis (RM) is characterized by acute and often severe skeletal muscle damage resulting in myoglobinuria and, in severe cases, acute renal failure. In adults is typically due to trauma, intoxication or infection, whereas in children is frequently associated with inherited muscle disorders. LPIN1 mutations were identified as a cause of severe recurrent RM, which usually begin in childhood, and infections are the most frequent trigger.
- Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High LandsPublication . Martins, E.; Marcão, A.; Bandeira, A.; Fonseca, H.; Nogueira, C.; Vilarinho, L.Methionine adenosyltransferase deficienc(MAT I/III deficiency) is an inborn error of metabolism resulting in isolated hypermethioninemia, and usually inherited as an autosomal recessive trait, although a dominant form has been reported in several families. During the last 6 years, approximately 520,000 newborns were screened in the Portuguese Newborn Screening Laboratory by MS/MS, and 21 cases of persistent hypermethioninemia were found. One case was confirmed to be a deficiency of cystathionine b-synthase and 20 cases were confirmed by MAT1A gene analysis to have an elevation of methionine due to MAT I/III deficiency, which indicates an incidence for this condition of 1/26,000. Twelve of the MAT I/III deficient newborns, belonging to 11 families, were identified in the northern region of Portugal and sent to the same treatment center, where they are under follow-up. Clinical, biochemical, and genetic characteristics of individuals from these 11 families are presented. Plasma methionine and homocysteine concentrations were found to be moderately increased in all newborns, and molecular analysis revealed that they all were heterozygous for R264H mutation. Normal growth,development, and neurological examination were observed in all cases, and cerebral MRI performed in six cases revealed myelination abnormalities in one case. Plasma methionine concentration for all 12 cases was always below 300 mM, and they are all on a normal diet for their age.
- Molecular investigation of pediatric portuguese patients with sensorineural hearing lossPublication . Nogueira, C.; Coutinho, M.; Pereira, C.; Tessa, A.; Santorelli, F.M.; Vilarinho, L.The understanding of the molecular genetics in sensorineural hearing loss (SNHL) has advanced rapidly during the last decade, but the molecular etiology of hearing impairment in the Portuguese population has not been investigated thoroughly. To provide appropriate genetic testing and counseling to families, we analyzed the whole mitochondrial genome in 95 unrelated children with SNHL (53 nonsyndromic and 42 syndromic) and searched for variations in two frequent genes, GJB2 and GJB6, in the non- syndromic patients. 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 biallelic GJB2 mutations in 20 of 53 non-syndromic cases and also detected two novel mutations (p.P70R and p.R127QfsX84). Our data further reinforce the notion that genetic heterogeneity is paramount in children with SNHL.
- Molecular picture of cobalamin C/D defects before and after newborn screening eraPublication . Nogueira, C.; Marcão, A.; Rocha, H.; Sousa, C.; Fonseca, H.; Valongo, C.; Vilarinho, L.Objective: Birth prevalence of Cobalamin (Cbl) C or D defects in Portugal is an estimated 1:85,000, one of the highest worldwide. We compared the genotype/phenotype of patients identified with CblC or CblD before and after the implementation of expanded newborn screening. Methods: Twenty-five Portuguese CblC/D patients, 14 symptomatic and 11 identified through screening, were diagnosed using gas chromatography or tandem mass spectrometry. Molecular characterization was performed through the study of MMACHC and MMADHC genes. Results: The most common MMACHC mutation, c.271dupA, was present in 100% of MMACHC alleles of all CblC screened patients, in contrast with the 61% identified before expanded newborn screening. All studied cases (except one, who presented a CblD deficiency) presented a CblC defect. More CblC late-onset patients were diagnosed before the introduction of newborn screening than in the post newborn screening era, probably because some early onset patients died without a definitive diagnosis. Conclusion: The molecular data found in this cohort contribute to the improvement of screening and diagnosis of Cbl defects and would enable a confirmatory diagnosis of these patients, reducing the need for complex, costly, laborious, and time-consuming biochemical/enzymatic tests.
- 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.
- Nuclear-Mitochondrial Intergenomic Communication DisordersPublication . Almeida, L.S.; Nogueira, C.; Vilarinho, L.The focus of this chapter is to review the clinical and molecular etiologies of nuclear defects involved in mtDNA stability and in mitochondrial protein synthesis. The overview done here will hopefully provide insights towards best diagnostic strategies of mitochondrial cross–talk disorders, being useful for clinicians when facing similar cases. Additionally we will present a diagnostic algorithm for these diseases based on our knowledge.