Browsing by Author "Santorelli, F.M."
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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.
- 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.
- 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.
- Novel mutation in the mitochondrial transfer RNACys gene in a childPublication . Almeida, L.S.; Martins, E.; Santorelli, F.M.; Vilarinho, L.Mitochondrial DNA (mtDNA) disorders are an important group of genetic diseases presenting with a multifacet array of clinical manifestations. Highly energy-dependent tissues such as central nervous system and skeletal and cardiac muscles are commonly involved either as multisystem or as isolated organ disease. Characteristic symptoms include epilepsy, myopathy, deafness and ophthalmoplegia, all associated with point mutations in the mtDNA. Pathogenic mtDNA mutations can be heteroplasmic or homoplasmic. Heteroplasmic mutations are typically associated with mutations in mt-tRNA genes. Mutations in mt-tRNAs genes are responsible for the majority of the presentations of a mitochondrial disease being associated with marked clinical heterogeneity. Although tRNA-encoding genes make up only 9% of the entire mitochondrial genome, over 40% of all point mutations reported in the mtDNA are located in tRNA genes. Here, we present a child with vomiting episodes and migraine in whom we found a novel variant in the mitochondrial tRNACys gene.
- 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
- Relative frequency of known causes of multiple mtDNA deletions: two novel POLG mutationsPublication . Ferreira, M.; Evangelista, T.; Almeida, L.S.; Martins, J.; Macario, M.C.; Martins, E.; Moleirinho, A.; Azevedo, L.; Vilarinho, L.; Santorelli, F.M.Diseases affecting mtDNA stability, termed nuclear–mitochondrial intergenomic communication disorders, are caused by a primary nuclear gene defect resulting in multiple mtDNA deletions. The aim of this study was to estimate the frequency of known etiologies and the spectrum of mutations in a cohort of 21 patients harboring multiple mtDNA deletions in skeletal muscle. We showed that 10 cases (48%) display mutations in POLG, including eight previously reported variants and two novel mutations (namely, p.Trp585X and p.Arg1081Gln). The novel mutations affect evolutionary conserved residues and were absent in a large set of control chromosomes. These findings expand the array of mutations associated with multiple rearranged mtDNA attributed to mutations in POLG. The relatively high diagnostic yield (about one in two cases) supports the notion that it is recommended to test POLG routinely in diagnostic laboratories whenever multiple mtDNA deletions are present, regardless of the age of onset of patients and their clinical phenotype.
- Syndromes associated with mitochondrial DNA depletionPublication . Nogueira, Célia; Almeida, Ligia S.; Nesti, C.; Pezzini, I.; Videira, A.; Vilarinh, Laura; Santorelli, F.M.Mitochondrial dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) and, consequently, deficient energy production. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. This impaired cross-talk gives rise to so-called nuclear-mitochondrial intergenomic communication disorders, which result in loss or instability of the mitochondrial genome and, in turn, impaired maintenance of qualitative and quantitative mtDNA integrity. In children, most MRC disorders are associated with nuclear gene defects rather than alterations in the mtDNA itself.The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of transmission that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. The MDSs can be divided into least four clinical presentations: hepatocerebral, myopathic, encephalomyopathic and neurogastrointestinal. The focus of this review is to offer an overview of these syndromes, listing the clinical phenotypes, together with their relative frequency, mutational spectrum, and possible insights for improving diagnostic strategies.