Browsing by Author "Vilarinho, L."
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- Characterization of mitochondrial proteome in a severe case of ETF-QO deficiencyPublication . Rocha, H.; Ferreira, R.; Carvalho, J.; Vitorino, R.; Santa, C.; Lopes, L.; Gregersen, N.; Vilarinho, L.; Amado, F.Multiple acyl-CoA dehydrogenase deficiency (MADD) is a mitochondrial fatty acid oxidation disorder caused by mutations that affect electron transfer flavoprotein (ETF) or ETF:ubiquinone oxidoreductase (ETF-QO) or even due to unidentified disturbances of riboflavin metabolism. Besides all the available data on the molecular basis of FAO disorders, including MADD, the pathophysiological mechanisms underlying clinical phenotype development, namely at the mitochondrial level, are poorly understood. In order to contribute to the elucidation of these mechanisms, we isolated mitochondria from cultured fibroblasts, from a patient with a severe MADD presentation due to ETF-QO deficiency, characterize its mitochondrial proteome and compare it with normal controls. The used approach (2-DE-MS/MS) allowed the positive identification of 287 proteins in both patient and controls, presenting 35 of the significant differences in their relative abundance. Among the differentially expressed are proteins associated to binding/folding functions, mitochondrial antioxidant enzymes as well as proteins associated to apoptotic events. The overexpression of chaperones like Hsp60 or mitochondrial Grp75, antioxidant enzymes and apoptotic proteins reflects the mitochondrial response to a complete absence of ETF-QO. Our study provides a global perspective of the mitochondrial proteome plasticity in a severe case of MADD and highlights the main molecular pathways involved in its pathogenesis.
- Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD databasePublication . Betsalel, O.T.; Rosenberg, E.H.; Almeida, L.S.; Kleefstra, T.; Schwartz, C.E.; Valayannopoulos, V.; Abdul-Rahman, O.; Poplawski, N.; Vilarinho, L.; Wolf, P.; den Dunnen, J.T.; Jakobs, C.; Salomons, G.S.The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n¼18) or to cause erroneous splicing (n¼7), with the exception of a pathogenic de novo 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.
- Clinical presentation and outcome in a series of 88 patients with the cblC defectPublication . Fischer, S.; Huemer, M.; Baumgartner, M.; Deodato, F.; Ballhausen, D.; Boneh, A.; Burlina, A.B.; Cerone, R.; Garcia, P.; Gökçay, G.; Grünewald, S.; Häberle, J.; Jaeken, J.; Ketteridge, D.; Lindner, M.; Mandel, H.; Martinelli, D.; Martins, E.G.; Schwab, K.O.; Gruenert, S.C.; Schwahn, B.C.; Sztriha, L.; Tomaske, M.; Trefz, F.; Vilarinho, L.; Rosenblatt, D.S.; Fowler, B.; Dionisi-Vici, C.The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors. Results: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with "overall impression" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.
- Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative projectPublication . McHugh, D.M.; Cameron, C.A.; Abdenur, J.E.; Vilarinho, L.; Zakowicz, W.M.; et al.To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort
- Diagnosis of a patient with a kinetic variant of medium and short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency by newborn screeningPublication . Vilarinho, L.; Sales Marques, J.; Rocha, H.; Ramos, A.; Lopes, L.; Narayan, S.B.; Bennett, M.J.Medium and short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a rare cause of impaired mitochondrial fatty acid oxidation. We present a case report of a patient with hyperinsulinism and homozygosity for a novel mutation causing a kinetic variant of the enzyme. The diagnosis was initially inferred by abnormal newborn screening acylcarnitine analysis with elevated C4-hydroxyacylcarnitine.
- "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.
- Enhanced interpretation of newborn screening results without analyte cutoff valuesPublication . Marquardt, G.; Currier, R.; McHugh, D.M.; Gavrilov, D.; Magera, M.J.; Matern, D.; Oglesbee, D.; Raymond, K.; Rinaldo, P.; Smith, E.H.; Tortorelli, S.; Turgeon, C.T.; Lorey, F.; Wilcken, B.; Wiley, V.; Greed, L.C.; Lewis, B.; Boemer, F.; Schoos, R.; Marie, S.; Vincent, M.F.; Sica, Y.C.; Domingos, M.T.; Al-Thihli, K.; Sinclair, G.; Al-Dirbashi, O.Y.; Chakraborty, P.; Dymerski, M.; Porter, C.; Manning, A.; Seashore, M.R.; Quesada, J.; Reuben, A.; Chrastina, P.; Hornik, P.; Atef Mandour, I.; Atty Sharaf, S.A.; Bodamer, O.; Dy, B.; Torres, J.; Zori, R.; Cheillan, D.; Vianey-Saban, C.; Ludvigson, D.; Stembridge, A.; Bonham, J.; Downing, M.; Dotsikas, Y.; Loukas, Y.L.; Papakonstantinou, V.; Zacharioudakis, G.S.; Baráth, Á.; Karg, E.; Franzson, L.; Jonsson, J.J.; Breen, N.N.; Lesko, B.G.; Berberich, S.L.; Turner, K.; Ruoppolo, M.; Scolamiero, E.; Antonozzi, I.; Carducci, C.; Caruso, U.; Cassanello, M.; la Marca, G.; Pasquini, E.; Di Gangi, I.M.; Giordano, G.; Camilot, M.; Teofoli, F.; Manos, S.M.; Peterson, C.K.; Mayfield Gibson, S.K.; Sevier, D.W.; Lee, S.Y.; Park, H.D.; Khneisser, I.; Browning, P.; Gulamali-Majid, F.; Watson, M.S.; Eaton, R.B.; Sahai, I.; Ruiz, C.; Torres, R.; Seeterlin, S.M.A.; Stanley, E.L.; Hietala, A.; McCann, M.; Campbell, C.; Hopkins, P.V.; de Sain-Van der Velden, M.G.; Elvers, B.; Morrissey, M.A.; Sunny, S.; Knoll, D.; Webster, D.; Frazier, D.M.; McClure, J.D.; Sesser, D.E.; Willis, S.A.; Rocha, H.; Vilarinho, L.; John, C.; Lim, J.; Caldwell, S.G.; Tomashitis, K.; Castiñeiras Ramos, D.E.; Cocho de Juan, J.A.; Rueda Fernández, I.; Yahyaoui Macías, R.; Egea-Mellado, J.M.; González-Gallego, I.; Delgado Pecellin, C.; García-Valdecasas Bermejo, M.S.; Chien, Y.H.; Hwu, W.L.; Childs, T.; McKeever, C.D.; Tanyalcin, T.; Abdulrahman, M.; Queijo, C.; Lemes, A.; Davis, T.; Hoffman, W.; Baker, M.; Hoffman, G.L.PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.
- 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.
- Liver transplantation prevents progressive neurological impairment in argininemiaPublication . Silva, E.S.; Cardoso, M.L.; Vilarinho, L.; Medina, M.; Barbot, C.; Martins, E.Argininemia is a rare hereditary disease due to a deficiency of hepatic arginase, which is the last enzyme of the urea cycle and hydrolyzes arginine to ornithine and urea. The onset of the disease is usually in childhood, and clinical manifestations include progressive spastic paraparesis and mental retardation. Liver involvement is less frequent and usually not as severe as observed in other UCDs. For this reason, and because usually there is a major neurological disease at diagnosis, patients with argininemia are rarely considered as candidates for OLT despite its capacity to replace the deficient enzyme by an active one. We report on long-term follow-up of two patients with argininemia. Patient 1 was diagnosed by the age of 20 months and despite appropriate conventional treatment progressed to spastic paraparesis with marked limp. OLT was performed at10 years of age with normalization of plasmatic arginine levels and guanidino compounds. Ten years post-OLT, under free diet, there is no progression of neurological lesions. The second patient (previously reported by our group) was diagnosed at 2 months of age, during a neonatal cholestasis workup study. OLT was performed at the age of 7 years, due to liver cirrhosis with portal hypertension, in the absence of neurological lesions and an almost-normal brain MRI. After OLT, under free diet, there was normalization of plasmatic arginine levels and guanidino compounds. Twelve years post-OLT, she presents a normal neurological exami- nation. We conclude that OLT prevents progressive neuro- logical impairment in argininemia and should be considered when appropriate conventional treatment fails.
- 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.
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