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Porto Alegre, Brazil

Wajner M.,Servico de Genetica Medica | Goodman S.I.,Aurora University
Journal of Bioenergetics and Biomembranes | Year: 2011

Organic acidurias or organic acidemias constitute a group of inherited disorders caused by deficient activity of specific enzymes of amino acids, carbohydrates or lipids catabolism, leading to large accumulation and excretion of one or more carboxylic (organic) acids. Affected patients usually present neurologic symptoms and abnormalities, sometimes accompanied by cardiac and skeletal muscle alterations, whose pathogenesis is poorly known. However, in recent years growing evidence has emerged indicating that mitochondrial dysfunction is directly or indirectly involved in the pathology of various organic acidemias. Mitochondrial impairment in some of these diseases are generally due to mutations in nuclear genes of the tricarboxylic acid cycle or oxidative phosphorylation, while in others it seems to result from toxic influences of the endogenous organic acids to the mitochondrion. In this minireview, we will briefly summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial homeostasis may represent a relevant pathomechanism of tissue damage in selective organic acidemias. The discussion will focus on mitochondrial alterations found in patients affected by organic acidemias and by the deleterious effects of the accumulating organic acids on mitochondrial pathways that are crucial for ATP formation and transfer. The elucidation of the mechanisms of toxicity of these acidic compounds offers new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group. © 2011 Springer Science+Business Media, LLC.

Brustolin S.,Servico de Genetica Medica | Giugliani R.,Servico de Genetica Medica | Giugliani R.,Federal University of Rio Grande do Sul | Felix T.M.,Servico de Genetica Medica
Brazilian Journal of Medical and Biological Research | Year: 2010

Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

Emy Dorfman L.,Federal University of Rio Grande do Sul | Leite J.C.L.,Servico de Genetica Medica | Giugliani R.,Federal University of Rio Grande do Sul | Riegel M.,Federal University of Rio Grande do Sul
Jornal de Pediatria | Year: 2015

Objective To identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array-CGH) in DNA samples of neonates with congenital anomalies of unknown cause from a birth defects monitoring program at a public maternity hospital. Methods A blind genomic analysis was performed retrospectively in 35 stored DNA samples of neonates born between July of 2011 and December of 2012. All potential DNA copy number variations detected (CNVs) were matched with those reported in public genomic databases, and their clinical significance was evaluated. Results Out of a total of 35 samples tested, 13 genomic imbalances were detected in 12/35 cases (34.3%). In 4/35 cases (11.4%), chromosomal imbalances could be defined as pathogenic; in 5/35 (14.3%) cases, DNA CNVs of uncertain clinical significance were identified; and in 4/35 cases (11.4%), normal variants were detected. Among the four cases with results considered causally related to the clinical findings, two of the four (50%) showed causative alterations already associated with well-defined microdeletion syndromes. In two of the four samples (50%), the chromosomal imbalances found, although predicted as pathogenic, had not been previously associated with recognized clinical entities. Conclusions Array-CGH analysis allowed for a higher rate of detection of chromosomal anomalies, and this determination is especially valuable in neonates with congenital anomalies of unknown etiology, or in cases in which karyotype results cannot be obtained. Moreover, although the interpretation of the results must be refined, this method is a robust and precise tool that can be used in the first-line investigation of congenital anomalies, and should be considered for prospective/retrospective analyses of DNA samples by birth defect monitoring programs. © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Diniz D.,Anis Institute Bioetica Direitos Humanos e Genero | Diniz D.,University of Brasilia | Medeiros M.,University of Brasilia | Schwartz I.V.D.,Servico de Genetica Medica | Schwartz I.V.D.,Federal University of Rio Grande do Sul
Cadernos de Saude Publica | Year: 2012

This study analyzes expenditures backed by court rulings to ensure the public provision of medicines for treatment of mucopolysaccharidosis (MPS), a rare disease that requires high-cost drugs not covered by the Brazilian government's policy for pharmaceutical care and which have disputed clinical efficacy. The methodology included a review of files from 196 court rulings ordering the Brazilian Ministry of Health to provide the medicines, in addition to Ministry of Health administrative records. According to the analysis, the "judicialization" of the health system subjected the Brazilian government to a monopoly in the distribution of medicines and consequently the loss of its capacity to manage drug purchases. The study also indicates that the imposition of immediate, individualized purchases prevents obtaining economies of scale with planned procurement of larger amounts of the medication, besides causing logistic difficulties in controlling the amounts consumed and stored. In conclusion, litigation results from the lack of a clear policy in the health system for rare diseases in general, thereby leading to excessive expenditures for MPS treatment.

Da Rosa M.S.,Federal University of Rio Grande do Sul | Joao Ribeiro C.A.,Federal University of Rio Grande do Sul | Seminotti B.,Federal University of Rio Grande do Sul | Teixeira Ribeiro R.,Federal University of Rio Grande do Sul | And 5 more authors.
Free Radical Biology and Medicine | Year: 2015

Patients affected by L-2-hydroxyglutaric aciduria (L-2-HGA) are biochemically characterized by elevated L-2-hydroxyglutaric acid (L-2-HG) concentrations in cerebrospinal fluid, plasma, and urine due to a blockage in the conversion of L-2-HG to α-ketoglutaric acid. Neurological symptoms associated with basal ganglia and cerebelar abnormalities whose pathophysiology is still unknown are typical of this neurometabolic disorder. In the present study we evaluated the early effects (30 min after injection) of an acute in vivo intrastriatal and intracerebellar L-2-HG administration on redox homeostasis in rat striatum and cerebellum, respectively. Histological analyses of these brain structures were also carried out 7 days after L-2-HG treatment (long-term effects). L-2-HG significantly decreased the concentrations of reduced (GSH) and total glutathione (tGS), as well as of glutathione peroxidase (GPx) and reductase (GR) activities, but did not change the activities of superoxide dismutase and catalase in striatum. Furthermore, the concentrations of oxidized glutathione (GSSG) and malondialdehyde (MDA), as well as 2′,7′-dichlorofluorescein (DCFH) oxidation and hydrogen peroxide (H2O2) production, were increased, whereas carbonyl formation and nitrate plus nitrite concentrations were not altered by L-2-HG injection. It was also found that the melatonin, ascorbic acid plus α-tocopherol, and creatine totally prevented most of these effects, whereas N-acetylcysteine, the noncompetitive glutamate NMDA antagonist MK-801, and the nitric oxide synthase inhibitor L-NAME were not able to normalize the redox alterations elicited by L-2-HG in striatum. L-2-HG intracerebellar injection similarly provoked a decrease of antioxidant defenses (GSH, tGS, GPx, and GR) and an increase of the concentrations of GSSG, MDA, and H2O2 in cerebellum. These results strongly indicate that the major accumulating metabolite in L-2-HGA induce oxidative stress by decreasing the antioxidant defenses and enhancing reactive oxygen species in striatum and cerebellum of adolescent rats. Regarding the histopathological findings, L-2-HG caused intense vacuolation, lymphocyte and macrophage infiltrates, eosinophilic granular bodies, and necrosis in striatum. Immunohistochemistry revealed that L-2-HG treatment provoked an increase of GFAP and a decrease of NeuN immunostaining, indicating reactive astroglyosis and reduction of neuronal population, respectively, in striatum. Similar macrophage infiltrates, associated with less intense vacuolation and lymphocytic infiltration, were observed in cerebellum. However, we did not observe necrosis, eosinophilic granular bodies, and alteration of GFAP and NeuN content in L-2-HG-teated cerebellum. From the biochemical and histological findings, it is presumed that L-2-HG provokes striatal and cerebellar damage in vivo possibly through oxidative stress induction. Therefore, we postulate that antioxidants may serve as adjuvant therapy allied to the current treatment based on a protein-restricted diet and riboflavin and L-carnitine supplementation in patients affected by L-2-HGA. © 2015 Elsevier Inc. All rights reserved.

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