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1.
J Inherit Metab Dis ; 41(5): 765-776, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29335813

RESUMO

Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ("organic acids") and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be "metabolically stable". This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.

2.
Ann Neurol ; 82(6): 1004-1015, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29205472

RESUMO

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.


Assuntos
Hidrolases de Éster Carboxílico/genética , Transtornos da Surdocegueira/diagnóstico por imagem , Transtornos da Surdocegueira/genética , Progressão da Doença , Distonia/diagnóstico por imagem , Distonia/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Mutação/genética , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Transtornos da Surdocegueira/terapia , Distonia/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/terapia , Masculino , Atrofia Óptica/terapia , Adulto Jovem
3.
JIMD Rep ; 32: 105-115, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27344647

RESUMO

BACKGROUND: The state of newborn screening (NBS) programmes for organic acidurias in Europe was assessed by a web-based questionnaire in the EU programme of Community Action in Public Health 2010/2011 among the - at that time - 27 EU member states, candidate countries, potential candidates and three EFTA countries. RESULTS: Thirty-seven data sets from 39 target countries were analysed. Newborn screening for glutaric aciduria type I (GA-I) was performed in ten, for isovaleric aciduria (IVA) in nine and for methylmalonic aciduria including cblA, cblB, cblC and cblD (MMACBL) as well as for propionic aciduria (PA) in seven countries. Samples were obtained at a median age of 2.5 days and laboratory analysis began at median age of 4.5 days. Positive screening results were mostly confirmed in specialised centres by analysis of organic acids in urine. Confirmation of a positive screening result usually did not start before the second week of life (median ages: 9.5 days [IVA], 9 days [GA-I], 8.5 days [PA, MMACBL]) and was completed early in the third week of life (median ages: 15 days [IVA, PA, MMA], 14.5 days [GA-I]). Treatment was initiated in GA-I and IVA at a median age of 14 days and in MMACBL and PA at a median age of 15 days. CONCLUSION: NBS for organic acidurias in Europe is variable and less often established than for amino acid disorders. While for GA-I its benefit has already been demonstrated, there is room for debate of NBS for IVA and especially PA and MMACBL.

5.
J Inherit Metab Dis ; 38(6): 1059-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25875216

RESUMO

BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. CONCLUSIONS: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Acidúria Argininossuccínica/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Glutaril-CoA Desidrogenase/deficiência , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Acidemia Propiônica/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Falência Renal Crônica/complicações , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Triagem Neonatal , Fenótipo , Sistema de Registros , Adulto Jovem
6.
Neuropediatrics ; 46(2): 98-103, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25642805

RESUMO

Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.


Assuntos
Gânglios da Base/patologia , Surdez/patologia , Distúrbios Distônicos/patologia , Doenças Mitocondriais/patologia , Pré-Escolar , Surdez/complicações , Surdez/genética , Progressão da Doença , Distúrbios Distônicos/complicações , Distúrbios Distônicos/genética , Humanos , Lactente , Imagem por Ressonância Magnética , Doenças Mitocondriais/complicações , Putamen/patologia , Síndrome
7.
Orphanet J Rare Dis ; 9: 130, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25205257

RESUMO

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/terapia , Humanos , Guias de Prática Clínica como Assunto
8.
Pediatr Nephrol ; 28(2): 227-35, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22814947

RESUMO

Methylmalonic acidurias are a heterogeneous group of inborn errors of branched-chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut°, cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Ácido Metilmalônico/metabolismo , Insuficiência Renal Crônica/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Dieta , Suplementos Nutricionais , Genótipo , Humanos , Transplante de Rim , Mitocôndrias/metabolismo , Fenótipo , Terapia de Substituição Renal
9.
J Inherit Metab Dis ; 35(5): 797-806, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22249333

RESUMO

Recurrent, life-threatening metabolic decompensations often occur in patients with methylmalonic aciduria (MMAuria). Our study evaluated (impending) metabolic decompensations in these patients aiming to identify the most frequent and reliable clinical and biochemical abnormalities that could be helpful for decision-making on when to start an emergency treatment. Seventy-six unscheduled and 179 regular visits of 10 patients with confirmed MMAuria continuously followed by our metabolic centre between 1975 and 2009 were analysed. The most frequent symptom of an impending acute metabolic decompensation was vomiting (90% of episodes), whereas symptoms of intercurrent infectious disease (29%) or other symptoms (such as food refusal and impaired consciousness) were found less often. Thirty-five biochemical parameters were included in the analysis. Among them, pathological changes of acid-base balance reflecting metabolic acidosis with partial respiratory compensation (decreased pH, pCO(2), standard bicarbonate, and base excess) and elevated ammonia were the most reliable biochemical parameters for the identification of a metabolic decompensation and the estimation of its severity. In contrast, analyses of organic acids, acylcarnitines and carnitine status were less discriminative. In conclusion, careful history taking and identification of suspicious symptoms in combination with a small number of rapidly available biochemical parameters are helpful to differentiate compensated metabolic condition and (impending) metabolic crisis and to decide when to start an emergency treatment.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Equilíbrio Ácido-Base , Acidose/sangue , Acidose/diagnóstico , Acidose/metabolismo , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Amônia/sangue , Bicarbonatos/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Adulto Jovem
10.
Mov Disord ; 26(1): 157-61, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20818608

RESUMO

Autosomal recessive guanosine triphosphate cyclohydrolase (GTPCH) type I deficiency is characterized by complex neurological dysfunction. Patients are usually diagnosed with hyperphenylalaninemia in newborn screening. We describe two unrelated patients without hyperphenylalaninemia who presented during early infancy with severe motor retardation, hypokinesia, and truncal hypotonia. CSF homovanillic acid and 5-hydroxyindoleacetic acid as well as tetrahydrobiopterin and neopterin were decreased. Diagnosis of recessive GTPCH deficiency was confirmed biochemically, and a novel homozygous mutation was identified in one patient and a compound-heterozygous mutation of GCH1 in the other. Treatment with Levodopa/Carbidopa resulted in striking clinical improvement, with age-appropriate development at follow-up at 6 years. Autosomal recessive GTPCH deficiency should be considered in infants with severe truncal hypotonia even if hyperphenylalaninemia or classical extrapyramidal symptoms are missing. Neurotransmitter analysis followed by enzyme or mutation analysis can confirm the diagnosis, and Levodopa treatment should be started at high-doses.


Assuntos
GTP Cicloidrolase/deficiência , Fenilcetonúrias/fisiopatologia , Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Pré-Escolar , Deficiências Nutricionais/diagnóstico , Deficiências Nutricionais/tratamento farmacológico , Deficiências Nutricionais/enzimologia , Combinação de Medicamentos , Feminino , Seguimentos , GTP Cicloidrolase/genética , Humanos , Lactente , Levodopa/uso terapêutico , Masculino , Mutação/genética , Neurotransmissores/metabolismo
11.
Pediatr Res ; 62(2): 225-30, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17597648

RESUMO

Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut-) or deficient synthesis of its cofactor 5'-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7-33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut- (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.


Assuntos
Alquil e Aril Transferases/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Cobamidas/metabolismo , Proteínas de Membrana Transportadoras/genética , Ácido Metilmalônico/metabolismo , Metilmalonil-CoA Mutase/genética , Proteínas Mitocondriais/genética , Mutação , Adolescente , Adulto , Idade de Início , Alquil e Aril Transferases/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Criança , Progressão da Doença , Feminino , Seguimentos , Gastroenteropatias/etiologia , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/etiologia , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Ácido Metilmalônico/urina , Metilmalonil-CoA Mutase/metabolismo , Proteínas de Transporte da Membrana Mitocondrial , Proteínas Mitocondriais/metabolismo , Doenças do Sistema Nervoso/etiologia , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico
12.
J Neurochem ; 97(3): 899-910, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16573641

RESUMO

Glutaric acid (GA) and 3-hydroxyglutaric acids (3-OH-GA) are key metabolites in glutaryl co-enzyme A dehydrogenase (GCDH) deficiency and are both considered to be potential neurotoxins. As cerebral concentrations of GA and 3-OH-GA have not yet been studied systematically, we investigated the tissue-specific distribution of these organic acids and glutarylcarnitine in brain, liver, skeletal and heart muscle of Gcdh-deficient mice as well as in hepatic Gcdh-/- mice and in C57Bl/6 mice following intraperitoneal loading. Furthermore, we determined the flux of GA and 3-OH-GA across the blood-brain barrier (BBB) using porcine brain microvessel endothelial cells. Concentrations of GA, 3-OH-GA and glutarylcarnitine were significantly elevated in all tissues of Gcdh-/- mice. Strikingly, cerebral concentrations of GA and 3-OH-GA were unexpectedly high, reaching similar concentrations as those found in liver. In contrast, cerebral concentrations of these organic acids remained low in hepatic Gcdh-/- mice and after intraperitoneal injection of GA and 3-OH-GA. These results suggest limited flux of GA and 3-OH-GA across the BBB, which was supported in cultured porcine brain capillary endothelial cells. In conclusion, we propose that an intracerebral de novo synthesis and subsequent trapping of GA and 3-OH-GA should be considered as a biochemical risk factor for neurodegeneration in GCDH deficiency.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Doenças Neurodegenerativas/fisiopatologia , Aminoácidos/metabolismo , Animais , Transporte Biológico/fisiologia , Western Blotting/métodos , Encéfalo/citologia , Carnitina/análogos & derivados , Carnitina/metabolismo , Células Cultivadas , Ácidos Dicarboxílicos/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Glucose/metabolismo , Coração/fisiologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Músculos/metabolismo , Doenças Neurodegenerativas/genética , Fatores de Risco , Estatísticas não Paramétricas , Suínos , Fatores de Tempo , Distribuição Tecidual/fisiologia
13.
Pediatr Res ; 59(4 Pt 1): 544-8, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16549526

RESUMO

Classical phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of PKU patients. PKU is neuropathologically characterized by reduced dendritic arborization, loss of synapses, and neurodegeneration. We investigated whether increased concentrations of phenylalanine cause reduced synaptic density and alter dendritic branching. We treated primary cortical neurons differentiated for 21 d in vitro with 5 mM phenylalanine in the presence of all essential amino acids. Immunocytochemical analysis of 12 and 21 d in vitro primary neurons revealed no changes of dendritic morphology or neuronal viability but a significant difference in synaptic density, suggesting that elevated concentrations of extracellular phenylalanine cause an impairment of synaptogenesis. Although impairment of cerebral energy metabolism has been identified as an important pathophysiological principal in many diseases, respiratory chain function has not been extensively studied in PKU before. We investigated whether phenylalanine inhibits respiratory chain complexes I-V. In vitro analysis revealed no inhibitory effect of phenylalanine on complexes I-V, but an inhibition of pyruvate kinase, a key enzyme of glycolysis, catalyzing the formation of pyruvate. Pyruvate kinase is part of the enzyme assay to investigate enzyme activity of mitochondrial complex V and it remains to be elucidated whether this finding is relevant in vivo. In conclusion, elevated concentrations of phenylalanine might be involved in mechanisms underlying impaired synaptogenesis in PKU, supporting the common therapeutic strategy to reduce phenylalanine concentrations in the brain to prevent neurodegeneration.


Assuntos
Córtex Cerebral/citologia , Fenilalanina/metabolismo , Sinapses/fisiologia , Animais , Células Cultivadas , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Embrião de Mamíferos/anatomia & histologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/metabolismo , Fenilcetonúrias/metabolismo , Fenilcetonúrias/patologia , Fenilcetonúrias/fisiopatologia , Piruvato Quinase/metabolismo
14.
Pediatr Nephrol ; 19(10): 1071-4, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15293040

RESUMO

Classical methylmalonic aciduria is a relatively rare inborn error of branched-chain amino acid metabolism, occurring in 1:50,000 to 1:80,000 newborns. Three decades after its recognition, major progress has been made in survival and prevention of neurological sequelae in affected children, if the diagnosis is made early and treatment and follow-up care are meticulous. Therapy consists of a specially formulated protein diet, carnitine supplementation, and vigorous emergency treatment during intercurrent illnesses aimed at preventing the development of catabolism. Recently the clinician has been challenged by partially unexpected long-term complications. These include chronic neurological symptoms, specifically an extrapyramidal movement disorder caused by progressive destruction of the basal ganglia, which are similar to those observed in other organic acid disorders, such as propionic aciduria or glutaric aciduria type I. Unexpected and unique is the development of chronic renal failure in a major subset of patients. As the pathophysiological basis of renal failure is still obscure, no causative treatment is available and hemodialysis may become necessary. Experience with transplantation of liver, kidney, or kidney and liver is very limited and allows as yet no conclusions. Interdisciplinary research efforts in this field should reveal new pathophysiological links and hopefully provide additional therapeutic approaches.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Ácido Metilmalônico/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia
16.
J Biol Chem ; 278(48): 47388-93, 2003 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-12972416

RESUMO

Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure. It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. To elucidate whether methylmalonic acid is a respiratory chain inhibitor, we used spectrophotometric analysis of complex II activity in submitochondrial particles from bovine heart, radiometric analysis of 14C-labeled substrates (pyruvate, malate, succinate), and analysis of ATP production in muscle from mice. Methylmalonic acid revealed no direct effects on the respiratory chain function, i.e. on single electron transferring complexes I-IV, ATPase, and mitochondrial transporters. However, we identified a variety of variables that must be carefully controlled to avoid an artificial inhibition of complex II activity. In summary, the study verifies our hypothesis that methylmalonic acid is not the major toxic metabolite in methylmalonic acidurias. Inhibition of respiratory chain and tricarboxylic acid cycle is most likely induced by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Transporte de Elétrons , Ácido Metilmalônico/química , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Acil Coenzima A/metabolismo , Trifosfato de Adenosina/metabolismo , Envelhecimento , Animais , Bovinos , Citratos/metabolismo , Ciclo do Ácido Cítrico , Relação Dose-Resposta a Droga , Feminino , Concentração de Íons de Hidrogênio , Masculino , Malonatos/metabolismo , Ácido Metilmalônico/urina , Camundongos , Camundongos Endogâmicos C57BL , Músculos/metabolismo , Miocárdio/metabolismo , Oxigênio/metabolismo , Fosforilação , Piruvatos/metabolismo , Espectrofotometria , Fatores de Tempo
17.
Eur J Neurosci ; 16(1): 21-8, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12153528

RESUMO

The inherited neurometabolic disease d-2-hydroxyglutaric aciduria is complicated by progressive neurodegeneration of vulnerable brain regions during infancy and early childhood, frequently presenting with hypotonia, epilepsy and psychomotor retardation. Here, we report that the pathogenetic role of the endogenously accumulating metabolite d-2-hydroxyglutarate (D-2), which is structurally similar to the excitatory amino acid glutamate, is mediated by at least three mechanisms. (i) D-2-induced excitotoxic cell damage in primary neuronal cultures from chick and rat involved N-methyl-d-aspartate (NMDA) receptor activation. Indeed, D-2 activated recombinant NMDA receptors (NR1/NR2A, NR1/NR2B) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors in HEK293 cells. (ii) Fluorescence microscopy using fura-2 as a calcium indicator and the oxidant-sensitive dye dihydrorhodamine-123 revealed that D-2 disturbed intracellular calcium homeostasis and elicited the generation of reactive oxygen species. (iii) D-2 reduced complex V (ATP synthase) activity of the mitochondrial respiratory chain, reflecting an impaired energy metabolism due to inhibition of ATP synthesis but without affecting the electron-transferring complexes I-IV. Thus, D-2 stimulates neurodegeneration by mechanisms well-known for glutamate, NMDA or mitochondrial toxins. In conclusion, excitotoxicity contributes to the neuropathology of d-2-hydroxyglutaric aciduria, highlighting new neuroprotective strategies.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Encefalopatias Metabólicas/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Glutaratos/efeitos adversos , Proteínas de Membrana/antagonistas & inibidores , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Doenças Neurodegenerativas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cálcio/metabolismo , Técnicas de Cultura de Células , Morte Celular/efeitos dos fármacos , Embrião de Galinha , Transporte de Elétrons/efeitos dos fármacos , Glutaratos/metabolismo , Hipocampo/metabolismo , Microscopia de Fluorescência , Neurônios/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores de AMPA/metabolismo
18.
Pediatr Res ; 52(2): 199-206, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12149496

RESUMO

Glutaryl-CoA dehydrogenase deficiency (also known as glutaric aciduria type I) is an autosomal, recessively inherited neurometabolic disorder with a distinct neuropathology characterized by acute encephalopathy during a vulnerable period of brain development. Neuronal damage in this disease was demonstrated to involve N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity of the endogenously accumulating metabolite 3-hydroxyglutarate (3-OH-GA). However, it remained unclear whether NMDA receptors are directly or indirectly activated and whether 3-OH-GA disturbs the intracellular Ca(2+) homeostasis. Here we report that 3-OH-GA activated recombinant NMDA receptors (e.g. NR1/NR2A) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (e.g. GluR-A/GluR-B) in HEK293 cells. Fluorescence microscopy using fura-2 as Ca(2+) indicator revealed that 3-OH-GA increased intracellular Ca(2+) concentrations in the presence of extracellular Ca(2+) in cultured chick neurons. Similar to glutamate-induced cell damage, 3-OH-GA neurotoxicity was modulated by extracellular Na(+). The large cation N-methyl-D-glucamine, which does not permeate NMDA receptor channels, enhanced 3-OH-GA-induced Ca(2+) increase and cell damage. In contrast, 3-OH-GA-induced neurotoxicity was reduced after replacement of Na(+) by Li(+), which permeates NMDA channels but does not affect the Na(+)/Ca(2+) exchanger in the plasma membrane. Spectrophotometric analysis of respiratory chain complexes I-V in submitochondrial particles from bovine heart revealed only a weak inhibition of 3-OH-GA on complex V at the highest concentration tested (10 mM). In conclusion, the present study revealed that NMDA receptor activation and subsequent disturbance of Ca(2+) homeostasis contribute to 3-OH-GA-induced cell damage.


Assuntos
Cálcio/metabolismo , Proteínas de Transporte , Glutaratos/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Sódio/metabolismo , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Animais , Cátions/metabolismo , Células Cultivadas , Embrião de Galinha , Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons , Complexo II de Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Rim/citologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Neurotoxinas/farmacologia , Oxirredutases/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/metabolismo , Succinato Desidrogenase/metabolismo , Telencéfalo/citologia
19.
J Neurosci Res ; 68(4): 424-31, 2002 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-11992468

RESUMO

Glutaryl-CoA dehydrogenase deficiency (GDD) is characterized biochemically by an accumulation of glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids and clinically by the development of acute striatal degeneration. 3-OH-GA was recently shown to induce neuronal damage via N-methyl-D-aspartate (NMDA) receptors. The pathogenetic role of GA, however, remains unclear. We demonstrate that GA exerts a dual action in cultured chick embryo neurons. Short-term incubation with millimolar concentrations of GA induces a weak neuronal damage, adding to 3-OH-GA neurotoxicity. In contrast, chronic treatment with subtoxic, micromolar concentrations of GA results in partial tolerance to 3-OH-GA- and NMDA-induced cell damage. A downregulation of NMDA receptors, in particular of the NR2B subunit, is critically involved in this GA-induced effect, resulting in a reduced Ca(2+) increase and generation of reactive oxygen species after acute exposure to NMDA or 3-OH-GA. Furthermore, GA decreases Na(+)/K(+)-ATPase activity, which is prevented by glutathione, suggesting a modulation of NMDA receptor function via resting membrane potential and Na(+)-dependent glutamate transport. In contrast, GA does not inhibit mitochondrial respiratory chain and beta-oxidation of fatty acids, virtually excluding an activation of NMDA receptors secondary to ATP depletion. These results strongly suggest that GA modulates the NMDA receptor-mediated neurotoxicity of 3-OH-GA, providing an explanatory basis for the non-linear relationship between organic acid concentrations and disease progression in GDD patients. Furthermore, GA-induced downregulation of NMDA receptors might be involved in the delayed cerebral maturation of GDD patients, resulting in frontotemporal atrophy and a reduced opercularization, which are common neuroradiological findings in GDD patients.


Assuntos
Glutaratos/toxicidade , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Telencéfalo/efeitos dos fármacos , Telencéfalo/metabolismo , Animais , Western Blotting , Cálcio/metabolismo , Técnicas de Cultura de Células , Embrião de Galinha , Regulação para Baixo/efeitos dos fármacos , Tolerância a Medicamentos , Eletroforese em Gel de Poliacrilamida , Glutaratos/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Telencéfalo/citologia
20.
J Biol Chem ; 277(17): 14674-80, 2002 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-11847233

RESUMO

Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.


Assuntos
Ciclo do Ácido Cítrico , Corpo Estriado/metabolismo , Erros Inatos do Metabolismo/fisiopatologia , Ácido Metilmalônico/urina , Complexos Multienzimáticos/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Succinato Desidrogenase/antagonistas & inibidores , Animais , Células Cultivadas , Citratos/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Corpo Estriado/patologia , Complexo II de Transporte de Elétrons , Feminino , Malonatos/metabolismo , Malonatos/farmacologia , Erros Inatos do Metabolismo/metabolismo , Ácido Metilmalônico/farmacologia , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar
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