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1.
JIMD Rep ; 48(1): 26-35, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31392110

RESUMO

Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched-chain 2-ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched-chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary-specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. Synopsis: Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis.

2.
Epilepsia ; 59(4): 854-865, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29512824

RESUMO

OBJECTIVE: Altered autonomic activity has been implicated in the development of cardiac dysfunction during seizures. This study investigates whether intervening in seizure progression with diazepam will reduce seizure-induced cardiomyopathy. Second, this study examines the hypothesis that combining atenolol with diazepam, as an intervention after seizure onset, will combat cardiac injury during status epilepticus. METHODS: Male Sprague-Dawley rats were implanted with electroencephalographic/electrocardiographic electrodes to allow simultaneous recordings during seizures induced by intrahippocampal (2 nmol, 1 µL) kainic acid (KA). Subcutaneous saline, atenolol (5 mg·kg-1 ), diazepam (5 mg·kg-1 ), or atenolol and diazepam (n = 12/group) were administered at 60 minutes post-KA and daily for 7 days, at which point echocardiography, susceptibility to aconitine-induced arrhythmias, and histology were evaluated. RESULTS: Seizure activity was associated with immediately increased heart rate, QTc interval, and blood pressure (BP; 10%-30% across indices). Seven days postseizure, saline-treated animals were found to have reduced left ventricular function, increased fibrotic scarring, and an elevated risk of aconitine-induced arrhythmias. Diazepam treatment significantly reduced cumulative seizure behaviors by 79% compared to saline-treated animals but offered no cardiac protection. Diazepam significantly raised BP (35%) and increased the risk of bigeminal arrhythmias (36%) compared to saline-treated animals. Atenolol administration, either alone or with diazepam, reduced heart rate, QTc interval, and BP back to control levels. Atenolol also preserved cardiac morphology and reduced arrhythmia risk. SIGNIFICANCE: Attenuation of seizure with diazepam offered no cardiac protection; however, coadministration of atenolol with diazepam prevented the development of seizure-induced cardiac dysfunction. This study demonstrates that atenolol intervention should be strongly considered as an adjunct clinical treatment to reduce cardiomyopathy during seizures.


Assuntos
Atenolol/administração & dosagem , Diazepam/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Convulsões/tratamento farmacológico , Fibrilação Ventricular/prevenção & controle , Animais , Antiarrítmicos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Quimioterapia Combinada , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Frequência Cardíaca/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Convulsões/complicações , Convulsões/fisiopatologia , Telemetria/métodos , Resultado do Tratamento , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologia
3.
Mol Genet Metab ; 122(3): 61-66, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28918066

RESUMO

Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder. We sought to evaluate the diagnostic sensitivity and variability of the various PDC enzyme assays in females and males at the Center for Inherited Disorders of Energy Metabolism (CIDEM). CIDEM data were filtered by lactic acidosis and functional PDC deficiency in at least one cell/tissue type (blood lymphocytes, cultured fibroblasts or skeletal muscle) identifying 186 subjects (51% male and 49% female), about half were genetically resolved with 78% of those determined to have a pathogenic PDHA1 mutation. Assaying PDC in cultured fibroblasts in cases where the underlying genetic etiology is PDHA1, was highly sensitive irrespective of gender; 97% (95% confidence interval [CI]: 90%-100%) and 91% (95% CI: 82%-100%) in females and males, respectively. In contrast to the fibroblast-based testing, the lymphocyte- and muscle-based testing were not sensitive (36% [95% CI: 11%-61%, p=0.0003] and 58% [95% CI: 30%-86%, p=0.014], respectively) for identifying known PDC deficient females with pathogenic PDHA1 mutations. In males with a known PDHA1 mutation, the sensitivity of the various cell/tissue assays (75% lymphocyte, 91% fibroblast and 88% muscle) were not statistically different, and the discordance frequency due to the specific cell/tissue used for assaying PDC was 0.15±0.11. Based on this data, a practical diagnostic algorithm is proposed accounting for current molecular approaches, enzyme testing sensitivity, and variability due to gender, cell/tissue type used for testing, and successive repeat testing.


Assuntos
Algoritmos , Ensaios Enzimáticos/métodos , Fibroblastos/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Complexo Piruvato Desidrogenase/genética , Acidose Láctica/metabolismo , Bioquímica/métodos , Células Cultivadas , Ensaios Enzimáticos/instrumentação , Feminino , Humanos , Linfócitos/metabolismo , Masculino , Mutação , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Sensibilidade e Especificidade
4.
Mol Genet Metab ; 120(4): 342-349, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28202214

RESUMO

Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain α-ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts were normal. Oxidative phosphorylation analysis on intact digitonin-permeabilized fibroblasts was suggestive of slightly reduced PDC activity relative to control range in mitochondria. We reviewed 16 other cases with mutations in ECHS1 where PDC activity was also assayed in order to determine how common and generalized secondary PDC deficiency is associated with primary SCEH deficiency. For reasons that remain unexplained, we find that about half of cases with primary SCEH deficiency also exhibit secondary PDC deficiency. The patient died on day-of-life 39, prior to establishing his diagnosis, highlighting the importance of early and rapid neonatal diagnosis because of possible adverse effects of certain therapeutic interventions, such as administration of ketogenic diet, in this disorder. There is a need for better understanding of the pathogenic mechanisms and phenotypic variability in this relatively recently discovered disorder.


Assuntos
Enoil-CoA Hidratase/deficiência , Doença da Deficiência do Complexo de Piruvato Desidrogenase/mortalidade , Análise de Sequência de DNA/métodos , Enoil-CoA Hidratase/genética , Exoma , Humanos , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética
5.
Mol Genet Metab ; 120(3): 213-222, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27913098

RESUMO

Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 developed Leigh syndrome, severe GI dysmotility, intermittent anemia, hypogammaglobulinemia and eventually succumbed to his disorder. The mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings. Pyruvate dehydrogenase complex, ketoglutarate dehydrogenase complex, and several mitochondrial electron transport chain (ETC) activities were low or at the low end of the reference range in frozen SM from S1 and/or S2. In contrast, activities of PDC, other mitochondrial enzymes of pyruvate metabolism, ETC and, integrated oxidative phosphorylation, in skin fibroblasts were not significantly impaired. Although we show that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM. A better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of mitochondrial enzymes of oxidative metabolism, and independently mitochondrial DNA depletion (common in other cases of A-SCS deficiency), is needed given the implications for control of lactic acidosis and possible clinical management.


Assuntos
Doenças Mitocondriais/genética , Músculo Esquelético/enzimologia , Polimorfismo de Nucleotídeo Único , Succinato-CoA Ligases/deficiência , Adolescente , Criança , DNA Mitocondrial/genética , Evolução Fatal , Humanos , Masculino , Doenças Mitocondriais/enzimologia , Músculo Esquelético/metabolismo , Deleção de Sequência , Irmãos , Succinato-CoA Ligases/genética
6.
Mol Genet Metab ; 113(3): 161-70, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24863970

RESUMO

The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/deficiência , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Receptores de N-Metil-D-Aspartato/genética , Síndrome de Smith-Magenis/diagnóstico , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Síndrome de Smith-Magenis/genética
7.
Mol Genet Metab Rep ; 1: 362-367, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27896109

RESUMO

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDHA1 gene. Males with hemizygous PDHA1 mutations are clinically more severely affected, while those with mosaic PDHA1 mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense PDHA1 mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of PDHA1 mosaicism.

8.
Neurotherapeutics ; 10(2): 307-19, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23361264

RESUMO

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.


Assuntos
Ensaios Clínicos como Assunto , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/terapia , Antioxidantes/uso terapêutico , Arginina/uso terapêutico , Creatina/uso terapêutico , Terapia por Exercício , Humanos , Ubiquinona/análogos & derivados , Ubiquinona/uso terapêutico
9.
Mol Genet Metab ; 107(3): 394-402, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23021068

RESUMO

Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ ≥ 70), 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ<25). Assessment by parents was comparable. Of 10 subjects who reached age 12 years, 9 had had professional IQ assessments, and only 4 had IQs ≥ 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID. Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%), and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more common in males. In a subgroup of 16 ambulatory subjects >3.5 years in whom balance was evaluated, ataxia was found in 13. Peripheral neuropathy was documented in 2 cases but not objectively evaluated in most subjects. Outcomes of this population with genetically confirmed PDC deficiency are heterogeneous and not distinctive. Correlations between specific genotypes and outcomes were not established. Although more females survive, related to the prevalence of X-linked PDHA1 mutations, symptomatic surviving females are generally more severely impaired cognitively and have a different pattern of neurological impairment compared to males. Neonatal or infant onset of symptoms was associated with poor outcomes. Males with PDHA1 mutations and low fibroblast PDC activity were less likely to survive beyond infancy. Recurrence rate in siblings of subjects with PDHA1 mutation was less than 5%. Paradoxically, in this retrospective review, potential factors considered possibly relevant to development, such as in vitro PDC activity, specific mutations, use of ketogenic diets, supplements, or medications, were generally not confirmed to be significantly correlated with objective outcomes of survival or neuro-cognitive function. Therefore, the basis of variability of these outcomes remains largely undetermined.


Assuntos
Autoantígenos/genética , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/genética , Doença de Leigh/genética , Proteínas Mitocondriais/genética , Mutação , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Criança , Pré-Escolar , Cognição , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Lactente , Doença de Leigh/mortalidade , Doença de Leigh/patologia , Masculino , Linhagem , Fenótipo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/mortalidade , Doença da Deficiência do Complexo de Piruvato Desidrogenase/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Taxa de Sobrevida
10.
Mitochondrion ; 12(6): 623-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23022402

RESUMO

We report the design and implementation of the first phase 3 trial of CoenzymeQ10 (CoQ10) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ10 by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation--and ultimate approval--of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism.


Assuntos
Doenças Mitocondriais/congênito , Doenças Mitocondriais/tratamento farmacológico , Ubiquinona/análogos & derivados , Pesquisa Biomédica , Humanos , Projetos de Pesquisa , Ubiquinona/uso terapêutico
11.
Mol Genet Metab ; 107(1-2): 43-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22846370

RESUMO

The primary treatment for phenylketonuria (PKU) is a low phenylalanine diet together with an amino acid-based, phenylalanine-free formula. Thus, PKU patients tend to consume a diet enriched in carbohydrates which could predispose to obesity. Studies in the 1980s and 1990s demonstrated that school-age phenylketonuria (PKU) patients have a higher mean body weight compared to a control population. However, no recent studies in the United States PKU population have examined whether this trend has persisted or whether adolescents are also affected. To investigate whether pediatric PKU populations (ages 2-20 years) in two major metropolitan areas of the United States (Cleveland, OH and Houston, TX) have a higher than expected percentage of overweight (BMI≥85th percentile) relative to the general population in the United States (NHANES), a retrospective chart review of PKU patients born between 1990 and 2008 and followed in Cleveland, OH (Rainbow Babies and Children's Hospital/University Hospitals Case Medical Center) and in Houston, TX (Texas Children's Hospital) was performed. Based on data from the U.S., 40% of pediatric PKU patients were overweight or obese. However, the percentage of overweight females (55%) and obese females (33%) is 1.8× and 2.1× higher respectively than expected based on comparison data from U.S. children. Further studies are necessary to identify potential strategies for prevention of excessive weight gain in children with PKU, especially in females.


Assuntos
Obesidade/complicações , Obesidade/epidemiologia , Fenilcetonúrias/complicações , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Dieta , Feminino , Humanos , Fórmulas Infantis , Masculino , Obesidade/sangue , Sobrepeso , Fenilalanina/sangue , Fenilcetonúrias/sangue , Prevalência , Fatores Sexuais , Adulto Jovem
12.
Mol Genet Metab ; 101(1): 87-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20591708

RESUMO

We present a patient with congenital lactic acidosis, agenesis of the corpus callosum, and profound developmental delay. Assays of pyruvate dehydrogenase complex function were normal in lymphocytes, but decreased in fibroblasts. Sequencing of the PDHA1 gene did not reveal deleterious mutations, and BAC based microarray analysis did not reveal any chromosomal abnormality. However, gene dosage analysis with oligonucleotide-based chromosomal microarray revealed a deletion of Xp22.12-Xp22.13 involving complete deletion of PDHA1. This is the first report of a whole gene deletion of PDHA1 detected by oligonucleotide-based microarray.


Assuntos
Acidose Láctica/genética , Cromossomos Humanos Par 22/genética , Deleção de Genes , Piruvato Desidrogenase (Lipoamida)/genética , Acidose Láctica/congênito , Pré-Escolar , Feminino , Humanos , Análise Serial de Proteínas
13.
Mol Genet Metab ; 100(3): 296-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20462777

RESUMO

Pyruvate dehydrogenase complex deficiency is a clinically heterogeneous disorder. Most cases are due to mutations in an X-linked PDHA1 gene encoding the E1alpha subunit of the multienzyme complex. Females with mutations in the PDHA1 gene may be asymptomatic or have a milder phenotype as a result of skewed X-inactivation, while males are typically more severely affected. We report a case of PDHA1 mosaicism in a male patient who had a milder phenotype.


Assuntos
Mosaicismo , Mutação de Sentido Incorreto , Piruvato Desidrogenase (Lipoamida)/deficiência , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/enzimologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Substituição de Aminoácidos , Sequência de Bases , Pré-Escolar , Cromossomos Humanos X/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Fenótipo
14.
Mol Genet Metab ; 100 Suppl 1: S97-105, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20188616

RESUMO

The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDC's accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.


Assuntos
Comportamento Cooperativo , Doenças Raras/terapia , Distúrbios Congênitos do Ciclo da Ureia/terapia , Humanos , Relações Interinstitucionais , Estudos Longitudinais , Sistema de Registros
15.
Mol Genet Metab ; 99(3): 246-55, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20060349

RESUMO

While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy. Arginine also has been used to treat MELAS with promising effects, although a controlled trial is still needed for this potentially toxic agent. The anti-oxidant coenzyme Q(10) is very widely used for primary mitochondrial disorders but has not yet undergone a controlled clinical trial; such a trial is now underway, as well as trials of the co-Q analogue idebenone for MELAS and LHON. Greater experience has accumulated with multi-center trials of coenzyme Q(10) treatment to prevent the progression of Parkinson disease. Although initial smaller trials indicated a benefit, this has not yet been confirmed in subsequent trials with higher doses; a larger Phase III trial is now underway. Similarly, a series of trials of idebenone for Friedreich ataxia have shown some benefit in slowing the progression of cardiomyopathy, and controlled clinical trials are now underway to determine if there is significant neurological protection. Uncontrolled trials of exercise showed an increase of exercise tolerance in patients with disorders of mitochondrial DNA, but did not selectively increase the percentage of normal mtDNA; a larger partially controlled trial is now underway to evaluate this possible benefit. In summary, none of the controlled trials so far has conclusively shown a benefit of treatment with the agents tested, but some promising therapies are currently being evaluated in a controlled manner. These experiences underscore the importance of controlled clinical trials for evaluation of benefits and risks of recommended therapies. Application of such clinical trials to future more effective therapies for mitochondrial disorders will require multi-center collaboration, organization, leadership, and financial and advocacy support.


Assuntos
Ensaios Clínicos como Assunto , Doenças Mitocondriais/tratamento farmacológico , Arginina/administração & dosagem , Arginina/efeitos adversos , Arginina/uso terapêutico , Ácido Dicloroacético/administração & dosagem , Ácido Dicloroacético/efeitos adversos , Ácido Dicloroacético/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ubiquinona/administração & dosagem , Ubiquinona/efeitos adversos , Ubiquinona/análogos & derivados , Ubiquinona/uso terapêutico
16.
Am J Hum Genet ; 84(1): 44-51, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19118815

RESUMO

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.


Assuntos
Predisposição Genética para Doença , Leucoencefalite Hemorrágica Aguda/genética , Chaperonas Moleculares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Éxons , Humanos , Influenza Humana/complicações , Leucoencefalite Hemorrágica Aguda/etiologia , Mutação de Sentido Incorreto , Mycoplasma pneumoniae , Infecções por Paramyxoviridae/complicações , Linhagem , Pneumonia por Mycoplasma/complicações , Recidiva
17.
Mol Genet Metab ; 94(4): 397-402, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18562231

RESUMO

Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the proteins that is essential for ureagenesis. We report on a cross-sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study. The study has been conducted by the Urea Cycle Disorders Consortium within the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institutes of Health. One-hundred eighty-three patients were enrolled into the study. Ornithine transcarbamylase (OTC) deficiency was the most frequent disorder (55%), followed by argininosuccinic aciduria (16%) and citrullinemia (14%). Seventy-nine percent of the participants were white (16% Latinos), and 6% were African American. Intellectual and developmental disabilities were reported in 39% with learning disabilities (35%) and half had abnormal neurological examination. Sixty-three percent were on a protein restricted diet, 37% were on Na-phenylbutyrate and 5% were on Na-benzoate. Forty-five percent of OTC deficient patients were on L-citrulline, while most patients with citrullinemia (58%) and argininosuccinic aciduria (79%) were on L-arginine. Plasma levels of branched-chain amino acids were reduced in patients treated with ammonia scavenger drugs. Plasma glutamine levels were higher in proximal UCD and in neonatal type disease. The RDCRN allows comprehensive analyses of rare inherited UCD, their frequencies and current medical practices.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Aminoácidos/metabolismo , Doenças Raras/epidemiologia , Ureia/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Criança , Pré-Escolar , Citrulinemia , Estudos Transversais , Grupos Étnicos , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença da Deficiência de Ornitina Carbomoiltransferase/epidemiologia , Doença da Deficiência de Ornitina Carbomoiltransferase/metabolismo , Doença da Deficiência de Ornitina Carbomoiltransferase/fisiopatologia , Doença da Deficiência de Ornitina Carbomoiltransferase/terapia , Doenças Raras/metabolismo , Doenças Raras/fisiopatologia , Doenças Raras/terapia , Estados Unidos
18.
Hepatology ; 46(4): 1218-27, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17694548

RESUMO

UNLABELLED: MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations. Importantly, 2 of these cases presented with isolated liver failure during infancy without notable neurologic dysfunction. CONCLUSION: We therefore propose that mutations in the MPV17 gene be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure.


Assuntos
Falência Hepática/genética , Proteínas de Membrana/genética , Mutação/genética , DNA Mitocondrial/metabolismo , Progressão da Doença , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Testes Genéticos , Hispano-Americanos/etnologia , Hispano-Americanos/genética , Humanos , Lactente , Recém-Nascido , Fígado/metabolismo , Fígado/patologia , Falência Hepática/diagnóstico , Falência Hepática/etnologia , Masculino , Linhagem , Texas
19.
Pediatrics ; 117(5): 1519-31, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16651305

RESUMO

OBJECTIVE: Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS: Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function. OUTCOME: There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor delta-aminolevulinate. CONCLUSIONS: In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.


Assuntos
Acidose Láctica/congênito , Acidose Láctica/tratamento farmacológico , Ácido Dicloroacético/uso terapêutico , Acidose Láctica/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Ácido Dicloroacético/efeitos adversos , Ácido Dicloroacético/farmacocinética , Feminino , Humanos , Lactente , Lactatos/metabolismo , Masculino , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Exame Neurológico , Testes Neuropsicológicos , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/metabolismo , Qualidade de Vida
20.
Am J Med Genet A ; 140(6): 580-5, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16470701

RESUMO

Encoded by the peptidase D (PEPD) gene located at 19q12-q13.11, prolidase is a ubiquitous cytosolic enzyme that catalyzes hydrolysis of oligopeptides with a C-terminal proline or hydroxyproline. We describe here four Amish children with a severe phenotype of prolidase deficiency in the Geauga settlements of Ohio as the first report of prolidase deficiency in the Amish population as well as in the United States. The patients presented with infection, hepatosplenomegaly, or thrombocytopenia, in contrast to most cases previously reported in the literature, presenting with skin ulcers. All four patients had typical facial features, classic skin ulcers, and multisystem involvement. Recurrent infections, asthma-like chronic reactive airway disease, hyperimmunoglobulins, hepatosplenomegaly with mildly elevated aspartate transaminase (AST), anemia, and thrombocytopenia were common and massive imidodipeptiduria was universal. Prolidase activity in our patients is nearly undetectable. Direct sequencing of PCR-amplified genomic DNA for all of the exons from the four patients revealed the same homozygous single nucleotide mutation c.793 T > C in exon 11, resulting in a premature stop-codon at amino acid residue 265 (p.R265X). It is speculated that the severe phenotype in these patients might be associated with the type of the PEPD gene mutation.


Assuntos
Códon sem Sentido , Dipeptidases/genética , Grupos Étnicos/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Sequência de Bases , Criança , Análise Mutacional de DNA , Dipeptidases/sangue , Dipeptidases/deficiência , Saúde da Família , Feminino , Hepatomegalia/patologia , Humanos , Masculino , Linhagem , Úlcera Cutânea/patologia , Esplenomegalia/patologia
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