The Experts below are selected from a list of 1584 Experts worldwide ranked by ideXlab platform
Douglas S Kerr - One of the best experts on this subject based on the ideXlab platform.
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controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children
Pediatrics, 2006Co-Authors: Peter W Stacpoole, Douglas S Kerr, Carie L Barnes, Terri S Bunch, Paul R Carney, Eileen M Fennell, Natalia M Felitsyn, Robin L Gilmore, Melvin Greer, George N HendersonAbstract: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 δ-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.
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outcome of Pyruvate Dehydrogenase Deficiency treated with ketogenic diets studies in patients with identical mutations
Neurology, 1997Co-Authors: Isaiah D Wexler, Mulchand S. Patel, S G Hemalatha, Judy Mcconnell, N R M Buist, H H M Dahl, Susan A Berry, Stephen D Cederbaum, Douglas S KerrAbstract:Inborn errors of the Pyruvate Dehydrogenase complex (PDC) are associated with lactic acidosis, neuroanatomic defects, developmental delay, and early death. PDC Deficiency is a clinically heterogeneous disorder, with most mutations located in the coding region of the X-linked α subunit of the first catalytic component, Pyruvate Dehydrogenase (E 1 ). Treatment of E 1 Deficiency has included cofactor replacement, activation of PDC with dichloroacetate, and ketogenic diets. In this report, we describe the outcome of ketogenic diet treatment in seven boys with E 1 Deficiency. These patients were divided into two groups based on their mutations (R349H, three patients; and R234G, four patients, two sibling pairs). All seven patients received ketogenic diets with varying degrees of carbohydrate restriction. Clinical outcome was compared within each group and between siblings as related to the intensity and duration of dietary intervention. Subjects who either had the diet initiated earlier in life or who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E 1 Deficiency.
George N Henderson - One of the best experts on this subject based on the ideXlab platform.
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controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children
Pediatrics, 2006Co-Authors: Peter W Stacpoole, Douglas S Kerr, Carie L Barnes, Terri S Bunch, Paul R Carney, Eileen M Fennell, Natalia M Felitsyn, Robin L Gilmore, Melvin Greer, George N HendersonAbstract: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 δ-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.
Garry Brown - One of the best experts on this subject based on the ideXlab platform.
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Defects of thiamine transport and metabolism
Journal of Inherited Metabolic Disease, 2014Co-Authors: Garry BrownAbstract:Thiamine, in the form of thiamine pyrophosphate, is a cofactor for a number of enzymes which play important roles in energy metabolism. Although dietary thiamine Deficiency states have long been recognised, it is only relatively recently that inherited defects in thiamine uptake, activation and the attachment of the active cofactor to target enzymes have been described, and the underlying genetic defects identified. Thiamine is transported into cells by two carriers, THTR1 and THTR2, and Deficiency of these results in thiamine-responsive megaloblastic anaemia and biotin-responsive basal ganglia disease respectively. Defective synthesis of thiamine pyrophosphate has been found in a small number of patients with episodic ataxia, delayed development and dystonia, while impaired transport of thiamine pyrophosphate into the mitochondrion is associated with Amish lethal microcephaly in most cases. In addition to defects in thiamine uptake and metabolism, patients with Pyruvate Dehydrogenase Deficiency and maple syrup urine disease have been described who have a significant clinical and/or biochemical response to thiamine supplementation. In these patients, an intrinsic structural defect in the target enzymes reduces binding of the cofactor and this can be overcome at high concentrations. In most cases, the clinical and biochemical abnormalities in these conditions are relatively non-specific, and the range of recognised presentations is increasing rapidly at present as new patients are identified, often by genome sequencing. These conditions highlight the value of a trial of thiamine supplementation in patients whose clinical presentation falls within the spectrum of documented cases.
GK Brown - One of the best experts on this subject based on the ideXlab platform.
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a putative exonic splicing enhancer in exon 7 of the pdha1 gene affects splicing of adjacent exons
Human Mutation, 2008Co-Authors: Cheryl K Ridout, Ruth M. Brown, P. Keighley, S Krywawych, GK BrownAbstract:A nonsense mutation (c.729C>A, Y243X) in exon 7 of the PDHA1 gene in a patient with Pyruvate Dehydrogenase Deficiency results in aberrant splicing of the primary transcript with production of stable mRNAs which lack either both exons 6 and 7 or exon 7 alone. Transfection and expression of genomic constructs covering exons 5 to 8 of the mutant PDHA1 gene reproduced this aberrant splicing in vitro. The same pattern of abnormal splicing was found when a silent mutation was introduced at the same position. Both the nonsense and silent mutations alter a strong consensus site for the binding of SRp40, suggesting that they may interfere with an exonic splicing enhancer in exon 7 of the gene. However, this appears to affect splicing of not only exon 7, but also the adjacent upstream exon. The splice acceptor site of intron 5 has weak homology to the consensus sequence and this may contribute to the combined splicing defect.
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Clinical and genetic spectrum of Pyruvate Dehydrogenase Deficiency: Dihydrolipoamide acetyltransferase (E2) Deficiency
ANN NEUROL, 2005Co-Authors: GK BrownAbstract:Pyruvate Dehydrogenase Deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. Most cases are caused by mutations in the X-linked gene for the E1 alpha subunit of the complex. Mutations in DLAT the gene encoding dihydrolipoamide acetyltransferase, the E2 core component of the complex, have not been described previously. We report two unrelated patients with Pyruvate Dehydrogenase Deficiency caused by defects in the E2 subunit. Both patients are less severely affected than typical patients with E1 alpha mutations and both have survived well into childhood. Episodic dystonia was the major neurological manifestation, with other more common features of Pyruvate Dehydrogenase Deficiency, such as hypotonia and ataxia, being less prominent. The patients had neuroradiological evidence of discrete lesions restricted to the globus pallidus, and both are homozygous for different mutations in the DLAT gene. The clinical presentation and neuroradiological findings are not typical of Pyruvate Dehydrogenase Deficiency and extend the clinical and mutational spectrum of this condition.
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isolated capillary proliferation in leigh s syndrome
Clinical Neuropathology, 1994Co-Authors: Paul M. Matthews, GK Brown, J.m. Land, Z. Nagy, M V SquierAbstract:An infant with hypotonia and recurrent apneic spells died with a diagnosis of Pyruvate Dehydrogenase Deficiency and showed typical pathological changes of Leigh's syndrome at post-mortem. Despite the prominence of symptoms suggesting dysfunction of brainstem respiratory centers during life, lesions were not found in the upper medulla. However, quantitative morphometric analysis demonstrated abnormal capillary hyperplasia in the region including and between the nucleus ambiguus and nucleus tractus solitarius. There was an average area of 8.0 ± 2.5 × 10 6 mm 2 occupied by capillaries per 0.75 mm 2 field in the patient's brainstem, compared with 4.6 ± 1.6 × 10 6 mm 2 and 5.5 ± 1.4 × 10 6 mm 2 in two age-matched controls (p < 0.01)
Kuang-lin Lin - One of the best experts on this subject based on the ideXlab platform.
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Ketogenic Diet: An Early Option for Epilepsy Treatment, Instead of A Last Choice Only
Biomedical Journal, 2013Co-Authors: Huei-shyong Wang, Kuang-lin LinAbstract:Ketogenic diet (KD) was usually tried as a last resort in the treatment of intractable epilepsy after failure of many antiepileptics and even epilepsy surgery. Glucose transporter-1 Deficiency and Pyruvate Dehydrogenase Deficiency must be treated with KD as the first choice because of inborn errors of glucose metabolism. Infantile spasms, tuberous sclerosis complex, Rett syndrome, Doose syndrome, Dravet syndrome, etc., appear to respond to KD, and it has been suggested by the international consensus statement to use KD early. We believe that all patients with epilepsy, except those with contraindicated situations such as Pyruvate carboxylase Deficiency, porphyria, β-oxidation defects, primary carnitine Deficiency, etc., may try KD before trying other regimens.
