The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Richard G Oles - One of the best experts on this subject based on the ideXlab platform.
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maternal inheritance in cyclic vomiting syndrome
American Journal of Medical Genetics Part A, 2005Co-Authors: Richard G Oles, Kathlee AdamsAbstract:Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a fairly common, disabling, predominately-childhood condition most often associated with migraine and dysautonomic features. Our group recently reported that children with CVS and additional neuromuscular disease manifestations demonstrate strong maternal inheritance of multiple disease manifestations and abnormal Urine Organic Acids, suggesting the presence of predisposing mitochondrial DNA (mtDNA) sequence variants. In order to determine if maternal inheritance is present in CVS in general, a clinical interview was administered regarding 80 unrelated individuals with CVS ascertained randomly from the database of the Cyclic Vomiting Syndrome Association (CVSA). Disease manifestations consistent with potential mitochondrial dysfunction were far more common in matrilineal (sharing the same mtDNA sequence) versus in non-matrilineal relatives, including mothers versus fathers (P = 3 × 10−9) and maternal versus paternal grandmothers (P = 2 × 10−6). Maternal inheritance is suggested in 52% of the 23 subjects with two or more neuromuscular abnormalities (“CVS+”) and in 54% of the 44 subjects without any neuromuscular abnormalities (“CVS−”). In both the CVS+ and CVS− sub-groups, subjects, and affected matrilineal relatives of all ages suffer at a far higher incidence from several dysautonomic-related conditions, including migraine and irritable bowel, as well as depression and hypothyroidism, while neuromuscular and cognitive disorders such as hypotonia and ADHD are common only in affected children. We conclude that mtDNA sequences predispose towards the development of protean disease manifestations in CVS patients ascertained through a disease-specific association, as well as among their matrilineal relatives, whether or not neuromuscular disease is present in the proband. Since CVS was absent in all but one matrilineal relative of our probands, CVS is apparently a rare clinical presentation in individuals carrying the predisposing mtDNA sequences. The four conditions reported most frequently among the matrilineal relatives of our cases, migraine, depression, irritable bowel, and hypothyroidism, are known to segregate together in families, and our findings suggest that a common predisposing genetic factor is likely present on the mtDNA. © 2005 Wiley-Liss, Inc.
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mitochondrial disease and cyclic vomiting syndrome
Digestive Diseases and Sciences, 1999Co-Authors: Richard G Oles, J C WilliamsAbstract:Mutations of mitochondrial DNA are being increasingly recognized as a cause of human disease. Six unrelated children have been evaluated with cyclic vomiting syndrome and a strong maternal family history suggesting a mitochondrial DNA mutation. Manifestations suggestive of migraine were present in each child. Additional clinical findings present in all cases include: developmental delay (3/6 cases), seizures (3/6), and poor growth (3/6). The age of onset for vomiting episodes was < or = 1 year in five cases. An elevated body fluid lactate (lactic acid) was found in 5/6 cases. A mitochondrial DNA mutation was confirmed in one child with the finding of a large rearrangement. These cases suggest that mitochondrial DNA mutations can cause cyclic vomiting syndrome. Mitochondrial disease should be considered in cases of cyclic vomiting, especially those with additional pathology or possible maternal inheritance. Initial screening should include plasma lactate and Urine Organic Acids obtained during an episode.
Sabine A Fuchs - One of the best experts on this subject based on the ideXlab platform.
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mdh1 deficiency is a metabolic disorder of the malate aspartate shuttle associated with early onset severe encephalopathy
Human Genetics, 2019Co-Authors: Melissa H Broeks, Hanan E Shamseldin, Amal Alhashem, Mais Hashem, Firdous Abdulwahab, Tarfa Alshedi, Iman Alobaid, Fried J T Zwartkruis, Denise Westland, Sabine A FuchsAbstract:The reversible oxidation of l-malate to oxaloacetate is catalyzed by NAD(H)-dependent malate dehydrogenase (MDH). MDH plays essential roles in the malate–aspartate shuttle and the tricarboxylic acid cycle. These metabolic processes are important in mitochondrial NADH supply for oxidative phosphorylation. Recently, bi-allelic mutations in mitochondrial MDH2 were identified in patients with global developmental delay, epilepsy and lactic acidosis. We now report two patients from an extended consanguineous family with a deleterious variant in the cytosolic isoenzyme of MDH (MDH1). The homozygous missense variant in the NAD+-binding domain of MDH1 led to severely diminished MDH protein expression. The patients presented with global developmental delay, epilepsy and progressive microcephaly. Both patients had normal concentrations of plasma amino Acids, acylcarnitines, lactate, and Urine Organic Acids. To identify the metabolic consequences of MDH1 deficiency, untargeted metabolomics was performed on dried blood spots (DBS) from the patients and in MDH1 knockout HEK293 cells that were generated by Crispr/Cas9. Increased levels of glutamate and glycerol-3-phosphate were found in DBS of both patients. In MDH1 KO HEK293 cells, increased levels of glycerol-3-phosphate were also observed, as well as increased levels of aspartate and decreased levels of fumarate. The consistent finding of increased concentrations of glycerol-3-phosphate may represent a compensatory mechanism to enhance cytosolic oxidation of NADH by the glycerol-P-shuttle. In conclusion, MDH1 deficiency is a new metabolic defect in the malate–aspartate shuttle characterized by a severe neurodevelopmental phenotype with elevated concentrations of glycerol-3-phosphate as a potential biomarker.
Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.
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Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment
Journal of Inherited Metabolic Disease, 2011Co-Authors: Annet M. Bosch, Ronald J A Wanders, Marinus Duran, Nico G. G. M. Abeling, Lodewijk Ijlst, Hennie Knoester, Alida E. M. Stroomer, Gepke Visser, Frits A. Wijburg, Hans R. WaterhamAbstract:We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and Urine Organic Acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation defect (MADD, ethylmalonic/adipic acid syndrome). Subsequently, a profound flavin deficiency in spite of a normal dietary riboflavin intake was established in the plasma of all three children, suggesting a riboflavin transporter defect. Genetic analysis of these patients demonstrated mutations in the C20orf54 gene which encodes the human homolog of a rat riboflavin transporter. This gene was recently implicated in the Brown-Vialetto-Van Laere syndrome, a rare neurological disorder which may either present in infancy with neurological deterioration with hypotonia, respiratory insufficiency and early death, or later in life with deafness and progressive ponto-bulbar palsy. Supplementation of riboflavin rapidly improved the clinical symptoms as well as the biochemical abnormalities in our patients, demonstrating that high dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome as well as for the Fazio Londe syndrome which is considered to be the same disease entity without the deafness.
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Succinyl-CoA Ligase Deficiency: A Mitochondrial Hepatoencephalomyopathy
Pediatric Research, 2010Co-Authors: Johan L K Van Hove, Margarita S Saenz, Janet A Thomas, Renata C Gallagher, Laura Z Fenton, Sarah Shanske, Sommer M Myers, Ronald J A Wanders, Mark A Lovell, Jos RuiterAbstract:This patient presented on the first day of life with pronounced lactic acidosis with an elevated lactate/pyruvate ratio. Urine Organic Acids showed Krebs cycle metabolites and mildly elevated methylmalonate and methylcitrate. The acylcarnitine profile showed elevated propionylcarnitine and succinylcarnitine. Amino Acids showed elevated glutamic acid, glutamine, proline, and alanine. From the age 2 of mo on, she had elevated transaminases and intermittent episodes of liver failure. Liver biopsy showed steatosis and a decrease of mitochondrial DNA to 50% of control. She had bilateral sensorineural hearing loss. Over the course of the first 2 y of life, she developed a progressively severe myopathy with pronounced muscle weakness eventually leading to respiratory failure, Leigh disease, and recurrent hepatic failure. The hepatic symptoms and the metabolic parameters temporarily improved on treatment with aspartate, but neither muscle symptoms nor brain lesions improved. Laboratory testing revealed a deficiency of succinyl-CoA ligase enzyme activity and protein in fibroblasts because of a novel homozygous mutation in the SUCLG1 gene: c.40A>T (p.M14L). Functional analysis suggests that this methionine is more likely to function as the translation initiator methionine, explaining the pathogenic nature of the mutation. Succinyl-CoA ligase deficiency due to an SUCLG1 mutation is a new cause for mitochondrial hepatoencephalomyopathy.
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novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase i deficiency
Molecular Genetics and Metabolism, 2005Co-Authors: Stanley H Korman, Hans R. Waterham, Alisa Gutman, Cornelis Jakobs, Ronald J A WandersAbstract:Abstract Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The Urine Organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/− hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C > A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive Organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C 12 dicarboxylic (dodecanedioic) acid. This C 12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic Acids by mitochondria after their initial shortening by β-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of Urine Organic Acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.
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Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency
Molecular Genetics and Metabolism, 2005Co-Authors: Stanley H Korman, Hans R. Waterham, Alisa Gutman, Cornelis Jakobs, Ronald J A WandersAbstract:Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The Urine Organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive Organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic Acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of Urine Organic Acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.
Hans R. Waterham - One of the best experts on this subject based on the ideXlab platform.
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Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment
Journal of Inherited Metabolic Disease, 2011Co-Authors: Annet M. Bosch, Ronald J A Wanders, Marinus Duran, Nico G. G. M. Abeling, Lodewijk Ijlst, Hennie Knoester, Alida E. M. Stroomer, Gepke Visser, Frits A. Wijburg, Hans R. WaterhamAbstract:We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and Urine Organic Acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation defect (MADD, ethylmalonic/adipic acid syndrome). Subsequently, a profound flavin deficiency in spite of a normal dietary riboflavin intake was established in the plasma of all three children, suggesting a riboflavin transporter defect. Genetic analysis of these patients demonstrated mutations in the C20orf54 gene which encodes the human homolog of a rat riboflavin transporter. This gene was recently implicated in the Brown-Vialetto-Van Laere syndrome, a rare neurological disorder which may either present in infancy with neurological deterioration with hypotonia, respiratory insufficiency and early death, or later in life with deafness and progressive ponto-bulbar palsy. Supplementation of riboflavin rapidly improved the clinical symptoms as well as the biochemical abnormalities in our patients, demonstrating that high dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome as well as for the Fazio Londe syndrome which is considered to be the same disease entity without the deafness.
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novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase i deficiency
Molecular Genetics and Metabolism, 2005Co-Authors: Stanley H Korman, Hans R. Waterham, Alisa Gutman, Cornelis Jakobs, Ronald J A WandersAbstract:Abstract Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The Urine Organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/− hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C > A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive Organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C 12 dicarboxylic (dodecanedioic) acid. This C 12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic Acids by mitochondria after their initial shortening by β-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of Urine Organic Acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.
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Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency
Molecular Genetics and Metabolism, 2005Co-Authors: Stanley H Korman, Hans R. Waterham, Alisa Gutman, Cornelis Jakobs, Ronald J A WandersAbstract:Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The Urine Organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive Organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic Acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of Urine Organic Acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.
Xin You - One of the best experts on this subject based on the ideXlab platform.
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Corrigendum: Urine Organic Acids as Potential Biomarkers for Autism-Spectrum Disorder in Chinese Children.
Frontiers in Cellular Neuroscience, 2019Co-Authors: Qiao Chen, You Qiao, Xin You, Ying TaoAbstract:[This corrects the article DOI: 10.3389/fncel.2019.00150.].
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Urine Organic Acids as Potential Biomarkers for Autism-Spectrum Disorder in Chinese Children.
Frontiers in Cellular Neuroscience, 2019Co-Authors: Qiao Chen, You Qiao, Xin You, Ying TaoAbstract:Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lacks clear biological biomarkers. Existing diagnostic methods focus on behavioral and performance characteristics, which complicates the diagnosis of patients younger than 3 years-old. The purpose of this study is to characterize metabolic features of ASD that could be used to identify potential biomarkers for diagnosis and exploration of ASD etiology. We used gas chromatography-mass spectrometry (GC/MS) to evaluate major metabolic fluctuations in 76 Organic Acids present in Urine from 156 children with ASD and from 64 non-autistic children. Three algorithms, Partial Least Squares-Discriminant Analysis (PLS-DA), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost), were used to develop models to distinguish ASD from typically developing (TD) children and to detect potential biomarkers. In an independent testing set, full model of XGBoost with all 76 Acids achieved an AUR of 0.94, while reduced model with top 20 Acids discovered by voting from these three algorithms achieved 0.93 and represent a good collection of potential ASD biomarkers. In summary, Urine Organic Acids detection with GC/MS combined with XGBoost algorithm could represent a novel and accurate strategy for diagnosis of autism and the discovered potential biomarkers could be valuable for future research on the pathogenesis of autism and possible interventions.
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Table_1_Urine Organic Acids as Potential Biomarkers for Autism-Spectrum Disorder in Chinese Children.docx
2019Co-Authors: Qiao Chen, You Qiao, Ying Tao, Xin YouAbstract:Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lacks clear biological biomarkers. Existing diagnostic methods focus on behavioral and performance characteristics, which complicates the diagnosis of patients younger than 3 years-old. The purpose of this study is to characterize metabolic features of ASD that could be used to identify potential biomarkers for diagnosis and exploration of ASD etiology. We used gas chromatography-mass spectrometry (GC/MS) to evaluate major metabolic fluctuations in 76 Organic Acids present in Urine from 156 children with ASD and from 64 non-autistic children. Three algorithms, Partial Least Squares-Discriminant Analysis (PLS-DA), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost), were used to develop models to distinguish ASD from typically developing (TD) children and to detect potential biomarkers. In an independent testing set, full model of XGBoost with all 76 Acids achieved an AUR of 0.94, while reduced model with top 20 Acids discovered by voting from these three algorithms achieved 0.93 and represent a good collection of potential ASD biomarkers. In summary, Urine Organic Acids detection with GC/MS combined with XGBoost algorithm could represent a novel and accurate strategy for diagnosis of autism and the discovered potential biomarkers could be valuable for future research on the pathogenesis of autism and possible interventions.
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Image_1_Urine Organic Acids as Potential Biomarkers for Autism-Spectrum Disorder in Chinese Children.JPEG
2019Co-Authors: Qiao Chen, You Qiao, Ying Tao, Xin YouAbstract:Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lacks clear biological biomarkers. Existing diagnostic methods focus on behavioral and performance characteristics, which complicates the diagnosis of patients younger than 3 years-old. The purpose of this study is to characterize metabolic features of ASD that could be used to identify potential biomarkers for diagnosis and exploration of ASD etiology. We used gas chromatography-mass spectrometry (GC/MS) to evaluate major metabolic fluctuations in 76 Organic Acids present in Urine from 156 children with ASD and from 64 non-autistic children. Three algorithms, Partial Least Squares-Discriminant Analysis (PLS-DA), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost), were used to develop models to distinguish ASD from typically developing (TD) children and to detect potential biomarkers. In an independent testing set, full model of XGBoost with all 76 Acids achieved an AUR of 0.94, while reduced model with top 20 Acids discovered by voting from these three algorithms achieved 0.93 and represent a good collection of potential ASD biomarkers. In summary, Urine Organic Acids detection with GC/MS combined with XGBoost algorithm could represent a novel and accurate strategy for diagnosis of autism and the discovered potential biomarkers could be valuable for future research on the pathogenesis of autism and possible interventions.
