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Regina Ensenauer - One of the best experts on this subject based on the ideXlab platform.
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Aspects of Newborn Screening in Isovaleric Acidemia
International journal of neonatal screening, 2018Co-Authors: Andrea Schlune, Ertan Mayatepek, Anselma Riederer, Regina EnsenauerAbstract:Isovaleric Acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). The inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an "acute neonatal" and a "chronic intermittent" form. An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with l-carnitine and/or l-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required.
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Clinical and neurocognitive outcome in symptomatic Isovaleric Acidemia Open Access
2013Co-Authors: Sarah C Grünert, Jerry Vockley, Willy Lehnert, Udo Wendel, Martin Lindner, Michael Leichsenring, Otfried K Schwab, Regina EnsenauerAbstract:Background: Despite its first description over 40 years ago, knowledge of the clinical course of Isovaleric Acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. Methods: Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. Results: 57 % of study patients (12/21) were diagnosed within the first weeks of life and 43 % (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44 % of investigated study patients (7/16) showed mild motor dysfunction and only 19 % (3/16) had cognitive deficits. No other organ complications were found. The patients ’ intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. Conclusions: Within the group of “classical ” organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening
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Clinical and neurocognitive outcome in symptomatic Isovaleric Acidemia
Orphanet Journal of Rare Diseases, 2012Co-Authors: Sarah C Grünert, Jerry Vockley, Willy Lehnert, Udo Wendel, Martin Lindner, Michael Leichsenring, K Otfried Schwab, Regina EnsenauerAbstract:Background Despite its first description over 40 years ago, knowledge of the clinical course of Isovaleric Acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. Methods Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. Results 57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. Conclusions Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.
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Newborn Screening for Isovaleric Acidemia Using Tandem Mass Spectrometry: Data from 1.6 Million Newborns
Clinical chemistry, 2011Co-Authors: Regina Ensenauer, Ralph Fingerhut, Esther M. Maier, Roman Polanetz, Bernhard Olgemöller, Wulf Röschinger, Ania C. MuntauAbstract:BACKGROUND: Electrospray ionization–tandem mass spectrometry (ESI-MS/MS) has been used in the Bavarian newborn screening (NBS) program since 1999. The use of ESI-MS/MS has led to the inclusion of Isovaleric Acidemia (IVA) into NBS. We retrospectively evaluated data on more than 1.6 million newborns screened during 9.5 years. METHODS: Acylcarnitines from whole blood spotted on filter paper were converted to their corresponding butyl esters, and the samples were analyzed by use of ESI-MS/MS with stable isotope labeled internal standards. RESULTS: A total of 24 individuals with IVA were detected by use of a multiparametric threshold criteria panel including isovalerylcarnitine (C5) and the ratios of C5 to octanoyl-, butyryl-, and propionylcarnitine. A cutoff set at the 99.99th percentile for isolated C5 or at the 99th percentile for C5 plus at least 2 ratios resulted in a positive predictive value for IVA screening of 7.0% and an overall recall rate of 0.024%. Adjusted reference ranges for age and birth weight were applied, and the incidence of IVA in the study population was calculated to be 1 in 67 000. Missed cases were not brought to our attention. IVA was also detectable in cord blood and early postnatal blood samples. CONCLUSIONS: IVA can be reliably detected in NBS through acylcarnitine analysis in dried blood spots by using multiparametric threshold criteria. Further improvement (positive predictive value 13.0%, recall rate 0.01%) can be achieved by using more stringent recall criteria. In view of the potentially life-threatening natural course of IVA in early life, presymptomatic diagnosis may thus prevent mortality and morbidity.
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Isovaleric Acidemia new aspects of genetic and phenotypic heterogeneity
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2006Co-Authors: Jerry Vockley, Regina EnsenauerAbstract:Isovaleric Acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic Acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and interfamilial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years. 2006 Wiley-Liss, Inc.
Jerry Vockley - One of the best experts on this subject based on the ideXlab platform.
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Clinical and neurocognitive outcome in symptomatic Isovaleric Acidemia Open Access
2013Co-Authors: Sarah C Grünert, Jerry Vockley, Willy Lehnert, Udo Wendel, Martin Lindner, Michael Leichsenring, Otfried K Schwab, Regina EnsenauerAbstract:Background: Despite its first description over 40 years ago, knowledge of the clinical course of Isovaleric Acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. Methods: Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. Results: 57 % of study patients (12/21) were diagnosed within the first weeks of life and 43 % (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44 % of investigated study patients (7/16) showed mild motor dysfunction and only 19 % (3/16) had cognitive deficits. No other organ complications were found. The patients ’ intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. Conclusions: Within the group of “classical ” organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening
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Clinical and neurocognitive outcome in symptomatic Isovaleric Acidemia
Orphanet Journal of Rare Diseases, 2012Co-Authors: Sarah C Grünert, Jerry Vockley, Willy Lehnert, Udo Wendel, Martin Lindner, Michael Leichsenring, K Otfried Schwab, Regina EnsenauerAbstract:Background Despite its first description over 40 years ago, knowledge of the clinical course of Isovaleric Acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. Methods Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. Results 57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. Conclusions Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.
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different spectrum of mutations of isovaleryl coa dehydrogenase ivd gene in korean patients with Isovaleric Acidemia
Molecular Genetics and Metabolism, 2007Co-Authors: Yong-wha Lee, Jerry Vockley, Dong Hwan Lee, Nam-doo Kim, You Kyoung LeeAbstract:Isovaleric Acidemia (IVA) is an autosomal recessive inborn error of the leucine metabolism that is caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD). Recent application of tandem mass spectrometry to newborn screening has allowed a significant expansion of the recognition of individuals with IVD deficiency. Although many patients have been reported worldwide, there are no genetically confirmed patients in Korea. This study characterizes IVD mutations in seven Korean IVA patients from six unrelated families. Bi-directional sequencing analysis identified two novel variations affecting consensus splice sites (c.144+1G>T in intron 1 and c.457-3_2CA>GG in intron 4) and three novel variations altering coding sequences (c.149G>T; Arg21Leu, c.832A>G; Ser249Gly, and c.1135T>G; Phe350Val). Five patients from four families were found to be compound heterozygotes while two unrelated patients were homozygous for the c.457-3_2CA>GG variation. Reverse-transcription polymerase chain reaction confirmed that both intron variations cause aberrant splicing. Furthermore, analysis of cultured lymphocyte extracts of the seven patients showed no detectable enzyme activity and reduced levels of IVD protein (<10.0% of control) in all samples. These results confirm IVD mutations in Korean patients with IVA and reveal that the mutation spectrum is different from previously reported patients.
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Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with Isovaleric Acidemia.
Molecular genetics and metabolism, 2007Co-Authors: Yong-wha Lee, Jerry Vockley, Dong Hwan Lee, Nam-doo Kim, You Kyoung LeeAbstract:Isovaleric Acidemia (IVA) is an autosomal recessive inborn error of the leucine metabolism that is caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD). Recent application of tandem mass spectrometry to newborn screening has allowed a significant expansion of the recognition of individuals with IVD deficiency. Although many patients have been reported worldwide, there are no genetically confirmed patients in Korea. This study characterizes IVD mutations in seven Korean IVA patients from six unrelated families. Bi-directional sequencing analysis identified two novel variations affecting consensus splice sites (c.144+1G>T in intron 1 and c.457-3_2CA>GG in intron 4) and three novel variations altering coding sequences (c.149G>T; Arg21Leu, c.832A>G; Ser249Gly, and c.1135T>G; Phe350Val). Five patients from four families were found to be compound heterozygotes while two unrelated patients were homozygous for the c.457-3_2CA>GG variation. Reverse-transcription polymerase chain reaction confirmed that both intron variations cause aberrant splicing. Furthermore, analysis of cultured lymphocyte extracts of the seven patients showed no detectable enzyme activity and reduced levels of IVD protein (
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Isovaleric Acidemia new aspects of genetic and phenotypic heterogeneity
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2006Co-Authors: Jerry Vockley, Regina EnsenauerAbstract:Isovaleric Acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic Acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and interfamilial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years. 2006 Wiley-Liss, Inc.
M. Dercksen - One of the best experts on this subject based on the ideXlab platform.
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Polyunsaturated fatty acid status in treated Isovaleric Acidemia patients
European Journal of Clinical Nutrition, 2016Co-Authors: M. Dercksen, W Kulik, L J Mienie, C J Reinecke, R J A Wanders, M DuranAbstract:Background/Objectives: Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with Isovaleric Acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. Subjects/Methods: We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. Results: The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P
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Polyunsaturated fatty acid status in treated Isovaleric Acidemia patients
European journal of clinical nutrition, 2016Co-Authors: M. Dercksen, L J Mienie, W Kulik, C J Reinecke, R J A Wanders, Marinus DuranAbstract:Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with Isovaleric Acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P
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polyunsaturated fatty acid status in treated Isovaleric Acidemia patients
European Journal of Clinical Nutrition, 2016Co-Authors: L J Mienie, M. Dercksen, W Kulik, C J Reinecke, R J A Wanders, M DuranAbstract:Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with Isovaleric Acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P<0.001) and omega-6 (in particular 20:3n-6 P<0.0001 and 20:4n-6 P=0.0005) fatty acids. In addition, an elevation in omega-9 fatty acids, with the exception of 20:3n-9 and C22:1n-9, was not suggestive of complete essential fatty acid deficiency but rather indicative of isolated and/or combined omega-3 and omega-6 fatty acid depletion. This study emphasizes the potential nutritional insufficiencies that may occur because of therapeutic intervention in IVA.
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Isovaleric Acidemia: an integrated approach toward predictive laboratory medicine
2014Co-Authors: M. DercksenAbstract:Isovaleric Acidemia (IVA) is an autosomal recessive disorder caused by isovaleryl-CoA dehydrogenase (IVD) deficiency (E.C.1.2.99.10) and patients present with a heterogeneous phenotype, ranging from metabolically mild and/or intermittent to metabolically severe. A cohort of ten IVA patients with a mutual homozygous mutation, c.367G>A (p.G123R), was identified. The IVA patient group however presented with a broad clinical phenotype despite the genetic homogeneity. The homozygous group as well as twelve obligate heterozygotes and relevant control subjects were available for an integrated investigation. This thesis, entitled "Isovaleric Acidemia: an integrated approach toward predictive laboratory medicine" presents the outcome of the well-established clinical, biochemical and genetic approach which is followed to characterize an inborn error of metabolism as well as the application of contemporary metabolomics technology consisting of semi-targeted GC-MS analysis as well as bioinformatics applications e.g. PCA, PLS-DA and CONCA, for the disclosure of the metabolic profiles prevailing in the IVA cohort. Furthermore, secondary hyperammonemia observed in IVA was expensively investigated and included the study of N-acetylglutamate synthase (NAGS) and the inhibition of this initial step in the urea cycle by isovaleryl-CoA and other short-chain- and short/branched acyl-CoAs. In additional, the study also resulted in the development of novel IVD and NAGS enzyme assays applicable in the diagnostics of IEMs. The integrated outcomes of these approaches opened the possibility to propose a model on future predictive laboratory medicine in the investigations of inherited metabolic diseases.
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Clinical variability of Isovaleric Acidemia in a genetically homogeneous population
Journal of inherited metabolic disease, 2012Co-Authors: M. Dercksen, L J Mienie, Marinus Duran, C J Reinecke, Lodewijk Ijlst, Jos P.n. Ruiter, Hans R. Waterham, R J A WandersAbstract:Isovaleric Acidemia (IVA) is one of the most common organic Acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.
L J Mienie - One of the best experts on this subject based on the ideXlab platform.
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Polyunsaturated fatty acid status in treated Isovaleric Acidemia patients
European journal of clinical nutrition, 2016Co-Authors: M. Dercksen, L J Mienie, W Kulik, C J Reinecke, R J A Wanders, Marinus DuranAbstract:Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with Isovaleric Acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P
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polyunsaturated fatty acid status in treated Isovaleric Acidemia patients
European Journal of Clinical Nutrition, 2016Co-Authors: L J Mienie, M. Dercksen, W Kulik, C J Reinecke, R J A Wanders, M DuranAbstract:Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with Isovaleric Acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P<0.001) and omega-6 (in particular 20:3n-6 P<0.0001 and 20:4n-6 P=0.0005) fatty acids. In addition, an elevation in omega-9 fatty acids, with the exception of 20:3n-9 and C22:1n-9, was not suggestive of complete essential fatty acid deficiency but rather indicative of isolated and/or combined omega-3 and omega-6 fatty acid depletion. This study emphasizes the potential nutritional insufficiencies that may occur because of therapeutic intervention in IVA.
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Organic acid profile of Isovaleric Acidemia: a comprehensive metabolomics approach
Metabolomics, 2013Co-Authors: Marli Dercksen, L J Mienie, Marinus Duran, Gerhard Koekemoer, Ronald J. A. Wanders, C J ReineckeAbstract:Isovaleric Acidemia (IVA, MIM 248600) can be a severe and potentially life-threatening disease in affected neonates, but with a positive prognosis on treatment for some phenotypes. This study presents the first application of metabolomics to evaluate the metabolite profiles derived from urine samples of untreated and treated IVA patients as well as of obligate heterozygotes. All IVA patients carried the same homozygous c.367 G > A nucleotide change in exon 4 of the IVD gene but manifested phenotypic diversity. Concurrent class analysis (CONCA) was used to compare all the metabolites from the original complete data set obtained from the three case and two control groups used in this investigation. This application of CONCA has not been reported previously, and is used here to compare four different modes of scaling of all metabolites. The variables important in discrimination from the CONCA thus enabled the recognition of different metabolic patterns encapsulated within the data sets that would not have been revealed by using only one mode of scaling. Application of multivariate and univariate analyses disclosed 11 important metabolites that distinguished untreated IVA from controls. These included well-established diagnostic biomarkers of IVA, endogenous detoxification markers, and 3-hydroxycaproic acid, an indicator of ketosis, but not reported previously for this disease. Nine metabolites were identified that reflected the effect of treatment of IVA. They included detoxification products and indicators related to the high carbohydrate and low protein diet which formed the hallmark of the treatment. This investigation also provides the first comparative metabolite profile for heterozygotes of this inherited metabolic disorder. The detection of informative metabolites in even very low concentrations in all three experimental groups highlights the potential advantage of the holistic mode of analysis of inherited metabolic diseases in a metabolomics investigation.
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Clinical variability of Isovaleric Acidemia in a genetically homogeneous population
Journal of inherited metabolic disease, 2012Co-Authors: M. Dercksen, L J Mienie, Marinus Duran, C J Reinecke, Lodewijk Ijlst, Jos P.n. Ruiter, Hans R. Waterham, R J A WandersAbstract:Isovaleric Acidemia (IVA) is one of the most common organic Acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.
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Amino-acid depletion induced by abnormal amino-acid conjugation and protein restriction in Isovaleric Acidemia
European Journal of Clinical Nutrition, 2007Co-Authors: D T Loots, L J Mienie, E ErasmusAbstract:Background: Previously, we detected 19 ‘new’ amino-acid conjugates in the urine of patients with Isovaleric Acidemia. There is currently a poor understanding of the relationship between the clinical symptoms and the excreted metabolites occurring in these patients, owing to insufficient metabolite characterization and quantification. Consequently, controversial treatment protocols exist, particularly pertaining to dietary protein restriction. Objective: To determine the effect of the previously identified amino-acid conjugates and conventional dietary protein restriction therapy, on the free amino-acid concentrations in Isovaleric Acidemia patients, to better explain the clinical symptoms and develop more effective therapy. Design: Free amino-acid quantification via liquid chromatography mass spectrometry (LC-MS-MS) was performed on pre- and post-treatment urine or serum samples collected from six Isovaleric Acidemia patients, previously investigated for the presence of new induced N -isovaleryl and N -acetyl-amino-acid conjugates. Results: Depleted amino-acid concentrations were detected in varying degrees in all six patients and did not recover after conventional treatment. Conclusions: The 19 potentially toxic metabolites previously identified and the consequent amino-acid depletions detected in this study, may explain many of the clinical symptoms associated with Isovaleric Acidemia. Furthermore, the occurrence of amino-acid depletions in these patients, steers away from the controversial dietary protein restriction treatment protocols, and towards dietary leucine restriction alone with essential amino-acid supplementation, in combination with glycine and L -carnitine supplementation.
Inmaculada Vives - One of the best experts on this subject based on the ideXlab platform.
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Genotype and phenotype characterization in a Spanish cohort with Isovaleric Acidemia
Journal of Human Genetics, 2017Co-Authors: María-luz Couce, María A Bueno, Patricia Barros, Amaya Belanger-quintana, Ana M Márquez-armenteros, Isidro Vitoria, María Teresa García-silva, Luís Aldámiz-echevarría, Javier Blasco, Inmaculada VivesAbstract:Isovaleric Acidemia (IVA) is a rare disorder of leucine metabolism. We carried out a multicenter study of IVA patients diagnosed by newborn screening (NBS) or symptoms clinics over a period of 28 years in Spain. Evaluated at diagnosis, data included age, detection method, levels of C5 and IVG, enzymatic studies, clinical presentation parameters and genotype in 16 patients. Follow-up data included C5 levels, intellectual quotient and correlation genotype–phenotype. IVA was detected by NBS in 8 patients (prevalence of 1/326 629). Except 1, all the 8 patients identified by NBS were asymptomatic at diagnosis and had isovalerylcarnitine (C5) levels of 1.6–6.4 μ M and isovalerylglycine (IVG) levels 3400 mmol per mol creatinine. The percentage of isovalerate incorporation in fibroblasts was 64–80% in patients detected by NBS and 4.9–13% in symptomatic patients. Cognitive function was within normal ranges in all patients but was negatively correlated with IVG at detection (−0.592; P
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genotype and phenotype characterization in a spanish cohort with Isovaleric Acidemia
Journal of Human Genetics, 2017Co-Authors: María-luz Couce, María A Bueno, Patricia Barros, Isidro Vitoria, Javier Blasco, Luis Aldamizechevarria, Amaya Belangerquintana, Mariateresa Garciasilva, Ana M Marquezarmenteros, Inmaculada VivesAbstract:Isovaleric Acidemia (IVA) is a rare disorder of leucine metabolism. We carried out a multicenter study of IVA patients diagnosed by newborn screening (NBS) or symptoms clinics over a period of 28 years in Spain. Evaluated at diagnosis, data included age, detection method, levels of C5 and IVG, enzymatic studies, clinical presentation parameters and genotype in 16 patients. Follow-up data included C5 levels, intellectual quotient and correlation genotype-phenotype. IVA was detected by NBS in 8 patients (prevalence of 1/326 629). Except 1, all the 8 patients identified by NBS were asymptomatic at diagnosis and had isovalerylcarnitine (C5) levels of 1.6-6.4 μM and isovalerylglycine (IVG) levels 3400 mmol per mol creatinine. The percentage of isovalerate incorporation in fibroblasts was 64-80% in patients detected by NBS and 4.9-13% in symptomatic patients. Cognitive function was within normal ranges in all patients but was negatively correlated with IVG at detection (-0.592; P<0.05). The genetic analysis revealed nine novel mutations. The clinical/biochemical phenotype correlated fairly well with the phenotype predicted by the mutations found. In conclusion, although blood C5 levels have traditionally been considered the prognostic marker of choice, urine IVG levels would appear to be a better predictor, as they correlated well with severity of mutations and were associated with a lower incorporation rate of IVA in fibroblasts and a less favorable clinical course.
