The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Saskia B Wortmann - One of the best experts on this subject based on the ideXlab platform.
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mild orotic Aciduria in umps heterozygotes a metabolic finding without clinical consequences
Journal of Inherited Metabolic Disease, 2017Co-Authors: Saskia B Wortmann, Margaret A Chen, Roberto Colombo, Alessandro Pontoglio, Bader Alhaddad, Lorenzo D Botto, Tatiana Yuzyuk, Curtis R CoughlinAbstract:Background Elevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic Aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic Aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue.
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leucine loading test is only discriminative for 3 methylglutaconic Aciduria due to auh defect
JIMD Reports, 2014Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Silvia Sequeira, R A Wevers, Eva MoravaAbstract:Currently, six inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature are known. The “Primary 3-methylglutaconic Aciduria,” 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted “Secondary 3-methylglutaconic Acidurias” (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, “not otherwise specified (NOS) 3-MGA-uria”), the origin of 3-methylglutaconic Aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic Aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic Aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic Aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic Aciduria in regular patient care.
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3-Methylglutaconic Aciduria—lessons from 50 genes and 977 patients
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike C. Vries, Pirjo IsohanniAbstract:Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH ), it derives from leucine degradation. In all other disorders with 3-methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH , TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature.
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3 methylglutaconic Aciduria lessons from 50 genes and 977 patients
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike De Vries, Pirjo IsohanniAbstract:Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature.
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inborn errors of metabolism with 3 methylglutaconic Aciduria as discriminative feature proper classification and nomenclature
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Eva Morava, M. Duran, Yair Anikster, P G Barth, Wolfgang Sperl, Johannes Zschocke, R A WeversAbstract:Increased urinary 3-methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic Aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I–V) in the order of discovery regardless of pathomechanism. Especially, the so called “unspecified” 3-methylglutaconic Aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these “inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature”. One should distinguish between “primary 3-methylglutaconic Aciduria” formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the—currently known—three groups of “secondary 3-methylglutaconic Aciduria”. The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-methylglutaconic Aciduria in whom the above mentioned syndromes have been excluded, should be referred to as “not otherwise specified (NOS) 3-MGA-uria” until elucidation of the underlying pathomechanism enables proper (possibly extended) classification.
Cornelis Jakobs - One of the best experts on this subject based on the ideXlab platform.
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Cerebral Organic Acidurias
Physician's Guide to the Diagnosis Treatment and Follow-Up of Inherited Metabolic Diseases, 2013Co-Authors: S. Kolker, E.a. Struijs, M.s. Van Der Knaap, Cornelis JakobsAbstract:A group of organic Acidurias, including Canavan disease (N-acetylaspartic Aciduria), glutaric Aciduria type I, l-2-hydroxylgutaric Aciduria and d-2-hydroxyglutaric Aciduria types I and II, are characterised by a predominantly or even exclusively neurological presentation and have therefore been termed ‘cerebral’. Frequent neurological symptoms are motor and/or mental retardation or regression, extrapyramidal movement disorders and epilepsy. These symptoms are the result of acute and/or chronic pathological changes in various brain regions including grey matter (cortex, basal ganglia, cerebellum) and white matter (periventricular and subcortical). Unlike ‘classic’ organic Acidurias (e.g. propionic and methylmalonic Aciduria), acute metabolic decompensations with hyperammonemia, metabolic acidosis and elevated concentrations of lactate and ketone bodies are uncommon for cerebral organic Acidurias. Biochemically, these diseases are characterised by accumulation of characteristic organic acids, mostly dicarboxylic acids, in body fluids. At high concentrations some of these may become neurotoxic. Since the blood–brain barrier has a low transport capacity for dicarboxylic acids, cerebral accumulation of dicarboxylic acids is facilitated. Impairment of brain energy metabolism is suggested to play a central role in the pathophysiology of this disease group. Metabolic treatment initiated in neonatally diagnosed patients with glutaric Aciduria type I has significantly improved the neurological outcome, whereas current treatment strategies for the other cerebral organic Acidurias are ineffective.
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Progress in understanding 2-hydroxyglutaric Acidurias.
Journal of Inherited Metabolic Disease, 2012Co-Authors: M. Kranendijk, Marjo S. Van Der Knaap, Eduard A. Struys, Gajja S. Salomons, Cornelis JakobsAbstract:The organic Acidurias d-2-hydroxyglutaric Aciduria (D-2-HGA), l-2-hydroxyglutaric Aciduria (L-2-HGA), and combined d,l-2-hydroxyglutaric Aciduria (D,L-2-HGA) cause neurological impairment at young age. Accumulation of d-2-hydroxyglutarate (D-2-HG) and/or l-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. The current review describes the knowledge gathered on 2-hydroxyglutaric Acidurias (2-HGA), since the description of the first patients in 1980. We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires.
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Mutations in phenotypically mild D‐2‐hydroxyglutaric Aciduria
Annals of Neurology, 2005Co-Authors: Eduard A. Struys, Nanda M. Verhoeven, Gajja S. Salomons, Stanley H. Korman, Younes Achouri, Emile Van Schaftingen, Ps Darmin, Cornelis JakobsAbstract:D-2-hydroxyglutaric Aciduria is a neurometabolic disorder with mild and severe phenotypes. Recently, we reported pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene as the cause of the severe phenotype of D-2-hydroxyglutaric Aciduria in two patients. Here, we report two novel pathogenic mutations in this gene in one patient with a mild presentation and two asymptomatic siblings with D-2-hydroxyglutaric Aciduria from two unrelated consanguineous Palestinian families: a splice error (IVS4-2A-->G) and a missense mutation (c.1315A-->G;p.Asn439Asp). Overexpression of this mutant protein showed marked reduction of the enzyme activity.
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mutations in the d 2 hydroxyglutarate dehydrogenase gene cause d 2 hydroxyglutaric Aciduria
American Journal of Human Genetics, 2005Co-Authors: Eduard A. Struys, Gajja S. Salomons, William J. Craigen, Younes Achouri, Emile Van Schaftingen, Salvatore Grosso, N M Verhoeven, Cornelis JakobsAbstract:d-2-hydroxyglutaric Aciduria is a neurometabolic disorder with both a mild and a severe phenotype and with unknown etiology. Recently, a novel enzyme, d-2-hydroxyglutarate dehydrogenase, which converts d-2-hydroxyglutarate into 2-ketoglutarate, and its gene were identified. In the genes of two unrelated patients affected with d-2-hydroxyglutaric Aciduria, we identified disease-causing mutations. One patient was homozygous for a missense mutation (c.1331T→C; p.Val444Ala). The other patient was compound heterozygous for a missense mutation (c.440T→G; p.Ile147Ser) and a splice-site mutation (IVS1-23A→G) that resulted in a null allele. Overexpression studies in HEK-293 cells of proteins containing the missense mutations showed a marked reduction of d-2-hydroxyglutarate dehydrogenase activity, proving that mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric Aciduria.
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D-2-hydroxyglutaric Aciduria and glutaric Aciduria type 1 in siblings: Coincidence, or linked disorders?
Neuropediatrics, 2004Co-Authors: Stanley H. Korman, Gajja S. Salomons, Alisa Gutman, R. Brooks, Cornelis JakobsAbstract:Glutaric Aciduria type 1 (GA1) and D-2-hydroxyglutaric Aciduria (D-2-HGA) are cerebral organic Acidurias characterized by the excretion of 3-hydroxyglutaric and D-2-hydroxyglutaric acids, respectively. GA1 is caused by a deficiency of glutaryl-CoA dehydrogenase encoded by the GCDH gene; the biochemical and genetic basis of D-2-HGA is unknown. We diagnosed GA1 in the son of consanguineous Palestinian parents, and D-2-HGA in his sister and brother. All three siblings were neurologically and developmentally normal. A small but abnormal increase in excretion of D-2-hydroxyglutaric acid was also found in the sibling with GA1. These observations suggested a possible pathophysiological link between these two disorders. The sibling with GA1 was homozygous whilst his siblings with D-2-HGA were heterozygous for a 1283 C>T missense mutation (T4161) in exon 11 of the GCDH gene. However, sequence analysis of the GCDH gene in 8 additional unrelated patients with D-2-HGA and 3 with combined D/L-2-HGA did not reveal any pathogenic mutations. The biochemical and genetic basis of D-2-HGA remains to be determined.
Leo A J Kluijtmans - One of the best experts on this subject based on the ideXlab platform.
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leucine loading test is only discriminative for 3 methylglutaconic Aciduria due to auh defect
JIMD Reports, 2014Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Silvia Sequeira, R A Wevers, Eva MoravaAbstract:Currently, six inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature are known. The “Primary 3-methylglutaconic Aciduria,” 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted “Secondary 3-methylglutaconic Acidurias” (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, “not otherwise specified (NOS) 3-MGA-uria”), the origin of 3-methylglutaconic Aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic Aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic Aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic Aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic Aciduria in regular patient care.
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3-Methylglutaconic Aciduria—lessons from 50 genes and 977 patients
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike C. Vries, Pirjo IsohanniAbstract:Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH ), it derives from leucine degradation. In all other disorders with 3-methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH , TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature.
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3 methylglutaconic Aciduria lessons from 50 genes and 977 patients
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike De Vries, Pirjo IsohanniAbstract:Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature.
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The 3-methylglutaconic Acidurias: what's new?
Journal of Inherited Metabolic Disease, 2010Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Udo F H Engelke, Ron A. Wevers, Eva MoravaAbstract:The heterogeneous group of 3-methylglutaconic Aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic Aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction.
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3 methylglutaconic Aciduria type i redefined a syndrome with late onset leukoencephalopathy
Neurology, 2010Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Ronald J.a. Wanders, Ference J Loupatty, Udo F H Engelke, Berry Kremer, A Graham, Michel A A P Willemsen, S L Hogg, Sabine IllsingerAbstract:Objective: 3-Methylglutaconic Aciduria type I is a rare inborn error of leucine catabolism. It is thought to present in childhood with nonspecific symptoms; it was even speculated to be a non-disease. The natural course of disease is unknown. Methods: This is a study on 10 patients with 3-methylglutaconic Aciduria type I. We present the clinical, neuroradiologic, biochemical, and genetic details on 2 new adult-onset patients and follow-up data on 2 patients from the literature. Results: Two unrelated patients with the characteristic biochemical findings of 3-methylglutaconic Aciduria type I presented in adulthood with progressive ataxia. One patient additionally had optic atrophy, the other spasticity and dementia. Three novel mutations were found in conserved regions of the AUH gene. In both patients, MRI revealed extensive white matter disease. Follow-up MRI in a 10-year-old boy, who presented earlier with isolated febrile seizures, showed mild abnormalities in deep white matter. Conclusion: We define 3-methylglutaconic Aciduria type I as an inborn error of metabolism with slowly progressive leukoencephalopathy clinically presenting in adulthood. In contrast to the nonspecific findings in pediatric cases, the clinical and neuroradiologic pattern in adult patients is highly characteristic. White matter abnormalities may already develop in the first decades of life. The variable features found in affected children may be coincidental. Long-term follow-up in children is essential to learn more about the natural course of this presumably slowly progressive disease. Dietary treatment with leucine restriction may be considered. Neurology (R) 2010;75:1079-1083
Stefan Kolker - One of the best experts on this subject based on the ideXlab platform.
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diagnosis and management of glutaric Aciduria type i revised recommendations
Journal of Inherited Metabolic Disease, 2011Co-Authors: Stefan Kolker, M. Duran, E Christensen, J V Leonard, Cheryl R Greenberg, Avihu Boneh, Alberto Burlina, M Dixon, Angels Garcia CazorlaAbstract:Glutaric Aciduria type I (synonym, glutaric acidemia type I) is a rare organic Aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric Aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric Aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.
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neurodegeneration and chronic renal failure in methylmalonic Aciduria a pathophysiological approach
Journal of Inherited Metabolic Disease, 2008Co-Authors: M A Morath, Jurgen G Okun, I Muller, Sven W Sauer, Friederike Horster, Georg F Hoffmann, Stefan KolkerAbstract:In the last decades the survival of patients with methylmalonic Aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called ‘toxic metabolite’ hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic Aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites (‘trapping’ hypothesis’) is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic Acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic Acidurias.
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neonatal screening for glutaric Aciduria type i strategies to proceed
Journal of Inherited Metabolic Disease, 2006Co-Authors: Martin Lindner, Georg F Hoffmann, S Ho, J Fanghoffmann, Stefan KolkerAbstract:Acute encephalopathic crisis in glutaric Aciduria type I results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and reduced life expectancy. A conditio sine qua non for the prevention of irreversible brain damage is timely diagnosis and start of therapy, i.e. before the onset of neurological disease. As there are no specific clinical signs or symptoms that allow a reliable detection of these patients before the manifestation of encephalopathic crises, neonatal screening programmes for glutaric Aciduria type I have been established in some countries using analysis of glutarylcarnitine in dried blood spots by tandem mass spectrometry. This article summarizes recent strategies, pitfalls and shortcomings of mass screening for glutaric Aciduria type I, focusing on the relevant risk of missing patients with a mild biochemical phenotype (i.e. low excretors). Furthermore, it evaluates a binary strategy – using glutarylcarnitine as primary variable and glutarylcarnitine/acylcarnitine ratios as secondary variable – to improve the diagnostic sensitivity and specificity of neonatal screening for glutaric Aciduria type I. An optimization of diagnostic as well as therapeutic procedures must be achieved before screening for glutaric Aciduria type I can be regarded as reliable and beneficial for all patients.
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neurodegeneration in methylmalonic Aciduria involves inhibition of complex ii and the tricarboxylic acid cycle and synergistically acting excitotoxicity
Journal of Biological Chemistry, 2002Co-Authors: Jurgen G Okun, Sven W Sauer, Friederike Horster, Georg F Hoffmann, Ertan Mayatepek, Lilla M Farkas, Patrik Feyh, Angela K Hinz, Klaus Unsicker, Stefan KolkerAbstract:Abstract Methylmalonic Acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic Aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.
Richard J. Rodenburg - One of the best experts on this subject based on the ideXlab platform.
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3-Methylglutaconic Aciduria—lessons from 50 genes and 977 patients
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike C. Vries, Pirjo IsohanniAbstract:Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH ), it derives from leucine degradation. In all other disorders with 3-methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH , TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature.
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3 methylglutaconic Aciduria lessons from 50 genes and 977 patients
Journal of Inherited Metabolic Disease, 2013Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike De Vries, Pirjo IsohanniAbstract:Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic Aciduria as discriminative feature.
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Coenzyme Q(10) is decreased in fibroblasts of patients with methylmalonic Aciduria but not in mevalonic Aciduria.
Journal of Inherited Metabolic Disease, 2009Co-Authors: Dorothea Haas, Richard J. Rodenburg, Friederike Horster, Georg F Hoffmann, Petra Niklowitz, E. R. Baumgartner, Chitra Prasad, Thomas Menke, Jurgen G OkunAbstract:The content of coenzyme Q10 (CoQ10) was examined in skin fibroblasts of 10 patients with mevalonic Aciduria (MVA) and of 22 patients with methylmalonic Aciduria (MMA). Patients with these inborn errors of metabolism are thought to be at risk for CoQ10 depletion either by direct inhibition of the proximal pathway of CoQ10 synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ10 concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ10 content in fibroblasts of patients with MMA was significantly reduced.
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biochemical and genetic analysis of 3 methylglutaconic Aciduria type iv a diagnostic strategy
Brain, 2009Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Richard J. Rodenburg, Maaike De Vries, Lambert P Van Den Heuvel, Marjan Huizing, An I Jonckheere, Katrin Heldt, U Wendel, Udo F H EngelkeAbstract:The heterogeneous group of 3-methylglutaconic Aciduria type IV consists of patients with various organ involvement and mostly progressive neurological impairment in combination with 3-methylglutaconic Aciduria and biochemical features of dysfunctional oxidative phosphorylation. Here we describe the clinical and biochemical phenotype in 18 children and define 4 clinical subgroups (encephalomyopathic, hepatocerebral, cardiomyopathic, myopathic). In the encephalomyopathic group with neurodegenerative symptoms and respiratory chain complex I deficiency, two of the children, presenting with mild Methylmalonic Aciduria, Leigh-like encephalomyopathy, dystonia and deafness, harboured SUCLA2 mutations. In children with a hepatocerebral phenotype most patients presented with complex I deficiency and mtDNA-depletion, three of which carried POLG1-mutations. In the cardiomyopathic subgroup most patients had complex V deficiency and an overlapping phenotype with that previously described in isolated complex V deficiency, in three patients a TMEM70 mutation was confirmed. In one male with a pure myopathic form and severe combined respiratory chain disorder, based on the pathogenomic histology of central core disease, RYR1 mutations were detected. In our patient group the presence of the biochemical marker 3-methylglutaconic acid was indicative for nuclear coded respiratory chain disorders. By delineating patient-groups we elucidated the genetic defect in 10 out of 18 children. Depending on the clinical and biochemical phenotype we suggest POLG1, SUCLA2, TMEM70 and RYR1 sequence analysis and mtDNA-depletion studies in children with 3-methylglutaconic Aciduria type IV.
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secondary mitochondrial dysfunction in propionic Aciduria a pathogenic role for endogenous mitochondrial toxins
Biochemical Journal, 2006Co-Authors: Marina A Schwab, Richard J. Rodenburg, Jurgen G Okun, Sven W Sauer, Georg F Hoffmann, Leo G Nijtmans, Lambert P Van Den Heuvel, Stefan Drose, Ullrich Brandt, Henk J Ter LaakAbstract:Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic Acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acidsdidnotinhibitPDHcactivity.InadditiontoPDHcinhibition, analysis ofrespiratory chain and tricarboxylic acid cycle enzymes alsorevealedaninhibitionbypropionyl-CoAonrespiratorychain complex III and α-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic Aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I‐IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.
