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Aciduria

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Saskia B Wortmann – 1st expert on this subject based on the ideXlab platform

  • mild orotic Aciduria in umps heterozygotes a metabolic finding without clinical consequences
    Journal of Inherited Metabolic Disease, 2017
    Co-Authors: Saskia B Wortmann, Margaret A Chen, Roberto Colombo, Alessandro Pontoglio, Bader Alhaddad, Lorenzo D Botto, Tatiana Yuzyuk, Curtis R Coughlin

    Abstract:

    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.

  • leucine loading test is only discriminative for 3 methylglutaconic Aciduria due to auh defect
    JIMD Reports, 2014
    Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Silvia Sequeira, R A Wevers, Eva Morava

    Abstract:

    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.

  • 3-Methylglutaconic Aciduria—lessons from 50 genes and 977 patients
    Journal of Inherited Metabolic Disease, 2013
    Co-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 Isohanni

    Abstract:

    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.

Cornelis Jakobs – 2nd expert on this subject based on the ideXlab platform

  • Cerebral Organic Acidurias
    Physician's Guide to the Diagnosis Treatment and Follow-Up of Inherited Metabolic Diseases, 2013
    Co-Authors: S. Kolker, E.a. Struijs, M.s. Van Der Knaap, Cornelis Jakobs

    Abstract:

    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.

  • Progress in understanding 2-hydroxyglutaric Acidurias.
    Journal of Inherited Metabolic Disease, 2012
    Co-Authors: M. Kranendijk, Marjo S. Van Der Knaap, Eduard A. Struys, Gajja S. Salomons, Cornelis Jakobs

    Abstract:

    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.

  • Mutations in phenotypically mild D‐2‐hydroxyglutaric Aciduria
    Annals of Neurology, 2005
    Co-Authors: Eduard A. Struys, Nanda M. Verhoeven, Gajja S. Salomons, Stanley H. Korman, Emile Van Schaftingen, Younes Achouri, Ps Darmin, Cornelis Jakobs

    Abstract:

    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.

Leo A J Kluijtmans – 3rd expert on this subject based on the ideXlab platform

  • leucine loading test is only discriminative for 3 methylglutaconic Aciduria due to auh defect
    JIMD Reports, 2014
    Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Silvia Sequeira, R A Wevers, Eva Morava

    Abstract:

    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.

  • 3-Methylglutaconic Aciduria—lessons from 50 genes and 977 patients
    Journal of Inherited Metabolic Disease, 2013
    Co-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 Isohanni

    Abstract:

    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.

  • 3 methylglutaconic Aciduria lessons from 50 genes and 977 patients
    Journal of Inherited Metabolic Disease, 2013
    Co-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 Isohanni

    Abstract:

    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.