Journal of Child Neurology http://jcn.sagepub.com/ Topical Review Article: Organic Acidurias: A Review. Part 1 Pinar T. Ozand and Generoso G. Gascon J Child Neurol 1991 6: 196 DOI: 10.1177/088307389100600302 The online version of this article can be found at: http://jcn.sagepub.com/content/6/3/196 Published by: http://www.sagepublications.com Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jcn.sagepub.com/content/6/3/196.refs.html >> Version of Record - Jul 1, 1991 What is This? Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 Topical Review Article Organic Acidurias: A Review. Part 1 Pinar T. Ozand, MD, PhD; Generoso G. Gascon, MD Organic acidemias are disorders of intermediary metabolism that lead to accumulation of organic acids in biologic fluids, disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resul- tant systemic disease and progressive encephalopathy. While in some organic acidemias, disturbed acid-base metabolism is the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50 different phenotypes include impaired metabolism of branched-chain amino acids, vitamins, glucose, lipids, glutathione, and γ-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic man- ifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervous system. The age of presentation and the associated systemic, hematologic, and immune findings provide additional guidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusual neurologic presentations. (J Child Neurol 1991;6:196-219). organic acid is a compound that generates exercise. An excessive rate of production, however, nprotons at the prevailing pH of the human will lead to overt metabolic acidosis, as in diabetic organism. The accumulation of an organic acid in ketoacidosis. Another disorder, glycogen storage cells and fluids (plasma, cerebrospinal fluid, or disease type 1, is associated with impaired gluconeo- urine) indicates impaired intermediary metabolism genesis and produces significant hyper-lactic aci- and leads to a disease state called organic acidemia demia under normal physiologic conditions or 3 or organic aciduria. Since isovaleric acidemia, the following a load of a sugar, such as fructose.3 oldest known and treated, was described in 1966,12 more than 50 phenotypically different organic aci- Excess Organic Acids demias are now known, thanks to gas chromatogra- Besides ketone bodies and lactate, other organic phy/mass spectrometry (GC/MS). acids may be produced in excess. While they are barely detectable under normal physiologic condi- tions, such compounds accumulate in large amounts Pathogenesis when an enzyme activity related to their further breakdown is deficient. Traditionally, the term or- Ketonuria and Hyper- Lactic Acidemia ganic acidemia has been confined to these latter Many organic acids are produced during the catabo- conditions. Good examples are methylmalonic aci- lism of carbohydrates, lipids, and amino acids. Un- demia,4 propionic acidemia,5 isovaleric acidemia,66 der usual physiologic conditions, the protons and 3-hydroxy-3-methylglutaric aciduria secondary generated by these compounds are neutralized by to 3-hydroxy-3-methylglutaryl coenzyme A (CoA) the buffer systems available in cells and biologic flu- lyase deficiency.’ The accumulation of such organic ids. Examples of normally compensated metabolic acids not only causes compensated or overt acidosis acidosis are ketone body production in the fasting but is usually associated with grave systemic or neu- state and lactic acid accumulation following vigorous rologic disease. The primary enzyme deficiency re- sponsible for the generation of these compounds Received Nov 9, 1990. Received revised Feb 26, 1991. Ac- causes significant derangements of intracellular and cepted for publication March 4, 1991. mitochondrial metabolism. From the Department of Pediatrics (Drs Ozand and Gascon), and Biological and Medical Research (Dr Ozand), King Faisal Spe- cialist Hospital and Research Centre, Riyadh, Saudi Arabia. Interference With Intracellular Metabolism Address correspondence to Dr Ozand, Department of Pedi- An is the accumulation of and atrics (MBC-58), King Faisal Specialist Hospital and Research Cen- example glutaric tre, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia. 3-methylglutaric acids in glutaric aciduria type 1.8 196 Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 These two compounds accumulate because the en- Mitochondriopathies zyme responsible for further metabolism of glutaryl- Energy is generated by adenosine triphosphate syn- CoA, glutaryl-CoA dehydrogenase, is deficient.8 The thesis in a specific cellular organelle, the mitochon- disease is diagnosed by the accumulation of these drion, while electrons are transported to oxygen. two organic acids in biologic fluids. This accumula- The transport of electrons requires several cofactors tion is usually associated with compensated meta- and a complex protein machinery whose synthesis is bolic acidosis and causes mild overt acidosis only controlled both by cellular and mitochondrial DNA.19 when excessive glutaryl-CoA is produced from a Any derangement in this process will lead to the ac- load of the precursor.’ Nevertheless, glutaric acid- cumulation of lactate or fatty acid intermediates. By uria type 1 may remain inconsequential, except that definition, such disorders should be included in or- the intracellular accumulation of glutaryl-CoA inhib- ganic acidemias, since not only do they lead to the its glutamate decarboxylase,l° ie, the synthesis of generation of protons that alters the buffer metabo- y-aminobutyric acid in the central nervous system lism, but they also lead to progressive disease be- and the malate-aspartate shuttle in the liver.11 The cause of the derangement of intracellular pathways first of these events is possibly responsible for necro- affecting many aspects of normal cell function. How- sis of the basal ganglia IO, 12 and the second, for hypo- ever, they are commonly considered as mitochondri- glycemia.11 opathies because a distinct cell organelle is Another example is the accumulation of methyl- implicated .20 We shall include some mitochondriop- malonyl-CoA intramitochondrially in patients with athies in this review because their symptom complex methylmalonic acidemia.44 Increased excretion of shows significant overlap with other organic aci- methylmalonic acid results from its increased hy- demias. drolysis. Hyperammonemial3 and hypoglycemia 14 result from inhibitory effects of methylmalonyl-CoA Aminoaciduria Versus Organic Aciduria on ureagenesis and on pyruvate carboxylase (and Disorders of amino acid metabolism are associated hence on gluconeogenesis). with the accumulation of organic acids but are not These two examples can be extended to other or- usually classified within the organic acidemias. ganic acidemias. These disease states lead to accumu- Branched-chain aminoacidemia or maple syrup lation of organic acids in biologic fluids that might urine disease, for example, is caused by the defi- cause compensated or overt metabolic acidosis but ex- ciency of a dehydrogenase specific for branched- ert most of their progressive neurologic and systemic chain 2-keto acids.21 This leads to significant effects as a result of increasing derangements of the elevation of three branched-chain amino acids-leu- intracellular biochemical pathways. cine, isoleucine, and valine-as well as significant accumulation of their 2-keto acids. Maple syrup Interference With Energy Metabolism urine disease can be diagnosed by detection of either Glycolysis and ketone body and fatty acid utilization amino acids or 2-keto acids in urine. Traditionally, it constitute the bulk of energy metabolism in humans. is considered an aminoacidemia, since it is primarily These pathways culminate in the generation of four diagnosed through the increased levels of branched- organic acids: pyruvate, lactate, 3-ketobutyrate (ace- chain amino acids. A related disorder, dihydrolipoyl toacetate), and 3-hydroxybutyrate, the turnover and dehydrogenase (or E3) deficiency, is caused by the pool of which are large.15,16 The pool size and rate of deficiency of one component of the branched-chain metabolism of these organic acids show significant 2-ketoacid dehydrogenase component, the E3.22 This increase and decrease under normal physiologic unit is shared by other dehydrogenases, such as conditions, since they are finely tuned by hormones pyruvate dehydrogenase, and 2-ketoglutaric dehy- through secondary messengers. 17,11 It is therefore drogenase. Therefore, in E3 deficiency, in addition not surprising to observe significant increases in to a moderate accumulation of branched-chain their levels, leading to compensated or overt meta- amino acids and their 2-keto intermediates, derange- bolic acidosis when the intracellular pathways are ment of several enzymes occurs. E3 deficiency is deranged secondary to the accumulation of organic therefore traditionally classified