Metabolic, nutritional, iatrogenic, and artifactual sources of urinary organic acids: a comprehensive table.
The analytical procedures for the determination of urinary organic acids usually include oximation, solvent extraction, and silylation followed by gas chromatography with mass detection in scan mode data acquisition. Both the retention time and the mass spectrum allow the identification of the urinary metabolites, with quantification being performed on a specific fragment abundance (1-3). Analytical considerations can be found in the reports by Jellum (4), Chalmers and Lawson (1), Tuchman and Ulstrom (5), Niwa (6), Sweetman (2), and Duez et al. (3).
More than 250 organic acids and glycine conjugates are either typically present or may possibly be encountered in urine. More than 65 inherited metabolic abnormalities are known to yield a characteristic urinary organic acid pattern, essential for diagnosis and follow-up (1,2,5,7,8). The interpretation of urinary organic acid profiles can be difficult because of the variability of the compounds excreted. Moreover, there may still be a considerable degree of ambiguity in the origin and/or significance of a given compound. To arrive at a diagnosis, organic acid data can be correlated with, or confirmed by, other analyses, including plasma amino acid determination, plasma and cerebrospinal fluid lactate and pyruvate assays, whole blood acylcarnitine profiling, enzymatic activity determinations in blood cells or other cells, and genome analysis (7-11).
This report aims to compile information on the origins of the most frequently encountered urinary organic acids. In addition to IEM, our classification (Table 1) also refers to other pathologic conditions and physiologic, nutritional, iatrogenic, and artifactual causes (1, 2, 4-8,10-13). This review is intended to assist in the interpretation of organic acid profiles and the identification of some preanalytical issues. Table 1, which is classified by organic compounds, is also proposed as a handy alternative that extends previously published compilations classified by inherited metabolic disorders (2,5-7,13).
Urine collected over 24 h allows for variations in volume excretion during the day. The practicality of a 24-h collection is, however, such that a random specimen, preferably the first morning voiding, is an acceptable alternative. This specimen usually consists of at least 2 mL and is stored until analysis at below -18[degrees]C without the use of any preservative.
Intraindividual variations will occur with respect to the time of sampling, the patient's clinical status, eventual diet management, and whether the sample is collected when the patient is fasted or fed. Sampling during fasting or metabolic decompensation is often considered to be most valuable because, in most cases, metabolites of interest are then excreted selectively or at a higher concentration. On the other hand, metabolic decompensation, such as lactic acidosis, ketosis, or liver failure, gives rise to an abnormal excretion of organic acids ([alpha]-keto branched, dicarboxylic, or aromatic acids, respectively) that are otherwise involved in particular IEM; this sometimes renders interpretation even more difficult.
Poor preservation of samples will lead to nonenzymatic conversion of all keto acids to the respective hydroxyacid; for example, acetoacetate is converted to 3-hydroxybutyrate, and 2-ketoglutarate is converted to 2-hydroxyglutarate.
Abnormal Excretion Patterns Not Attributable to IEM
An increase in excretion may be nonspecific because some metabolites are reported to be abnormally excreted in conditions not attributable to IEM (drug therapy, diet, non-IEM diseases, or physiologic conditions), as indicated in Table 1.
Two frequent abnormal excretions not necessarily related to IEM are lactic aciduria and ketonuria. Whatever its origin, lactic aciduria is generally accompanied by other compounds; the greater the lactate excretion, the more likely the extent of the excretion of pyruvate, p-hydroxyphenyllactate, 2-hydroxyisovalerate, 2-hydroxybutyrate, and to a lesser extent, branched-chain 2-ketoacids. The abnormal excretion of these branched compounds implies the need for differentiation from dihydrolipoyl dehydrogenase deficiency.
Ketonuria (3-hydroxybutyrate and acetoacetate) is often accompanied by 3-hydroxyisobutyrate, 3-hydroxyisovalerate, 2-hydroxybutyrate, and dicarboxylic acids, particularly their 3-hydroxy derivatives with chain lengths up to C14. In this latter case, the pattern could mimic a long-chain 3-hydroxyacyl-CoA dehydrogenase or a trifunctional protein deficiency profile, except for the very high excretion of ketone bodies [in fatty acid oxidation defects, ketone bodies may appear increased in urine during fasting, but the ketosis remains at an inappropriately low level and the ratio of urinary adipate to 3-hydroxybutyrate is >0.5 (14)].
Another common misinterpretation may arise from bacterial metabolism. Of possible endogenous origin (e.g., intestinal infection) is the abnormal excretion of D-lactate (not chromatographically separated from L-lactate), methylmalonate, p-hydroxyphenylacetate, p-hydroxyphenyllactate, phenylacetylglutamine, phenylpropionylglycine, glutarate, benzoate, and hippurate. Of possible exogenous origin (bacterial growth in urine) are n-lactate, 2-ketoglutarate, n-2-hydroxyglutarate, succinate, 3-hydroxypropionate, and phenol derivatives (phenol, p-cresol, hippurate) (15).
The drug valproic acid may lead to increased excretion of 3-hydroxyisovalerate, 5-hydroxyhexanoate, 7-hydroxyoctanoate, p-hydroxyphenylpyruvate, dicarboxylic acids, and to a lesser extent, hexanoylglycine, tiglylglycine, and isovalerylglycine. The metabolites of this anticonvulsant drug are an important clue to the analyst, however.
The administration of medium-chain triglycerides may yield a pattern resembling fatty acid [beta]-oxidation defects, with increased saturated even-numbered dicarboxylic acids, mainly sebacate, as well as increased 5-hydroxyhexanoate and 7-hydroxyoctanoate, and the presence of octanoate but the absence or low excretion of glycine derivatives (16,17).
Misleading Normal or Near-Normal Excretion
The excretion of organic acids in pathologic conditions may be characterized by large variability and thus casts doubt on the clinical sensitivity of the results. Interindividual variations are also possible because, for some diseases, urinary biochemical features may depend on what have been called "excretory' and "non-excretory' patients. Indeed, compounds typically excreted in large amounts may also appear at only slightly increased or even normal concentrations in some IEM. This is particularly true when a patient is clinically well (not in a state of metabolic decompensation) or under suitable dietary control. Among these inborn errors are glutaric aciduria type I (18,19) (glutarate concentrations may be within reference values, whereas 3-hydroxyglutarate is present); medium-chain acyl-CoA dehydrogenase deficiency (adipate, suberate, and sebacate concentrations may be within reference values, but the presence of suberylglycine and hexanoylglycine will reveal the disorder) (20); multiple acyl-CoA dehydrogenase deficiency, particularly in its mild forms (metabolites suggesting such a disease, including ethylmalonate and glutarate, are quite variable); and 2-ketoglutarate dehydrogenase deficiency (2-ketoglutarate excretion ranges from within reference values to 10 times higher than the upper limit of the reference interval).
Respiratory chain defects give an unpredictable organic acid pattern, but nearly always with marked lactic aciduria; Krebs cycle acids, ethylmalonate, 3-methylglutaconate, and 3-methylglutarate may also be excreted in varying quantities. Urinary orotate may be high but possibly borderline in citrullinemia, ornithine carbamoyl-transferase deficiency, lysinuric protein intolerance, and the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, all disorders for which the biochemical diagnosis, however, is based on plasma ammonium and plasma and urinary amino acid profiles.
Interpretation and Misinterpretations (7,8,10,11)
The relevance of the abnormal excretion of some characteristic metabolites in the diagnosis of IEM has to be emphasized. For example, the presence of succinylacetone and succinylacetoacetate is pathognomonic of tyrosinemia type I (fumarylacetoacetate hydrolase deficiency). Other compounds may also be quite specific, including 3-hydroxyglutarate for glutaric aciduria type I, mevalonic acid for mevalonic aciduria, N-acetylaspartate for Canavan disease, 4-hydroxycyclohexylacetate for hawkinsinuria, and 2-ketoadipate and 2-hydroxyadipate for 2-amino/2-ketoadipate aciduria.
Cooperation between clinical chemists and clinicians is essential for the interpretation of the results. On the one hand, information on diet, drug intake, and clinical symptoms and signs may often be required by the clinical chemist to refine his or her interpretation. The clinical chemist can inform the clinician of pitfalls, the possible origins of abnormal results, and further analyses that can be performed (21). On the other hand, a final diagnosis can be established only in terms of the patient's history and clinical picture, in addition to results from biochemical and medical examinations.
As a practical consequence of possible misinterpretations, urinary organic acid patterns must be interpreted in the context of the complete clinical picture. In this context, both an abnormal organic acid pattern in the urine from an asymptomatic individual and a normal profile from a patient suspected of IEM must be considered as indications for repeated sampling: in the former circumstance, more information on possible drug therapy, diet, non-IEM pathology, and physiologic conditions is mandatory, whereas in the latter case, a period of illness would be preferred for resampling.
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ALAIN KUMPS, PIERRE DUEZ, and YVES MARDENS *
Laboratoire de Biochimie Medicale, Institut de Pharmacie, Universite Libre de Bruxelles (ULB), Campus Plaine CP 205/3, Boulevard du Triomphe, B-1050 Brussels, Belgium.
* Author for correspondence. Fax 32-2-650-5324; e-mail biochmed@ulb. ac.be.
Received November 29, 2001; accepted January 25, 2002.
Table 1. Possible origins of abnormal excretion patterns of urinary organic acids. Acid/Metabolite Non-IEM (4, 12, 15, 16, 22) Aromatic amino acid metabolism (23) 2-Hydroxyphenylacetate Uremia 4-Hydroxyphenylacetate Bacterial gut metabolism and (24, 25) bacterial contamination (from tyrosine); short bowel syndrome; liver diseases 4-Hydroxyphenyllactate Bacterial gut metabolism; short (24-27) bowel syndrome; liver diseases (e.g., secondary to PA, galactosemia, fructosemia); scurvy; lactic acidosis 4-Hydroxyphenylpyruvate VPA; liver diseases (e.g., secondary to PA, galactosemia, fructosemia) Homogentisate Mandelate (28) Preservative in albumin solution for intravenous perfusion; methenamine mandelale; gastrointestinal malabsorption diseases N-Acetyltyrosine Some parenteral solutions Phenylacetate Intestinal bacterial origin (from phenylalanine) Phenylacetylglutamine Bacterial metabolism (from phenylacetate); hyperammonemia treated with phenylbutyrate or phenylacetate; uremia Phenyllactate (29) Bacterial gut metabolism (D-form); liver diseases Phenylpyruvate Bacterial gut metabolism; liver Succinylacetoacetate diseases Succinylacetone Branched-chain amino acid metabolism 2-Hydroxy-3-methylvalerate 2-Hydroxyisocaproate (23) Short bowel syndrome (D-form) 2-Hydroxyisovalerate Ketosis; lactic acidosis 2-Keto-3-methylvalerate Lactic acidosis; ketosis 2-Ketoisocaproate Lactic acidosis; ketosis 2-Ketoisovalerate Lactic acidosis; ketosis 2-Methyl-acetoacetate (30) 2-Methylglutaconate 3-Hydroxy-2-ethylyglutarate 3-Hydroxy-2-ethylpropionate Ketosis (31, 32) 3-Hydroxy-2-methylbutyrate Ketosis (30, 33-35) 3-Hydroxy-3-methylglutarate Ketosis 3-Hydroxyisovalerate (30, 34) Reye & Reye-like syndromes; VPA; ketosis 3-Hydroxypropionate Bacterial metabolism and (hydracrylate) contamination; short bowel (33, 34, 36) syndrome; lactic acidosis 3-Keto-2-methylbutyrate (33) 3-Keto-2-methylvalerate (33) 3-Methylcrotonylglycine Reye & Reye-like syndromes 3-Methylglutaconate (37-42) Uremia; acquired HMG-CoA lyase deficiency; other biochemical origin still unknown; pregnancy 3-Methylglutarate 4-Hydroxyisovalerate Isovalerylglycine (34) VPA Methylcitrate (33, 34, 43) Malnutrition Methylmalonate [B.sub.12] vitamin deficiency, (27, 34, 43-49) pernicious anemia; bacterial gut metabolism; gastroenteritis in very young infants; short bowel syndrome; apnea; "benign" MMA; decreased GFR (in plasma); malnutrition Propionylglycine (33, 34) Tiglylglycine Reye & Reye-like syndromes; VPA (30, 31, 33-35, 50) Fatty acid oxidation (16, 51-55) DCA (even, saturated): adipate, Seriously ill states: suberate, sebacate infection, malnutrition, fever, (17, 26, 43, 56-59) seizures, liver diseases, pulmonary stenosis; MCT administration; ketosis; VPA or acetaminophen; lactic acidosis; hypoglycemia; Reye & Reye-like syndromes; Jamaican vomiting sickness Odd DCA (57, 58) As even DCA; from plastic containers; uremia Unsaturated DCA (59) Ketosis 3-Hydroxy DCA (60) MCT administration; fasting; ketosis; celiac disease 2-Hydroxysebacate (58) 2-Methylbutyrylglycine VPA 3-Hydroxyadipic (lactone) See 3-hydroxy DCA 3-Hydroxydo-/ Hepatocellular disease; ketosis; tetradecanedioate (61) acetaminophen intoxication 3-Hydroxysebacate (31, 62) See 3-hydroxy DCA; progressive liver disease; acetaminophen 3-Hydroxysuberate See 3-hydroxy DCA 4-Octenedioate Jamaican vomiting sickness; neonates on fasting 5-Hydroxyhexanoate (59) MCT administration; VPA; Reye & Reye-like syndromes; ketosis 5-Hydroxysebacate 7-Hydroxyoctanoate (59) MCT administration; VPA Adipate See DCA; food additive (Jello); lithium; neonates on fasting Butyrylglycine MCT administration; ketosis; Jamaican vomiting sickness Decenedioate Do-/Tetradecanedioate (63) Ketosis Ethylmalonate (11, 64-67) Jamaican vomiting sickness; neonates on fasting; diet (?) Hexanoylglycine (20, 59) VPA; MCT administration; Jamaican vomiting sickness Isobutyrylglycine Methylsuccinate Octanoate (59) MCT administration Phenylpropionylglycine (20) Bacterial gut metabolism and bacterial contamination Suberylglycine (20, 59) MCT administration; ketosis; Reye & Reye-like syndromes Tetradecanedioate Krebs cycle/respiratory chain (68-71) 2-Ketoglutarate (38, 72) Bacterial contamination; lithium; uremia; increase with younger age Aconitate Citrate, isocitrate High carbohydrate intake; parathyroid extract; saturnism; citrate intake; fruit juice added to urine; hyperparathyroidism; increase with younger age Fumarate Lithium; renal tubular reabsorption defect (fumaric aciduria); increase with younger age Malate (73-75) Lithium; uremia; increase with younger age Succinate (72, 76) Bacterial (on storage); 2-ketoglutarate degradation; lithium; ketosis; tissue ischemia; increase with younger age Lactic acid, ketone bodies (30, 71, 77) 2-Hydroxybutyrate Ketosis; lactic acidosis 2-Hydroxyisobutyrate Lactic acidosis 3-Hydroxybutyrate Ketosis (e.g., vomiting, (32, 49, 77-79) prolonged fasting, diabetic ketoacidosis); B12 vitamin deficiency; Reye & Reye-like syndromes; pulmonary infections; viral gastroenteritis; von Gierke disease; hyperthyroidism; pregnancy; heat stroke; ethanol; protein malnutrition; high-fat diet Acetoacetate (78) As 3-hydroxybutyrate; acetylsalicylate Lactate and pyruvate Gut bacteria and bacterial (29, 78, 80-82) contamination (D-lactate); short bowel syndrome (D-lactate); secondary lactic acidosis (e.g., apnea, septicemia, seizures, respiratory or cardiac insufficiency); diabetic ketoacidosis; Reye & Reye-like syndromes; increase with younger age; saccharose, fructose, lactose; drugs inducing hyperlactemia; dialysis bath; MCT administration Lysine, glycine, serine metabolism Glutaconate Glycerate Uremia; increase with younger age Glycolate (83, 84) Ethylene glycol poisoning Glyoxylate 2-Hydroxyadipate (85) 3-Hydroxyglutarate (85) 2-Ketoadipate (85) Glutarate (18, 19, 85-87) 2-Ketoglutarate degradation; bacterial gut metabolism; uremia; ethylene glycol poisoning; lithium Oxalate (83, 88-90) Enteric malabsorption (regional enteritis or ileitis, celiac sprue disease, resection of ileum, Crohn disease); idiopathic stone disease; pyridoxine deficiency; increase with younger age; diet (e.g., beans, leafy vegetables, rhubarb, spinach, tomatoes, strawberries, tea, chocolate); infant formula; ascorbic acid; xylitol; ethylene glycol; methoxyflurane Other acids and metabolites 2-Hydroxyglutarate (82, 85) Bacterial contamination (D-form); lithium; uremia; increase with younger age; 2-ketoglutarate degradation 3,4-Dihydroxybutyrate Diet (2-deoxytetronate) 3-Hydroxyisobutyrate (32) Ketosis 4,5-Dihydroxyhexanoate 4-Hydroxybutyrate Ketosis (?) 4-Hydroxycyclohexylacetate Bacterial gut metabolism (?) (91) Glycerol Contamination (suppository, Malonate (92) emollients); uremia Mevalonate and/or its lactone N-Acetylaspartate Orotate (93-95) Allopurinol treatment; azauridine; high cell turnover (tissue breakdown, menstruation); folate malabsorption Pyroglutamate (L- or From glutamine of hydrolyzed D-5-oxoproline) proteins (infant formula); (82, 91, 96-102) acetaminophen; vigabatrin; fludoxacillin, netilmicin (?); glutamine degradation (in hyperammonemia, urea cycle defects); vegetarian or low-protein diets, undernutrition; iron oxoprolinate; Steven-Johnson syndrome; burns; premature newborns; transitory (?); glycine deficiency; increase with younger age; renal insufficiency; pregnancy (increased metabolic demand for glycine) Thymine Caffeine (?) Uracil Caffeine (?) Vanillactate (103) Catecholamine-containing foodstuff (e.g., bananas); L- dopa decarboxylase inhibitors; neuroblastoma Nutritional, exogenous, or artifactual compounds (6) 2,5-Furane dicarboxylate Heated furanoic sugars and 5-hydroxymethyl-2- (chocolates, fruit juice, furanoate intravenous perfusion) 2-Furoylglycine Chocolate; heated fruit juice or parenteral solution; uremia 3-(3-Hydroxyphenyl)- From nutrition hydracrylate 4-Hydroxycyclohexane-1- Diet; bacterial gut metabolism carboxylate (104) (from tyrosine) 4-Hydroxyhippurate Bacterial gut metabolism Benzoate (61, 105) Bacterial metabolism (gut, urinary tract) from hippurate or from aromatic amino acids; benzoate treatment; food additive; ethylene glycol poisoning; toluene; hyperammonemia Hippurate (106) As benzoate; uremia Maleate Fluvoxamine maleate Palmitate Soap; Jamaican vomiting sickness p-Cresol Bacterial metabolism from tyrosine; toluene; uremia Phenol Bacterial metabolism from tyrosine; exposure to benzene or phenol; malabsorption; uremia Pivalate Pivampicillin or pivmecillinam Tartarate Food additive; uremia Acid/Metabolite IEM Aromatic amino acid metabolism (23) 2-Hydroxyphenylacetate PKU; BH4 (a) deficiency 4-Hydroxyphenylacetate Tyrosinemia; PKU; hawkinsinuria (24, 25) 4-Hydroxyphenyllactate Tyrosinemia; PKU; Zellweger; (24-27) hawkinsinuria; lactic acidosis 4-Hydroxyphenylpyruvate Tyrosinemia; hawkinsinuria Homogentisate Alcaptonuria Mandelate (28) PKU N-Acetyltyrosine Tyrosinemia Phenylacetate PKU; BH4 deficiency Phenylacetylglutamine PKU Phenyllactate (29) PKU; tyrosinemia (L-form); BH4 deficiency Phenylpyruvate PKU; BH4 deficiency Succinylacetoacetate Tyrosinemia type I Succinylacetone Tyrosinemia type I Branched-chain amino acid metabolism 2-Hydroxy-3-methylvalerate MSUD; dihydrolipoyl DH (E3) deficiency 2-Hydroxyisocaproate (23) MSUD; dihydrolipoyl DH (E3) deficiency 2-Hydroxyisovalerate MSUD; dihydrolipoyl DH (E3) deficiency; MAD deficiency; lactic acidosis 2-Keto-3-methylvalerate MSUD; dihydrolipoyl DH (E3) deficiency; lactic acidosis 2-Ketoisocaproate MSUD; dihydrolipoyl DH (E3) deficiency; lactic acidosis 2-Ketoisovalerate MSUD; dihydrolipoyl DH (E3) deficiency; lactic acidosis 2-Methyl-acetoacetate (30) Mitochondrial acetoacetyl-CoA-thiolase deficiency 2-Methylglutaconate PA; MMA (?)(b); [beta]-ketothiolase deficiency 3-Hydroxy-2-ethylyglutarate PA 3-Hydroxy-2-ethylpropionate 3-Methylglutaconic aciduria (type (31, 32) II); methylmalonic semialdehyde DH deficiency (c); respiratory chain defects (complex I and II) 3-Hydroxy-2-methylbutyrate Mitochondrial (30, 33-35) acetoacetyl-CoA-thiolase deficiency; 2-methyl-3- hydroxybutyryl-CoA DH deficiency; PA; Pearson syndrome 3-Hydroxy-3-methylglutarate HMG-CoA lyase deficiency 3-Hydroxyisovalerate (30, 34) IVA; multicarboxylase deficiency; HMG-CoA lyase deficiency; 3- methylcrotonyl-CoA carboxylase deficiency; 3-methylglutaconyl- CoA hydratase deficiency; succinyl-CoA:3-oxoacid-CoA transferase deficiency; MAD deficiency 3-Hydroxypropionate PA; MMA; multiple carboxylase (hydracrylate) deficiency; succinic semialdehyde (33, 34, 36) DH deficiency; methylmalonic semialdehyde DH deficiency (c); lactic acidosis (with pyruvate carboxylase deficiency) 3-Keto-2-methylbutyrate (33) PA; MMA (?); [beta]-ketothiolase deficiency 3-Keto-2-methylvalerate (33) PA; MMA (?); [beta]-ketothiolase deficiency 3-Methylcrotonylglycine 3-Methylcrotonyl-CoA carboxylase deficiency; multiple carboxylase deficiency; HMG-CoA lyase deficiency 3-Methylglutaconate (37-42) 3-Methylglutaconyl-CoA hydratase deficiency (methylglutaconic aciduria type I); HMG-CoA lyase deficiency; 3-methylglutaconic aciduria (other than type I); respiratory chain defects (e.g., Pearson syndrome or mitochondrial ATP synthase deficiency); Smith-Lemli-Opitz syndrome; carbamyl phosphate synthetase deficiency 3-Methylglutarate As 3-methylglutaconate 4-Hydroxyisovalerate IVA Isovalerylglycine (34) IVA; MAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency (c)) Methylcitrate (33, 34, 43) PA; MMA; multiple carboxylase deficiency Methylmalonate MMA; transcobalamine II (27, 34, 43-49) deficiency; malonic aciduria Propionylglycine (33, 34) PA; MMA Tiglylglycine PA; 2-methyl-3-hydroxybutyryl-CoA (30, 31, 33-35, 50) DH deficiency; mitochondrial acetoacetyl-CoA-thiolase deficiency; multiple carboxylase deficiency; respiratory chain defects (e.g., complex I) Fatty acid oxidation (16, 51-55) DCA (even, saturated): adipate, [beta]-Oxidation defects (MAD, suberate, sebacate MCAD, SCAD, VLCAD, SCHAD, LCHAD/ (17, 26, 43, 56-59) TFP); HMG-CoA lyase deficiency; systemic carnitine deficiency; succinic semialdehyde DH deficiency; CPT II deficiency; peroxisomal diseases; glycogen storage disorders I & II; lactic acidosis; fructose intolerance Odd DCA (57, 58) Peroxisomal diseases Unsaturated DCA (59) VLCAD deficiency; CPT II deficiency 3-Hydroxy DCA (60) LCHAD/TFP deficiency; VLCAD deficiency 2-Hydroxysebacate (58) Peroxisomal diseases 2-Methylbutyrylglycine MAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency (c)) 3-Hydroxyadipic (lactone) See 3-hydroxy DCA 3-Hydroxydo-/ LCHAD/TFP deficiency tetradecanedioate (61) 3-Hydroxysebacate (31, 62) See 3-hydroxy DCA; MCAD deficiency; glycogen storage disorders I & II; secondary to respiratory chain defects 3-Hydroxysuberate See 3-hydroxy DCA 4-Octenedioate MCAD deficiency; MAD deficiency; VLCAD deficiency; LCHAD/TFP deficiency; nonketotic dicarboxyluria; systemic carnitine deficiency; peroxisomal diseases 5-Hydroxyhexanoate (59) MAD deficiency; MCAD deficiency; nonketotic dicarboxyluria 5-Hydroxysebacate Peroxisomal diseases 7-Hydroxyoctanoate (59) MCAD deficiency Adipate See DCA Butyrylglycine SCAD deficiency; MAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency (c)) Decenedioate MCAD deficiency; VLCAD deficiency; LCHAD/TFP deficiency Do-/Tetradecanedioate (63) VLCAD deficiency; LCHAD/TFP deficiency; MAD deficiency; CPT II deficiency Ethylmalonate (11, 64-67) SCAD deficiency; MAD deficiency (severe form); MAD deficiency (mild form); acetyl-CoA carboxylase deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency (c)); respiratory chain defects Hexanoylglycine (20, 59) MCAD deficiency; MAD deficiency; SCAD deficiency Isobutyrylglycine MAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency, muscle COX deficiency (c)) Methylsuccinate As EMA Octanoate (59) MCAD deficiency Phenylpropionylglycine (20) In MCAD deficiency (from phenylalanine bacterial metabolism or after load) Suberylglycine (20, 59) MCAD deficiency; MAD deficiency Tetradecanedioate VLCAD deficiency; LCHAD/TFP deficiency; MAD deficiency Krebs cycle/respiratory chain (68-71) 2-Ketoglutarate (38, 72) As malate; 2-ketoglutaric DH deficiency; GA I; 2-amino/2- ketoadipate acidemia; dihydrolipoyl DH (E3) deficiency; glycogen storage disorder I; 2-hydroxyglutaric aciduria (D-form); fumarase deficiency Aconitate Respiratory chain defects (e.g., complex I); Pearson syndrome Citrate, isocitrate Dihydrolipoyl DH (E3) deficiency; fumarase deficiency; pyruvate carboxylase deficiency; Pearson syndrome Fumarate As malate; fumarase deficiency Malate (73-75) Respiratory chain defects; pyruvate carboxylase deficiency; PDH complex (E1, E3) deficiency; Pearson syndrome Succinate (72, 76) As malate; malonic aciduria; fumarase deficiency Lactic acid, ketone bodies (30, 71, 77) 2-Hydroxybutyrate Lactic acidosis; GA I; respiratory chain defects 2-Hydroxyisobutyrate Lactic aciduria 3-Hydroxybutyrate Gluconeogenesis; PHD complex (32, 49, 77-79) deficiency; respiratory chain defects; IVA; PA; MMA; multiple carboxylase deficiency; 3- methylcrotonyl-CoA carboxylase deficiency; glyceroluria; MSUD; GA I; MAD deficiency; -ketothiolase deficiencies; 2-amino/2- ketoadipic acidemia; mitochondrial SCHAD; fatty acids oxidation deficiency (inappropriate ketosis) Acetoacetate (78) As 3-hydroxybutyrate Lactate and pyruvate Primary lactic acidosis; PDH (29, 78, 80-82) complex (E1, E2, E3) deficiency; oxidative phosphorylation and respiratory chain defects (e.g., MERRF, MELAS, Kearns-Sayre), Krebs acid cycle defects, gluconeogenesis defects (e.g., pyruvate carboxylase, fructose- 1, 6-diphosphatase, glycogen storage I disorder); (short- branched chain acyl-CoA DH deficiency; muscle COX deficiency (c)); MAD deficiency (severe form); VLCAD deficiency; GA I; multiple carboxylase deficiency; some other organic aciduria (MMA, PA, IVA); citrullinemia, glycerol kinase deficiency; HMG-CoA lyase deficiency; EMA aciduria Lysine, glycine, serine metabolism Glutaconate GA I Glycerate D-Glyceric aciduria; hyperoxaluria type II (L-form); succinic semialdehyde DH deficiency Glycolate (83, 84) Hyperoxaluria type I; succinic semialdehyde DH deficiency; isolated glycolic aciduriac Glyoxylate Hyperoxaluria type I 2-Hydroxyadipate (85) 2-Amino/2-Ketoadipic aciduria 3-Hydroxyglutarate (85) GA I 2-Ketoadipate (85) 2-Amino/2-Ketoadipic aciduria Glutarate (18, 19, 85-87) GA I; MAD deficiency (severe form); MAD deficiency (mild form); 2-amino/2-ketoadipic aciduria; malonic aciduria; other mitochondrial dysfunctions Oxalate (83, 88-90) Hyperoxaluria type I and II; hyperoxaluria without known enzyme deficit Other acids and metabolites 2-Hydroxyglutarate (82, 85) 2-Hydroxyglutaric aciduria (L- and D-forms); MAD deficiency, severe (D-form); MAD deficiency, mild (D-form); 2-amino/2-ketoadipic aciduria; malonic aciduria 3,4-Dihydroxybutyrate Succinic semialdehyde DH deficiency (2-deoxytetronate) 3-Hydroxyisobutyrate (32) 3-Hydroxyisobutyric DH deficiency and/or methylmalonic semialdehyde DH deficiency (c) 4,5-Dihydroxyhexanoate Succinic semialdehyde DH deficiency 4-Hydroxybutyrate Succinic semialdehyde DH deficiency 4-Hydroxycyclohexylacetate Hawkinsinuria (91) Glycerol Gylcerol kinase deficiency; fructose-1,6-phosphatase deficiency Malonate (92) Malonyl-CoA-decarboxylase deficiency; malonic aciduria with normal malonyl-CoA-decarboxylase activity Mevalonate and/or its lactone Mevalonate kinase deficiency N-Acetylaspartate Canavan disease Orotate (93-95) Argininemia; orotic aciduria; citrullinemia; OCT deficiency; hyperornithinemia- hyperammonemia-homocitrulliuria syndrome; lysinuric protein intolerance; purine nucleoside deficincy; Lesh-- Nyhan disease Pyroglutamate (L- or Glutathione synthetase D-5-oxoproline) deficiency; 5-oxoprolinase (82, 91, 96-102) deficiency; nephropathic cystinosis; hawkinsinuria; homocystinuria; OCT deficiency; PA Thymine Dihydropyrimidine DH deficiency Uracil Dihydropyrimidine DH deficiency; OCT deficiency; citrullinemia Vanillactate (103) L-Amino acid decarboxylase deficiency Nutritional, exogenous, or artifactual compounds (6) 2,5-Furane dicarboxylate and 5-hydroxymethyl-2- furanoate 2-Furoylglycine 3-(3-Hydroxyphenyl)- hydracrylate 4-Hydroxycyclohexane-1- carboxylate (104) 4-Hydroxyhippurate Benzoate (61, 105) Hippurate (106) Maleate Palmitate p-Cresol Phenol Pivalate Tartarate (a) PKU, phenylketonuria; BH4, tetrahydrobiopterin; PA, propionic acidemia; VPA, valproate; MSUD, maple syrup urine disease; DH, dehydrogenase; MMA, methylmalonic acidemia; HMG, 3-hydroxy-3-methylglutarate; IVA, isovaleric acidemia; MAD, multiple acyl-CoA dehydrogenase; EMA, ethylmalonate; COX, cytochrome c oxidase; GFR, glomerular filtration rate; DCA, dicarboxylic acid; MCT, medium-chain triglyceride; MCAD, medium-chain acyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; VLCAD, very long-chain acyl-CoA dehydrogenase; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; LCHAD/TFP, long-chain 3-hydroxyacyl-CoA dehydrogenase/trifunctional protein; CPT, carnitine palmitoyltransferase; GA I, glutaric aciduria type I; PDH, pyruvate dehydrogenase; OCT, ornithine carbamoyltransferase. (b) (?) indicates that this information remains to be confirmed. (c) Enzymatic confirmation not yet established.
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|Author:||Kumps, Alain; Duez, Pierre; Mardens, Yves|
|Date:||May 1, 2002|
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