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Metabolic, nutritional, iatrogenic, and artifactual sources of urinary organic acids: a comprehensive table.

In the field of inborn errors of metabolism (IEM), "organic acids" are low-molecular weight (relative molecular weight less than ~300), water-soluble carboxylic acids that are intermediates or end products of amino acid, carbohydrate, lipid, or biogenic amine metabolism. Amino acids are excluded from this definition, whereas acylglycine conjugates and some decarboxylated derivatives are included because of their common clinical interest.

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).

Sampling Conditions

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.

CONCLUSION

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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(104.) Bindel TH, Fennessey PV, Miles BS, Goodman SI. 4-Hydroxycyclohexane-1-carboxylic acid: an unusual compound isolated from the urine of children with suspected disorders of metabolism. Clin Chim Acta 1976;66:209-17.

(105.) Jone CM, Wu AH. An unusual case of toluene-induced metabolic acidosis. Clin Chem 1988;34:2596-9.

(106.) Liebich HM, Pickert A, Tetschner B. Gas chromatographic and gas chromatographic-mass spectrometric analysis of organic acids in plasma of patients with chronic renal failure. J Chromatogr 1984;289:259-66.

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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Publication:Clinical Chemistry
Date:May 1, 2002
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