Assessment of the Infant with Acute Metabolic Problems

HOBART E. WILTSE, M.D., Ph .D.

Department o f Pediatrics, University of Nebraska College of Medicine Omaha, NB 68198-2165

ABSTRACT Those inborn errors of metabolism which characteristically produce acute illness during the first year of life often resemble infectious illnesses in their nonspecific modes of presentation. Grouping of signs and symp toms into prototypes, followed by an active search for clinical and labora tory clues with higher specificity, often proves helpful in making an appro priate choice of confirmatory diagnostic tests.

Introduction within this group than on general famil iarity with important prototypes, such as The diagnosis of inborn errors of galactosemia, maple syrup urine disease, metabolism causing acute disease during hyperammonemia, the organic acide the neonatal period or later infancy can mias, and the beta oxidation defects. be a daunting task. Experience has pro Diagnostic strategies can appropriately vided clinicians with the symptom recog be organized around these prototypes. nition skills generally needed for initiat The reader seeking more detailed ing a metabolic investigation, and recent information about the clinical presenta laboratory innovations have brought us tion of these diseases than found here is improved tools for confirmatory diag referred to the landmark reviews by nosis. Differential diagnosis, the inter Burton8 and by Greene and coworkers.19 mediate step between diagnostic suspi cion and confirmation, usually The Initial Clues to Metabolic Illness constitutes the difficult step because of complexity and rarity of the diseases and The symptoms and signs which first poor specificity of their early manifesta call attention to the possibility of an tions. This review has as its purpose inherited metabolic disease in an acutely helping the clinician, or clinician-in- ill infant are likely to be nonspecific and training, to achieve maximum success in perhaps more suggestive of infection the identification of those metabolic dis than disordered metabolism. A search eases of infancy which are life-threaten should be undertaken for more specific ing and potentially treatable, and espe chemical clues at the same time as the cially those which are relatively common bacteriologic studies, since valuable time in occurrence. Most clinicians rely less can be lost if consideration of metabolic on extensive knowledge of diseases disease is delayed until the infant is 40 0091-7370/91/0100-0040 $02.00 © Institute for Clinical Science, Inc. ASSESSMENT OF THE INFANT WITH ACUTE METABOLIC PROBLEMS 41 found not to have septicemia. Vomiting, TABLE II interruption of feedings, and the com Initial Screening Tests from the monly used infusions of 10 percent glu Clinical Laboratory cose can normalize an elevated blood ammonia in an infant with a urea cycle Blood: defect, or cause galactose to disappear Glucose Urea nitrogen pH, electrolytes Uric acid from the urine in a neonate with galacto Ammonia Lactic acid semia, or glutaric acid to disappear from Liver enzymes * the urine of an infant with glutaric acide Complete blood count with differential mia type I. A blood transfusion given to a jaundiced infant might interfere with the Urine, Qualitative Tests for: Acetone Glucose diagnosis of galactosemia by enzyme Reducing sugar Methylmalonic acid assay on the erythrocytes, unless the Ketoacids (2,4-dinitrophenylhydrazine) neonatal metabolic screening panel has Sulfur-containing amino acids been carried out prior to transfusion. (cyanide - nltroprusside) In table I are listed examples of the Tyrosine derivatives (nltrosonaphthol) important but non-specific clues which * Alanine aminotransferase (ALT) can alert one to the presence of acute Asparate transamlnase(AST)) metabolic disease. Such clues offer little Lactate dehydrogenase (LD) help in indicating directions for the meta bolic studies, and the physician is therefore advised to explore actively for response to the aggravated fasting and additional clues having greater specifici acute catabolism which accompany ty. These might be found in the clinical an intercurrent illness with vomiting presentation itself or in the results of and fever. preliminary screening tests readily availa ble in the clinical laboratory (table II). Based on abnormalities which might Beyond Screening—Selection of More be found in the preliminary screening, Specialized Laboratory Tests table III offers suggestions for differen tial diagnosis. The age group organiza Prototype diseases are listed in table tion of this table is based upon a consid IV and the confirmatory tests listed in eration that acute metabolic symptoms table V. A physician dealing with one of in the neonate tend to be provoked by the diagnostic problems in table I might intolerance to protein or carbohydrate in use table II for preliminary screening. If the feedings, whereas the older infant this leads to a close fit with one or more more typically develops symptoms in of the diagnostic clues in table III, table IV can be used for developing diagnostic hypotheses and table V for selecting TABLE I appropriate laboratory tests. Several of Valuable But Nonspecific Clues the procedures listed in table V (e.g., to Metabolic Disease quantitative amino acid analysis, organic acid screen, and acyl carnitine profile) Poor feeding Vomiting are notably efficient screening tools in Jaundice Hepatomegaly their own right, offering considerable Hypoglycemia Hypotonia Seizures Apnea potential for yielding information of Failure to thrive diagnostic value, even if the original Family history of neonatal or Infantile death suspicion which prompted the test is not supported. TABLE III Diagnostic Clues with Greater Specificity for Neonate and Older Infant In the Neonate Possible Significance Hyperventilation Acidosis, hyperammonemia Hyperammonemia Urea cycle defect, transient hyperammonemia of the newborn, organic acidemia with 2° elevation in NH3, pyruvate carboxylase deficiency, holocarboxylase synthetase deficiency Metabolic acidosis with increased anion gap Propionic acidemia, methylmalonic acidemia, isovaleric acidemia, 1° or 2° lactic acidosis Lactic acidosis Pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, biotinidase deficiency, holocarboxylase synthetase deficiency, propionic acidemia, methylmalonic acidemia, glycogen storage disease, fructose-1,6-bisphosphatase deficiency, 3-hydroxy-

3-fnethylglutaryl CoA lyase deficiency, glutaric acidemia II, respiratory chain defects WILTSE (important non-genetic alternatives: hypoxia, liver necrosis) Ketosis Propionic acidemia, methylmalonic acidemia, isovaleric acidemia, branched-chain ketoaclduria, fructose-1,6-bisphosphatase deficiency Neutropenia a Propionic, methylmalonic, or isovaleric acidemia; lysinuric protein intolerance Hypothermia Isovaleric acidemia, Menkes syndrome Distinctive odor Branched-chain ketoaciduria, isovaleric acidemia, glutaric acidemia II Jaundice, hepatomegaly, diarrhea, elevation Galactosemia, tyrosinemia 1, alpha-1-antitrypsin deficiency, 3-hydroxydicarboxyllc aciduria of liver enzymes, prolongation of prothrombin time and partial thromboplastin time t>,c,d.e Apnea, seizures, hiccupping, myoclonic jerking Nonketotic hyperglycinemia Dysmorphic features in association with Pyruvate dehydrogenase deficiency, glutaric acidemia li, Zellweger syndrome, neonatal hypotonia and seizures adrenoleukodystrophy continued TABLE III continued Diagnostic Clues with Greater Specificity for Neonate and Older Infant

In the Older Infant Possible Significance SESET F H IFN WT AUE EAOI PROBLEMS METABOLIC ACUTE WITH INFANT THE OF ASSESSMENT Lethargy, coma, seizures, and acidosis. Hereditary fructose intolerance, urea cycle defects, lysinuric protein intolerance. precipitated by food intake, often 3-methylcrotonyl CoA carboxylase deficiency associated with food aversion Lethargy, coma, seizures with prominent 2-Methylacetoacetyl CoA thiolase deficiency, intermittent branched-chaln ketoaciduria. ketosis, associated with aggravated fasting glutaric acidemia 1 (important non-genetic alternative: ketotlc hypoglycemia) Lethargy, coma, seizures with hypoglycemia Beta oxidation defects (particularly medlum-chain acyl CoA dehydrogenase deficiency). and minimal or absent ketosis (hypoketotlc 3-hydroxy-3-methylglutaryl CoA lyase deficience, glutaric acidemia II (Important non- hypoglycemia) associated with aggravated genetic alternative: hyperinsulinism) fasting Leigh disease (subacute necrotizing Pyruvate dehydrogenase deficiency f, complex 1 & complex IV respiratory chain defect 0 encephalomyelopathy) U biotinidase deficiency h Dystonia Lesch-Nyhan disease, glutaric acidemia 1, homocystlnuria k, methylmalonic acidemia1 Osteoporosis Propionic acidemia, lysinuric protein intolerance, homocystlnuria Renal tubular reabsorptive defects Tyrosinemia 1, galactosemia, hereditary fructose intolerance, glycogen storage disease

a J, Pediatr. 700:62-65,1985 bj. Pediatr. 7 7 7:1039-1045,1987. cj. Pediatr. 777:313-319, 1987. d New Engl. J. Med. 327:1014-1021, 1092-1099, 1989. e J. Inher. Metab. DIs. 72:339-342,1989. f Pediatrics 79:370-373,1987. 0 J. Inher. Metab. Dis. 72Ó247-256, 1989. h Pediatr. Res. 26:260-266,1989. i Scriver, C.R.: The Metabolic Basis of Inherited Disease. 1989, pp. 869-888. JJ. Pedlatr. 174:340, 1989. kj. Pediatr. 7 73:863-864, 1988. 1J. Pediatr. 773:1022-1027,1988. TABLE IV Major Diseases and Recommended Tests Disease Prominent Features Tests

Ornithine transcarbamylase deficiency a b ,c ,d .e Hyperammonemia, severe in males, Quantitative amino acids (blood) variable in females orotic acid (urine) allopurlnol challenge (urine) Argininosucclnic aciduria b Hyperammonemia, abnormal hair Quantitative amino acids (blood) quantitative amino acids (urine) orotic acid (urine) Transient hyperammonemia of newborn w Hyperammonemia Quantitative amino acids (blood) orotic add (urine)

Lysinuric protein intolerance 9 Hyperammonemia, failure to thrive, Quantitative amino acids (blood) E WILTS osteoporosis h quantitative amino acids (urine) orotic acid (urine) Propionic acidemia i Acidosis, ketosis, hyperammonemia, Quantitative amino acids (blood) neutropenia carnitine, total and free (blood) organic acid screen (urine) Methylmalonic acidemia i Acidosis, ketosis, hyperammonemia, Quantitative amino acids (blood) neutropenia carnitine, total and free (blood) organic acid screen (urine) Isovaleric acidemia i Acidosis, ketosis, hyperammonemia, Quantitative amino acids (blood) neutropenia, pungent odor carnitine, total and free (blood) organic acid screen (urine) Pyruvate dehydrogenase deficiency k Lactic acidosis, Leigh encephalopathy Lactate/pyruvate ratio (blood) quantitative amino acids (blood) organic acid screen (urine) pyruvate dehydrogenase (enzyme) continued TABLE IV (continued) Major Diseases and Recommended Tests Disease Prominent Features Tests

Pyruvate carboxylase deficiency * Lactic acidosis, hyperammonemia, Lactate/pyruvate ratio (blood) hepatomegaly quantitative amino acids (blood) organic add screen (urine) pyruvate carboxylase (enzyme) Holocarboxylase synthetase deficiency i Early onset, lactic acidosis, ketosis, Lactate/pyruvate ratio (blood) hyperammonemia, coma, seizures, organic acid screen (urine) alopecia, frequent Infections biotinidase (enzyme) holocarboxylase synthetase (enzyme) Biotinidase deficiency1 Late onset, lactic acidosis, ketosis, Lactate/pyruvate ratio (blood) hyperammonemia, coma, seizures, organic acid screen (urine) alopecia, frequent infections biotinidase (enzyme) Fructose-1,6-bisphosphatase deficiency m Hypoglycemia, lactic acidosis, Lactate/pyruvate ratio (blood) ketosis, hyperuricemia quantitative amino acids (blood) organic acid screen (urine) fructose-1,6-blsphosphatase (enzyme) Hereditary fructose intolerance m,n Hypoglycemia, lactic acidosis, hyperuricemia, Lactate/pyruvate ratio (blood) aversion to sweets quantitative amino acids (blood) oral fructose tolerance test (blood) organic acid screen (urine) fructose-l-phosphate aldolase (enzyme) 3-Methylcrotonyl CoA carboxylase Hypoglycemia, acidosis, coma Organic acid screen (urine) deficiency ° 3-Methylcrotonyl-CoA carboxylase (enzyme)

continued TABLE IV (continued) Major Diseases and Recommended Tests

Disease Prominent Features Tests

Glycogen storage type I p Hypoglycemia, lactic acidosis, Glucose-6-phosphatase (enzyme) hyperuricemia, marked hepatomegaly

Glycogen storage type III p Mild hypoglycemia, lactic acidosis, Debrancher enzyme (enzyme) hyperuricemia, hepatomegaly

Glycogen storage type IV p Progressive cirrhosis with early fatal outcome Branching enzyme (enzyme) Glycogen storage type VI (liver Relatively mild hypoglycemia and Phosphorylase (enzyme) phosphorylase or phosphorylase hepatomegaly Phosphorylase b kinase (enzyme) p

kinase deficiency) WILTSE 3-Hydroxy-3-methylglutaryl CoA Hypoglycemia, hyperammonemia, Organic add screen (urine) lyase deficiency aw acidosis without ketosis 3-hydroxy-3-methylglutaryl-CoA lyase (enzyme) Glutaric acidemia, type II t Hepatomegaly, hypotonia, hypoglycemia, Organic acid screen (urine) acidosis without ketosis Respiratory chain defects (complex I) * Lactic acidosis, hypotonia, early death, Lactate/pyruvate ratio (blood Leigh encephalopathy u organic acid screen (urine) Respiratory chain defects (complex IV) u Lactic acidosis, myopathy, renal dysfunction, Lactate/pyruvate ratio (blood) Leigh encephalopathy v quantitative amino acids (urine) organic acid screen (urine) Branched-chaln ketoacidurla w* Ketosis, coma, seizures, ophthalmoplegia, Quantitative amino acids (blood) distinctive odor organic acid screen (urine) branched-chain alpha-keto acid dehydrogenase (enzyme)

continued TABLE IV (continued) Major Diseases and Recommended Tests

Disease Prominent Features Tests SESET F H IFN WT AUE EAOI PROBLEMS METABOLIC ACUTE WITH INFANT THE OF ASSESSMENT

Glutaric acidemia, type 1 y^aa Episodic ketoacidosis, hypoglycemia, Quantitative amino acids (blood) hyperammonemia, dystonia organic acid screen (urine) Glutaryl CoA dehydrogenase (enzyme) 2-Methylacetoacetyl CoA thlolase Ketoacidosis, hyperglycinemia, Quantitative amino acids (blood) deficiency * hematemesls, coma organic acid screen (urine) 2-methylacetoacetyl CoA thiolase (enzyme) Medium-chaln acyl CoA dehydrogenase Hypoketotlc hypoglycemia, Carnitine, total and free (blood) deficiency bb dlcarboxyllc aciduria, 2° carnitine organic acid screen (urine) depletion, hepatomegaly acyl carnitine profile (urine) medlum-chain acyl CoA dehydrogenase (enzyme) DNA study with polymerase chain reaction amplification Long-chaln acyl CoA dehydrogenase Hypoketotlc hypoglycemia, hepatomegaly, Carnitine, total and free (blood) deficiency t>b cardiomyopathy (few cases) acyl carnitine profile (blood) organic acid screen (urine) Short-chaln acyl CoA dehydrogenase Muscle weakness, episodic hypoglycemia Carnitine, total and free (blood) deficiency bb and acidosis (few cases, variable acyl carnitine profile (blood) manifestations) organic acid screen (urine) acyl carnitine profile (urine) Primary carnitine deficiency cc Hypoketotlc hypoglycemia, hepatomegaly, Carnitine, total and free (blood) coma (few cases) acyl carnitine profile (urine)

continued -a TABLE IV (continued) Major Diseases and Recommended Tests

Disease Prominent Features Tests

3-Hydroxydicarboxylic aciduria dd Positive phenylketonuria screen (elevation Quantitative amino acids (blood) in phenylalanine and tyrosine), coma, carnitine, total and free (blood) seizures, hypoglycemia, acidosis, jaundice, organic acid screen (urine) hyperammonemia, fatty infiltration of liver and cirrhosis, cardiomyopathy Galactosemia ®e Vomiting, diarrhea, jaundice, hepatomegaly, Erythrocyte galactose 1-phosphate cerebral edema, cataracts, galactosuria (blood) galactose-1-phosphate uridyl transferase (enzyme) WILTSE Alpha-l-antitrypsin deficiency Neonatal cholestasis, variable progression to Alpha-1-antitrypsln (blood) cirrhosis or resolution Tyrosinemia type 199 Fulminating neonatal liver failure or variable Quantitative amino acids (blood) progressive cirrhosis and deToni-Fanconl alpha-fetoprotein (blood) syndrome with rickets hh succinyl acetone (urine) fumarylacetoacetate hydrolase (enzyme) Nonketotic hyperglycinemia « Hypotonia, apnea, seizures, myoclonic jerking, Quantitative amino acids (blood) hiccups organic add screen (urine) cerebrospinal fluid glycine Lesch-Nyhan hyperuricemia ii Developmental delay, choreiform movements, Hypoxanthine-guanine phospho- self-mutllatlon ribosyltransferase (enzyme)

continued TABLE IV (continued) Major Diseases and Recommended Tests

Disease Prominent Features Tests SESET F H IFN WT AUE EAOI PROBLEMS METABOLIC ACUTE WITH INFANT THE OF ASSESSMENT Zellweger syndrome kk High forehead, epicanthal folds, cataracts, Very-long-chain fatty acid analysis Brushfield spots, hypotonia, neonatal seizures (blood) plasmalogen (blood) dihydroxyacetone phosphate acyltransferase (enzyme) subcellular localization of catalase (enzyme) Neonatal adrenoleukodystrophy kk Hypotonia and seizures Very-long-chain fatty acid analysis (blood) plasmalogen (blood) dihydroxyacetone phosphate acyltransferase (enzyme) subcellular localization of catalase (enzyme) Menkes syndrome « Neonatal hypothermia and hyperbilirubinemia, Copper (blood) abnormal hair, cerebral degeneration ceruloplasmin (blood)

a New Engl. J. Med. 322:1652-1655, 1990. b Scriver, C.R.: The Metabolic Basis of Inherited Disease,1989, pp.629-663. cj. Pediatr. ? 75:415-417. 1989. d j. Pediatr. 7 75:611-614, 1989. e Pediatr. Res. 26:27-82, 1989. f J. Pediatr. 707:712-719, 1985. 9 Scriver, C.R.: The Metabolic Basis of Inherited Disease., 1989, pp. 2497-2513. h New Engl. J. Med. 372:290-294, 1985. ' Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 821-844. ) Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 791-819. k Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 869-888. ' Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 2083-2103. m Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 399-424. n Pediatrics 85:600-603,1990. ° J, Inher. Metab. Dis. 72:339-341,1989. p Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 425-452. continued TABLE IV (continued) Major Diseases and Recommended Tests q J. Inher. Metab. Dis.73:156-164,1990. 'J. Inher. Metab. DIs. 7 7:76-87,1988. s J. Inher. Metab. Dis. 9:225-233,1986. t Pediatr. Res. 27:311-315,1990. u J. Pediatr. 770:84-87,1990. v Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 845-853. w Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 671-692. x Scrìver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 791-819. y J. Pediatr. 774:983-989, 1989. z Pediatrics 83:228-234,1989. aa Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 845-853. bb Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 889-914. cc New. Eng. J. Med. 379:1331-1336,1988. dd j. Pediatr. 7 70:387-392, 1990. e« scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 453-480. ff Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 2409-2437. 99 Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 547-562. hh J. Pediatr. 7 72:734-739,1988. « Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 743-753. ii Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 1007-1028, kk Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 1479-1509. il Scriver, C.R.: The Metabolic Basis of Inherited Disease, 1989, pp. 1411-1431. ASSESSMENT OF THE INFANT WITH ACUTE METABOLIC PROBLEMS 51 TABLE V Specialized Diagnostic Procedures from Clinical, Reference, or Research Laboratory

Blood Urine 1. Lactate/pyruvate ratio 13. Quantitative amino acids 2. Quantitative amino acids 14. Orotic acid 3. Carnitine, free and total 15. Organic acid screen 4. Acyl carnitine profile 16. Acyl carnitine profile 5. Alpha-fetoproteln 17. Succlnyl acetone 6. Alpha-l-antitrypsin 18. Allopurinol challenge0 7. Erythrocyte galactose-l-phosphate 8. Very-long-chain fatty acid analysis 9. Plasmalogen 10. Copper 11. Ceruloplasmin 12. Oral fructose tolerance test Enzyme Assays 19. Biotinidase Serum 20. Holocarboxylase synthetase Fibroblasts 21.3-Methylcrotonyl-CoA carboxylase Leukocytes, fibroblasts 22. Galactose-l-phosphate uridyltransferase Erythrocytes 23. Pyruvate dehydrogenase Fibroblastsb 24. Pyruvate carboxylase Fibroblasts 25. Fructose-1,6-blsphosphatase Liver 26. Fructose-1-phosphate aldolase Liver 27. Glucose-6-phosphatase Liver 28. Debrancher enzyme Liver 29. Branching enzyme Leukocytes, fibroblasts 30. Phosphorylase Liver 31. Phosphorylase b kinase Liver 32. Branched-chaln alpha-keto acid dehydrogenase Leukocytes, fibroblasts 33. Glutaryl CoA dehydrogenase Leukocytes, fibroblasts 34. 2-Methylacetoacetyl CoAthlolase Fibroblasts 35. 3-Hydroxy-3-methylglutaryl-CoA lyase Leukocytes, fibroblasts 36. Medium-chain acyl CoA dehydrogenase Leukocytes, fibroblasts 37. Fumarylacetoacetate hydrolase Liver, fibroblasts 38. Hypoxanthine-guanine phosphoribosyltransferase Erythrocytes 39. Dihydroxyacetone phosphate acyltransferase Fibroblasts 40. Subcellular localization of catalase Fibroblasts Other 41. Cerebrospinal fluid glycine 42. DNA study with polymerase chain reaction amplification«:

aNew Engl. J. Med. 322:1641-1645.1990. <=J. Clin. Invest. 86:1000-1013, 1990. bAn unusual sibship has been reported (Pediatr. Res. 24.-95-100, 1988) in which pyruvate dehydro genase activity was normal In cultured skin fibroblasts but virtually undetectable in liver, heart, and skeletal muscle. In most instances, fibroblast assay avoids the problems of enzyme lability encountered with tissue assay of pyruvate dehydrogenase.

Discussion metabolic diseases will often reveal non specific abnormalities of interest, but Analysis of the plasma amino acids in distinctive or pathognomonic patterns infants with these acutely symptomatic are found rather infrequently. Examples 52 WILTSE of distinctive findings include elevated urea cycle disorders. Accordingly, a high branched-chain amino acids and espe plasma glutamine may have the same cially L-alloisoleucine44 in branched- significance as a high ammonia in a child chain ketoaciduria, argininosuccinic acid with a defect in ureagenesis or lysinuric and perhaps citrulline in argininosuc protein intolerance, or it may serve as an cinic aciduria, methionine and homocys early warning of impending hyperam- tine in homocystinuria, and 2-aminoaci- monemic coma. dipic acid in glutaric aciduria type I. A urinary amino acid study may be Nonspecific elevations in plasma gly preferable to a blood study when argi cine are characteristically found in ninosuccinic aciduria is suspected; the propionic acidemia, methylmalonic low renal threshold for argininosuccinic acidemia, isovaleric acidemia, 2-methyl- acid causes it to appear in urine in large acetoacetyl CoA lyase deficiency, and amounts even at low blood levels. This lysinuric protein intolerance. Elevated substance has a tendency to form cyclic glycine levels have also been observed in anhydrides under conditions of analysis, children treated with valproic acid. For causing it to be misidentified unless the these reasons, a diagnosis of nonketotic chromatographer is experienced. A uri hyperglycinemia requires demonstration nary study may be particularly informa of elevated cerebrospinal fluid glycine tive in lysinuric protein intolerance, levels and absence of distinctive organic demonstrating large amounts of lysine, acids in the urine, in addition to eleva arginine, and ornithine in contrast to tion in plasma glycine.38 The plasma their low levels in plasma. alanine tends to elevate in parallel with Pyruvate is more likely than lactate to lactate and pyruvate in several condi be the metabolite of direct interest in tions, such as hereditary fructose intoler the diseases being considered here, but ance, fructose-1, 6-bisphosphatase defi measurements of lactate alone will ciency, glycogen storage disease type I, usually suffice. With the exception of and pyruvate carboxylase deficiency. severe pyruvate carboxylase deficiency, Elevations in alanine may characteristi where the lactate/pyruvate ratio may be cally occur in patients with urea cycle elevated, departures from the normal defects and lysinuric protein intolerance, ratio are unusual in metabolic disease. without simultaneous increases in lactate By contrast, the ratio is often elevated in and pyruvate. Low alanine levels may be patients with circulatory failure, found in branched-chain ketoaciduria asphyxia, or shock, all of which are and in the syndrome of ketotic hypogly usually distinguishable on clinical cemia of childhood. grounds from metabolic conditions. Tyrosine and methionine tend to ele Analysis of urinary organic acids by vate nonspecifically in infants with hepa means of combined capillary gas chroma tocellular disease. Alone, these abnor tography/mass spectrometry has emerged malities would not support a diagnosis of as a remarkably powerful screening and tyrosine type I, and this diagnosis should diagnostic tool. The method possesses be based on finding succinylacetone in excellent sensitivity and specificity for the urine and an abnormal assay for pathologic organic acids, their glycine fumarylacetoacetate hydrolase. Brusilow adducts, and the dicarboxylic acids charac and Horwich7 have called attention to teristic of medium-chain acyl CoA dehy the significance of glutamine as a protec drogenase deficiency and other defects in tive but saturatable “buffer” against beta oxidation. One should recognize that excessive ammonia accumulation in the dicarboxylic aciduria can occur innocendy ASSESSMENT OF THE INFANT WITH ACUTE METABOLIC PROBLEMS 53 in normal neonates13 and in infants given desoxynbonucleic acid (DNA) analysis feeding formulas containing medium-chain for confirming the diagnosis of medium- triglycerides. Unusual but non-pathologic chain acyl CoA dehydrogenase defi organic acids have also been found in the ciency.56 The unusual high frequency of urine of infants with gastroenteritis.30 a single mutation accounting for the Another highly significant innovation defect makes this procedure feasible. is the acyl carnitine profile obtained by means of fast atom bombardment/mass References spectrometry. This has proven particu larly useful in the diagnosis of organic 1. A mir, N ., E l p e l e g , O . N ., S h a l e v , R. S ., and C h r i s t e n s e n , E.: Glutaric aciduria type I: acidemias and beta oxidation defects Enzymatic and neuroradiologic investigations of through their characteristic carnitine two kindreds. J. Pediatr. 114:983 - 989, 1989. esters. Octanoyl carnitine, pathogno 2. A r b o u r , L ., R o s e n b l a t t , B., C l o w , C ., and W il s o n , G. N.: Postoperative dystonia in a monic of medium-chain acyl CoA dehy female patient with homocystinuria. J. Pediatr. drogenase deficiency, is readily demon 113:863-864, 1988. strable in urine by this technique. In the 3. A r n , P. H ., H a u s e r , E. R ., T h o m a s , G. H., H e r m a n , G., H e s s , D ., and B r u s il o w , S. W.: few years since this procedure became Hyperammonemia in women with a mutation at available, medium-chain acyl CoA dehy the ornithine carbamoyltransferase locus: a drogenase deficiency has become a rela cause of postpartum coma. New Engl. J. Med. 322:1652-1655, 1990. tively common diagnosis, with an inci 4. B arash , V , M a n d e l , H ., S e l l a , S ., and G e i dence now estimated at 0.4 to 1 per g er , R.: 3-Hydroxy-3-methylglutaryl-coenzyme 10,000. Long-chain acyl CoA dehydroge A lyase deficiency—biochemical studies and fam ily investigation of four generations. J. Inher. nase deficiency requires a plasma sample Metab. Dis. i3:156-164, 1990. for diagnosis, rather than urine, and is 5. B a u m g a r t n e r , E ., S u o r m a l a , T , W ic k , H ., considerably more rare. P r o bst, A., B l a u e n s t e in ,, U., B a c h m a n n , C., and V e s t , M .: Biotinidase deficiency-a cause of On a case-by-case basis, the diagnosti subacute necrotizing encephalomyelopathy cian must weigh the need for diagnostic (Leigh syndrome)-report of a case with lethal certainty (as this relates to prognosis, outcome. Pediatr. Res. 26:260-266, 1989. 6. B e r g m a n , I., F in e g o l d , D ., G a r t n e r , J. C ., treatment options, and genetic advice) Z it e l l i, B . J., C l a a se n , D ., Sc a r a n o , J., Ro e , against the relative availability or C . R ., St a n l e y , C ., and G o o d m a n , S. I.: Acute unavailability of confirmatory enzyme profound dystonia in infants with glutaric acide mia. Pediatrics 83:228— 234, 1989. assays. The need for confirmatory assay 7. B r u s il o w , S. and H o r w ic h , A.: Urea cycle will vary greatly. The diagnosis of pyru enzymes. In: Scriver, C. R., ed. The Metabolic vate dehydrogenase deficiency on clini Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, pp. 629-663. cal grounds alone would be very uncer 8. B u r t o n , B . K.: Inborn errors of metabolism: tain prior to assay. By contrast, a The clinical diagnosis in early infancy. Pediatrics confident clinical diagnosis of isovaleric 79:359-369, 1987. 9 . C a r p e n t e r , T. O ., L e v y , H . L ., H o l t r o p , acidemia might be made on the basis of M . D ., S h ih , V. E ., an d A n a st , C. S.: Lysinuric the clinical presentation, urinary organic protein intolerance presenting as childhood acid study, and urinary acyl carnitine osteoporosis. New Eng. J. Med. 312:2 9 0 —294, 1985. profile. A confirmatory enzyme assay for 10. Cox, D.: Alpha-l-antitrypsin deficiency. In: ornithine transcarbamylase deficiency Scriver, C. R., ed. The Metabolic Basis of requires liver3 or duodenal23 biopsy, but Inherited Disease, 6th ed. New York, McGraw- Hill, 1989, pp. 2409-2437. a newly described allopurinol challenge 11. D a n k s , D.: Disorders of copper transport. In: te s t24 makes it possible to identify Scriver, C. R., ed. The Metabolic Basis of women who are heterozygous for this x- Inherited Disease, 6th ed. New York, McGraw- Hill, 1989, pp. 1411-1431. linked defect without an invasive biopsy. 12. D a nn e r , D . and E lsas, L.: Disorders of branched A significant innovation is the use of chain amino acid and keto acid metabolism. In: 54 WILTSE

Scriver, C. R., ed. The Metabolic Basis of 25. H ayasaka, K ., B r o w n , G ., D a n k s , D ., D r o st e , Inherited Disease, 6th ed. New York, McGraw- M ., and Ka d e n b a c h , B .: Cytochrome c oxidase Hill, 1989, pp. 671-692. deficiency in subacute necrotizing encephalopa 13. D o w n in g , M ., R o s e , P., B e n n e t t , M ., M a n thy (Leigh’s syndrome). J. Inher. Metab. Dis. n i n g , N., and POLLITT, R.: Generalized dicar- 12:247-256, 1989. boxylic aciduria-a common finding in neonates. 26. H e l d e n r e ic h , R., N a to w ic z , M ., H a in l in e , J. Inher. M etab. Dis. 12:321-324, 1989. B. E ., B e r m a n , P., K e l l e y , R. I., H il l m a n , 14. EDSTROM, C. S.: Hereditary fructose intoler R. E., and B erry, G. T.: Acute extrapyramidal ance in the vomiting infant. Pediatrics 85:6 0 0 - syndrome in methylmalonic acidemia: "meta 603, 1990. bolic stroke” involving the globus pallidus. J. 15. E sq u iv e l , C. O., Iw a tsu k i, S ., G o r d o n , R. D., Pediatr. 773:1022-1027, 1988. M a r s h , W. W ., Ko n e r u , B ., M a k o w k a , L ., 27. H e r s , H .-G ., V an H o o f , F., and d e B arsy, T.: T z a k is, A . G ., T o d o , S ., and St a r z l , T. E .: Glycogen storage diseases. In: Scriver, C. R., Indications for pediatric liver transplantation. J. ed. The Metabolic Basis of Inherited Disease, Pediatr. H J: 1039-1045, 1987. 6th ed. New York, McGraw-Hill, 1989, pp. 16. F u j ii, T., It o , M ., O k u n o , T., M u t o h , K ., 425-452. N is h ik o m o r i, R., and M ik aw a, H.: Complex I 28. H u d a k , M. L., Jo n e s , M. D., and B r u s il o w , (reduced nicotinamide-adenine dinucleotide- S. W.: Differentiation of transient hyperammo coenzyme Q reductase) deficiency in two nemia of the newborn and urea cycle enzyme patients with probable Leigh syndrome. J. defects by clinical presentation. J. P ediatr. P ediatr 116:84- 87, 1990. 107:712-719, 1985. 17. G ib s o n , K ., B r e u e r , J., Ka ise r , K ., N y h a n , 29. H u t c h in s o n , R. J., B u n n e l l , K., andTHOENE, W ., M c C oy, E ., F e r r e ir a , P., G r e e n e , C ., J. G.: Suppression of granulopoietic progenitor B l i t z e r , M ., S h a p i r a , E . , R e v e r t e , F ., cell proliferation by metabolites of the C o n d e , C ., B a g n e l l , P., and C o l e , D .: 3- branched-chain amino acids. J. Pediatr. 106:6 2 - Hydroxy-3-methylglutaryl coenzyme A lyase 65, 1985. defiency—report of five new patients. J. Inher. 30. Kay, M. A., O’B r ie n , W., K e ssl e r , B ., M c V i e , Metab. Dis. 11:76-87, 1988. R., U r s in , S ., D ie t r ic h , K ., and M c C a b e , 18. G it z e l m a n n , R., St e in m a n , B ., and van d e n E. R. B .: Transient organic aciduria and methe B e r g h e , G .: Disorders of fructose metabolism. moglobinemia with acute gastroenteritis. Pediat In: Scriver, C. R., e d . The Metabolic Basis of rics 85:589- 592, 1990. Inherited Disease, 6th ed. New York, McGraw- 31. Ker r , D ., B erry, S ., L u s k , M., H o , L ., and H ill, 1989, pp. 399-424. Pa t e l , M .: A deficiency of both subunits of 19. G r e e n e , C. L ., B litzer, M. G ., and S h a p ir a , pyruvate dehydrogenase which is not expressed E.: Inborn errors of metabolism and Reye syn in fibroblasts. Pediatr. Res. 24:95-100, 1988. drome: differential diagnosis. J. Pediatr. 32. K r e t z sc h m a r , H. A ., D e A r m o n d , S. J., K o c h , 773:156-159, 1988. T . K ., Pa t e l , M . S . , N e w t h , C. J. L., 20. G o l d s m it h , L. and La b e r g e , C.: Tyrosinemia S c h m i d t , K. A., and Pa c k m a n , S.: Pyruvate and related disorders. In: Scriver, C. R., ed. dehydrogenase complex deficiency as a cause of The Metabolic Basis of Inherited Disease, 6th subacute necrotizing encephalopathy (Leigh dis ed. New York, McGraw-Hill, 1989, pp. ease). Pediatrics 79:370— 373, 1987. 547-562. 33. La r g il l ie r e , C ., H o u s s in , D ., G o t t r a n d , F , 21. G o o d m a n , S. and F r e r m a n , F.: Organic acide M a th e y , C ., C h e c o u r y , A ., A l a g il l e , D ., and mias due to defects in lysine oxidation-2-ketoa- F a r r ia u x , J. P.: Liver transplantation for orni dipic acidemia and glutaric acidemia. In: thine transcarbamylase deficiency in a girl. J. Scriver, C. R., ed. The Metabolic Basis of Pediatr. 115:415-417, 1989. Inherited Disease, 6th ed. New York, McGraw- 34. La y w a r d , E ., T a n n e r , M ., Po l l it t , R., and Hill, 1989, pp. 845-853. B a r t l e t t , K .: Isolated biotin-resistant 3-meth- 22. H a g e n f e l d t . L ., v o n D ö b e l n , U ., H o l m e , ylcrotonyl-CoA carboxylase deficiency present E ., A l m , J., B r a n d b e r g , G ., E n o c k s s o n , E ., ing as a Reye syndrome-like illness. J. Inher. and L in d e b e r g , L .: 3-Hydroxydicarboxylic ac- Metab. Dis. 72:339-341, 1989. iduria-a fatty acid oxidation defect with severe 35. La z a r o w , P. and M o se r , H.: Disorders of per prognosis. J. Pediatr. 116:387-392, 1990. oxisome biogenesis. In: Scriver, C . R., ed. The 23. H a m a n o , Y., K o d a m a , H ., F u jik a w a , Y., T a Metabolic Basis of Inherited Disease, 6th ed. n a k a , Y., N is h im u r a , K ., and Ya n a g isa w a , M.: New York, McGraw-Hill, 1989, pp. 1479-1509. Use of immunocytochemical analysis of a duo 36. L o e h r , J., G o o d m a n , S ., an d F r e r m a n , F .: denal biopsy specimen to identify a carrier of Glutaric acidemia type II-heterogeneity of clini ornithine transcarbamylase deficiency. New cal and biochemical phenotypes. Pediatr. Res. Engl. J. Med. 378:1521-1523, 1988. 27:311-315, 1990. 24. H a u s e r , E. R ., F in k e l s t e in , J. E ., V a l l e , D ., 37. N a g a o , M ., T s u c h iy a m a , A ., A o y a m a , T ., and B r u s il o w , S. W.: Allopurinol-induced oro- M o r i, T ., and O y a n a g i, K .: Secondary carnitine tidinuria: a test for mutations at the ornithine deficiency in the newborn period in twins of a carbamoyltransferase locus in women. New mother with partial ornithine transcarbamylase Engl. J. Med. 322:1641-1645, 1990. deficiency. J. Pediatr. 775:611—614, 1989. ASSESSMENT OF THE INFANT WITH ACUTE METABOLIC PROBLEMS 55

38. N yh a n , W.: Nonketotic hyperglycinemia. In: D.: Liver transplantation. New Eng. J. Med. Scriver, C. R., ed. The Metabolic Basis of 322:1014-1021, 1092-1099, 1989. Inherited Disease, 6th ed. New York, McGraw- 49. St o u t , F. and C ask ey, C .: Hypoxanthine phos- Hill, 1989, pp. 743- 753. phoribosyltransferase deficiency—the Lesch- 39. O g ie r , H ., L o m b e s , A ., Sc h o l t e , H. R., P o l l - Nyhan syndrome and gouty arthritis. In: Scriver, T h e , B. T., F a r d e a u , M , A l c a r d i, J., V ig n e s , C. R., ed. The Metabolic Basis of Inherited Dis B., N ia u d e t , P., and S a u d u b r a y , J. M .: de ease, 6th ed. New York, McGraw-Hill, 1989, pp. Toni-Fanconi-Debre syndrome with Leigh syn 1007-1028. drome revealing severe muscle cytochrome C 50. Sweetman, L.: Branched chain organic ac oxidase deficiency. J. P ediatr. 112:7 3 4 -7 3 9 , idurias. In: Scriver, C. R., ed. The Metabolic 1988. Basis of Inherited Disease, 6th ed. N ew York, 40. R o b i n s o n , B.: Lactic acidemia. In: Scriver, McGraw-Hill, 1989, pp. 791-819. C. R., ed. The Metabolic Basis o f Inherited Dis 51. T u c h m a n , M., T sa i, M., H o l z k n e c h t , R., and ease, 6th ed. New York, McGraw-Hill, 1989, pp. B r u sil o w , S.: Carbamyl phosphate synthetase 8 6 9 - 888. and ornithine transcarbamylase activities in 41. Ro e , C. and C o a t e s, P.: Acyl-CoA dehydroge enzyme-deficient human liver measured by nase deficiencies. In: Scriver, C . R ., ed. The radiochromatography and correlated with out Metabolic Basis of Inherited Disease, 6th ed. come. Pediatr. Res. 26:77-82, 1989. New York, M cGraw-Hill, 1989, pp. 889-914. 52. T r e e m , W . R ., S t a n l e y , C . A ., F i n e g o l d , 42. Ro s e n b e r g , L. and F e n t o n , W.: D isorders of D. N., H a l e , D. E., and C o a t e s , P. M.: Pri propionate and methylmalonate metabolism. In: mary carnitine deficiency due to a failure of car Scriver, C. R ., ed. The Metabolic Basis of nitine transport in kidney, muscle, and fibro Inherited Disease, 6th ed. New York, McGraw- blasts. New Eng. J. Med. 37.9:1331-1336, 1988. Hill, 1989, pp. 821-844. 53. v a n S p r o n s e n , F ., B e r g e r , R., S m it , G., d e 43. R u s s e l l , G. J., F it z g e r a l d , J. F., and C lar k , K l e r k , J ., D u r a n , M ., B ij l e v e l d , C ., v a n J. H.: Fulminant hepatic failure. J. Pediatr. F a a s s e n , H ., S l o o f , M ., and H e y m a n s , H .: Iii:313—319, 1987. Tyrosinaemia type I-orthotopic liver transplan 44. S c h a d e w a l d t , P., H a m m e n , H ., D a l l e -F e s t e , tation as the only definitive answer to a meta C., and WENDEL, U.: On the mechanism of L- bolic as well as an oncological problem. J. Inher. alloisoleucine formation—studies on a healthy Metab. Dis. 12:339-342, 1989. subject and in fibroblasts from normals and 54. W o l f , B. and H e a r d , G. S.: Disorders of biotin patients with maple syrup disease. J. Inher. metabolism. In: Scriver, C. R ., ed. The M eta Metab. Dis. 13:137-150, 1990. bolic Basis of Inherited Disease, 6th ed. New 45. S e g a l , S.: Disorders of galactose metabolism. York, M cGraw-Hill, 1989, pp. 2083-2103. In: Scriver, C . R ., ed. The Metabolic Basis of 55. W y so c k i, S. J. and H a h n e l , R.: 3-Hydroxy-3- Inherited Disease, 6th ed. New York, McGraw- methylglutaryl-coenzyme A lyase deficiency: a Hill, 1989, pp. 453-480. review. J. Inher. Metab. Dis. 9:225-233, 1986. 46. SlMELL, O.: Lysinuric protein intolerance. In: 56. Yo k o t a , I., Ya s u h ir o , I., C o a t e s, P., and Ta Scriver, C. R., ed. The Metabolic Basis of n a k a , K .: Molecular basis of medium-chain acyl- Inherited Disease, 6th ed. New York, McGraw- coenzyme A dehydrogenase deficiency—an A to Hill, 1989, pp. 2497-2513. G transition at position 985 that causes a lysine- 47. S p e r l , W. and R e n ie r , W .: Definition of Leigh 304 to glutamate substitution in the mature pro syndrome (letter). J. Pediatr. 114:340, 1989. tein is the single prevelant mutation. J. Clin. 48. St a r zl, T. E ., D e m e t r is, A. J., and V a n T h ie l , Invest. 86:1000—1013, 1990.