Laboratory Medicine and PathologyInitial Assessment of Infants and Children WithSuspected Inborn Errors of Metabolism

NORALANE M. LINDOR, M.D., AND PAMELA S. KARNES, M.D.

Inborn errors of metabolism (IEM) include a vast array of disordersthat are caused by specific enzyme deficiencies or transport proteindefects. The result is an excessive accumulation of substancesnormally present in small amounts or a deficiency of critical inter­mediates or end products of a specific metabolic pathway. Themanifestations of IEM are most often clinically nonspecific andrange from acute life-threatening crises to subacute degenerativedisorders to episodic disorders associated with lengthyasymptomatic periods or nonspecific developmental delay. Formany patients with IEM, rapid diagnosis and institution of therapyare lifesaving or may optimize long-term outcome. Although IEMare individually rare, collectively they account for a major propor­tion of childhood morbidity and mortality. Primary-care providersare unlikely to amass expertise in the management of specific IEM;however, they are often the first to suspect an IEM. This article waswritten to facilitate rapid diagnosis of IEM in potentially affectedpatients, whose subsequent assessment and treatment may necessi­tate consultation with a metabolic specialist.

Signs and Symptoms.-The clinical signs and symptoms thatshould prompt physicians to consider the possibility of an IEM aredifficult to summarize because IEM can affect literally every bio­logic process necessary for life. Of importance, the biochemicaldefects that cause IEM are not necessarily an all-or-none phenom­enon, and atypical manifestations at atypical ages are reported foralmost all the disorders, a suggestion that symptoms exist on acontinuum. The signs and symptoms of IEM that are most likely tobe evident during infancy or early childhood are listed in Table 1.

Initial Assessment-s-The suggested initial assessment of a seri­ously ill infant or child in whom an IEM is suspected is shown inTable 2. (We presume that concurrent evaluation for other condi­tions, such as sepsis, would be undertaken.) This battery of testsprovides a wealth of information and allows refinement of the nextlevel of testing.

The clinical manifestation in conjunction with the initial screen­ing tests outlined in Table 2 will usually facilitate classification ofthe IEM. Further laboratory testing for refining the diagnosis isbased on the class of suspected IEM.

ClassesofIEM. Organic Acidemias.-Organic acidemias (forexample, methylmalonic or propionic acidemia) are a group ofdisorders caused by abnormal metabolism of proteins, and theymay be characterized clinically by metabolic acidosis with ketosis,secondary mild to moderate hyperammonemia (ammonia, up to500 mg/dL), and secondary carnitine deficiency. These disordersmay be associated with developmental delay and impaired neuro­logic development, hypotonia, weakness, alopecia or rashes, abnor­mal urinary odors, protein avoidance or intolerance, pancreatitis,

From theDepartment ofMedical Genetics, MayoClinic Rochester, Roches­ter,Minnesota.

Address reprint requests to Dr. N. M. Lindor, Department of MedicalGenetics, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN55905.

and, in some conditions such as mevalonic aciduria, with craniofa­cial dysmorphism. If such defects are suspected, assess plasmaamino acids, urine organic acids and amino acids, and blood levelsof ammonia, biotinidase, and carnitine.

Aminoacidopathies.-Aminoacidopathies (for example,phenylketonuria, nonketotic hyperglycinemia, and homocystin­uria) as a group have considerable clinical and laboratory overlapwith the organic acidurias but are due to accumulation of a Ninhy­drin-positive amino acid in urine. They may be associated withdevelopmental delay and abnormal neurologic development, char­acteristic urinary odors, or, in the case of homocystinuria, with atall, long-limbed habitus and a predisposition to thrombotic events.If these disorders are suspected, perform the same tests as fororganic acidemias.

Urea Cycle Defects.-Urea cycle defects include six disordersthat result in the inability to excrete nitrogenous waste products, asituation that eventuates in severe hyperammonemia with respira­tory alkalosis. If such defects are suspected on the basis of initialscreening results, assess plasma quantitative amino acids and urineorotic acids and organic acids.

Disorders of Carbohydrate Metabolism.-Disorders of car­bohydrate metabolism (for example, galactosemia and hereditaryfructose intolerance) may manifest with vomiting, diarrhea, failureto thrive, hypoglycemia, hepatosplenomegaly, jaundice, cataracts,and seizures and may predispose to sepsis. If such disorders aresuggested by positive reducing substances in the urine, oralfeedings that contain the offending sugar should be withheld pend­ing additional diagnostic evaluation, and glucose should be admin­istered intravenously. Failure to follow this strategy can causepermanent brain damage or death.

Glycogen Storage Disease.--Glycogen storage diseases, a sub­set of disorders of carbohydrate metabolism, are caused by aberrantglycogen synthesis or degradation and result in decreased energysubstrates for cellular respiration. These disorders may manifestwith hepatosplenomegaly, hypoglycemia, hyperlipidemia, hyper­uricemia, lactic acidosis, increased liver transaminases, macro­glossia, and myopathy. A glucagon challenge in the postabsorptivestate typically fails to stimulate increases in blood glucose levels inmany such conditions. The diagnosis is often confirmed by specificenzyme assays, usually performed on liver biopsy specimens.

Disorders ofGluconeogenesis.-Disorders of gluconeogenesis(for example, fructose lfi-diphosphatase deficiency and pyruvatedecarboxylase deficiency) can result in difficulty in maintainingglucose homeostasis, and thus alternative energy sources are used,a situation that eventuates in lactic acidosis, hyperalaninemia, keto­sis, and, sometimes, hyperammonemia and hyperuricemia. Clini­cal features may include failure to thrive, hypotonia, hyporeflexia,growth retardation, and seizures. Specific enzymes must be as­sayed in order to establish the diagnosis.

Lysosomal Storage Disorders.-Lysosomal storage disorders,including mucolipidosis, mucopolysaccharidosis, sphingolipidosis,Hurler's syndrome, and Tay-Sachs disease, are caused by an accu-

Mayo CUn Proc 1995; 70:987-988 987 © 1995 Mayo Foundation for Medical Education and Research

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

988 INBORN ERRORS OF METABOLISM

Table I.-Signs and Symptoms That May Suggestan Inborn Error of Metabolism

Acute life-threatening crisisLethargy or coma, with or without a symptom-free periodSeizuresPersistent vomitingRespiratory distress, apneaPoor feeding, failure to thriveHypotonicity or hypertonicity, ataxia, posturingHepatosplenomegaly or jaundice (or both)Dysmorphic features, facial coarsening, macroglossiaOcular findings: cataract, retinopathy, corneal clouding,

eye movementsHair: sparse, abnormal textureAbnormal odor of urine, body, cerumenLoss of developmental milestonesUnusual response to fasting or intercurrent illnessesFluctuating neurologic status

mulation of various glycosaminoglycans, glycoproteins, or glyco­lipids within lysosomes in various tissues. These disorders maymanifest with some of the following signs: subacute neurode­generation, facial coarseness, organomegaly, skeletal changes,macular cherry red spots, and corneal clouding. If these defects aresuspected, further biochemical screening would include urinequalitative and quantitative mucopolysaccharides and oligosaccha­rides. Specific enzyme assays are necessary for the definitivediagnosis of most of these disorders and should be directed byclinical findings.

~-Oxidation Defects.-~-Oxidation defects (metabolism offatty acids) are characterized by hypoketotic hypoglycemia, whichmay be episodic. Alternatively, the clinical findings may be energydepletion with weakness, myopathy, myoglobinuria, andneuropathy. One disorder in this group, medium-chain acyl-CoAdehydrogenase deficiency, has been associated with sudden infantdeath syndrome in some families. If such disorders are suspected,assess urine organic acids, urine acylglycines, and acylcamitines inblood (dietary supplementation with camitine can alter findings) toseek excess excretion of medium- or long-chain dicarboxylic acidsrelative to short chains (3-hydroxybutyrate) or an abnormal patternof dicarboxylic acids.

Peroxisomal Disorders.-Peroxisomal disorders, includingsingle enzyme deficiency, failure of two or more enzymes, andcomplete failure, can be subdivided into the Zellweger syndrome,which is characterized by severely decreased function of all 40peroxisomal enzymes, and other disorders that result from singleprotein or enzyme defects. The clinical features of the Zellwegersyndrome include characteristic craniofacial dysmorphism,hepatosplenomegaly, hypotonia, and severe psychomotor retarda­tion. Features of other peroxisomal disorders are diverse andinclude subacute myeloneuropathies, skeletal dysplasia with limbshortening and epiphyseal stippling, and renal nephrolithiasis. Ifone of these disorders is suspected, plasma very long-chain fattyacids and phytanic acid should be assessed.

Miscellaneous IEM.-Miscellaneous IEM that may manifestin infancy or childhood that would not be detected by the previouslymentioned tests include, but are not limited to, the following.

Carbohydrate Deficient Glycoprotein Syndrome.-The carbo­hydrate deficient glycoprotein syndrome manifests with ataxia,strabismus, and gluteal adipose deposits, as well as severe liver dys-

Mayo Clin Proc, October 1995, Vol 70

Table 2.-Suggested Initial Laboratory Assessment of aSeriously III Infant or Child Suspected of Having

an Inborn Error of Metabolism*

Blood gas studiesGlucoseUrinary ketonesPlasma ammoniaElectrolytesNonglucose reducing substances in urineComplete blood cell count (cytopenias are common in inborn

errors of metabolism)Serum uric acidSerum liver function testsBlood lactate and pyruvateBlood camitine, blood free fatty acids, blood ~-hydroxybutyrate,

acetoacetate

*Plasma and urine should be frozen for assay of additional metabo­lites or hormones that might be present only during acute decom­pensation.

function, seizures, and strokelike episodes. It is assessed by testingserum isoelectric focusing of carbohydrate-deficient transferrin.

Smith-Lemli-Opitz Syndrome.-Smith-Lemli-Opitz syndromeis characterized by multiple anomalies, including growth and psy­chomotor retardation, hypotonia, clefting, and genital anomalies. Ifthis disorder is suspected, the serum total cholesterol level shouldbe tested because this syndrome has recently been shown to be dueto a defect in cholesterol biosynthesis. If the cholesterol level islow, a 7-dehydroxycholesterollevel is then assessed.

Lesch-Nyhan Syndrome.-Lesch-Nyhan syndrome, character­ized by progressive choreoathetosis, spasticity, and self-mutilation,is detected by the finding of a high level of serum uric acid (in 90%of patients with this disorder) and an increased urate:creatinineratio.

Menkes' Syndrome.-The manifestations of the Menkes' syn­drome include pale, full cheeks; kinky hair; bone fractures; delayeddevelopment; and occasional subdural hematomas and abnormalradiographic appearance of the bones; this syndrome may occasion­ally be mistaken for child abuse. The disorder is due to a coppertransport defect that results in low levels of serum copper andceruloplasmin.

Molybdenum Cofactor Deficiency and Sulfite Oxidase Defi­ciency.-Molybdenum cofactor deficiency and sulfite oxidase defi­ciency manifest with intractable neonatal seizures. Urine sulfitedipstick test results are positive when fresh specimens are used; theserum uric acid level is usually low for the cofactor deficiency only.Specific enzyme assays are available for both disorders.

Conclusion.-These guidelines are not comprehensive and in­tentionally do not address how or where to obtain definitive enzymeassays for diagnostic confirmation, because that level of testing canbe done in a less urgent fashion than the initial biochemical screen­ing. The critical message of this article is to encourage consider­ation of IEM in the setting of perplexing clinical manifestations.

BIBLIOGRAPHY1. Emery AE, Rimoin DL. Principles and Practice of Medical Genetics.

2nd ed. Edinburgh: Churchill-Livingstone, 19902. McKusick VA. Mendelian Inheritance in Man. lith ed. Baltimore:

Johns Hopkins University Press, 19943. Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and

Molecular Bases of Inherited Disease. 7th ed. New York: McGraw­Hill, 1995

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.