Chapter 76 Inborn Errors of Metabolism

• Unexpected and unexplained clinical deterioration in a previously healthy infant or child is an important clue to the presence of an inborn error of metabolism (IEM).

• Loss of previously attained developmental milestones during childhood is an important clue to the presence of a neurodegenerative disorder such as lysosomal storage disease.

• Blood glucose less than 40 mg/dL is distinctly unusual after the first 24 hours of life, particularly in infants who have started feeding, and should be thoroughly investigated.

• Laboratory evaluation for inborn errors of metabolism should be undertaken in any child with a suggestive clinical history regardless of the results of newborn screening. A normal newborn screen, although perhaps reassuring, does not rule out the possibility of an IEM.

• With catastrophic illness in a previously well child without signs of any particular IEM, the “shotgun” diagnostic evaluation should minimally include plasma amino acid analysis, urine organic acid analysis by gas chromatography-mass spectrometry, and a so-called urine metabolic screen.

Metabolism can be defined as the sum of all biochemical processes that convert food to smaller molecules and energy for the purposes of structure and function. An inborn error of metabolism (IEM) is an inherited deficiency of any critical step in metabolism. Although genetic deficiency of catalytic enzymes in intermediary metabolic pathways is the classic paradigm for IEM, the pathophysiology of metabolic disorders may involve abnormalities of any number of cellular processes, including transmembrane transport, cell signaling, cell differentiation and development, energy production, and others. Many IEMs are individually rare, although a few, including phenylketonuria (PKU) and medium-chain acyl-coenzyme A (acyl-CoA) dehydrogenase deficiency (MCADD), a defect in fatty acid oxidation, exhibit a population incidence approaching 1:10,000 live births.^1,² Specific IEMs may be more common in certain ethnic groups with a history of relative reproductive isolation. Collectively, the population incidence of all IEMs may approach 1:1500 live births, depending upon how broadly IEM is defined. Many IEMs are associated with catastrophic illness necessitating advanced life support. Although IEMs may present very rarely within the professional lifetime of the average medical practitioner, critically ill children with IEMs will not be uncommon visitors to the pediatric intensive care unit (ICU), especially in a tertiary care center.

The key to successful treatment of IEMs is the initial suspicion and timely diagnosis of the disorder. Certain features of the clinical history, physical signs and symptoms, and results of routine laboratory studies often suggest the possibility of IEM. Second-tier screening metabolic studies provide further evidence for the presence of a disorder. The results of routine neonatal screening studies may suggest a specific disorder prior to development of any diagnostic suspicion on the part of the clinician or even prior to the onset of symptoms in the neonate. In the case of a critically ill child with a suspected metabolic disease or with an abnormal neonatal screening test result for a specific metabolic disorder, immediate consultation with a biochemical geneticist, even if only by telephone, is paramount. The genetic consultant helps direct the diagnostic laboratory evaluation and recommends nonspecific emergency treatment, if any is warranted, prior to the availability of the definitive diagnostic studies. Communication among the intensivist, genetic consultant, and biochemical genetic diagnostic laboratory is critical to achieving the timely and correct diagnosis of IEM. A satisfactory clinical outcome for the affected child is completely dependent upon the collaborative efforts of this tripartite team approach.

Other published textbooks on the diagnosis and treatment of IEM provide an exhaustive list of known disorders.^3,⁴ Rather than recapitulate an encyclopedia of possible diseases, this chapter presents a diagnostic rationale based upon specific clinical symptom complexes that are likely to occur in the critically ill child. Algorithms for the differential diagnosis of specific clinical scenarios are given in support of this rationale. Symptoms often begin during early infancy in the biochemically most-severe IEMs; naturally, these IEMs with neonatal onset are the focus of our discussion in this chapter. However, “milder” or late-onset variants of virtually every IEM have been described, with onset of symptoms occurring at all ages, even during adulthood. Some IEMs uniformly present after the neonatal period; age of symptom onset (late infancy, childhood, or adulthood) often is an important clue to the specific diagnosis. The clinical presentation, diagnostic workup, and treatment of neonatal onset disorders provide a paradigm for the evaluation and management of possible IEM in a child of any age.

Pathophysiology of Inborn Errors of Metabolism

Under the classic paradigm, an IEM is associated with deficiency of a specific protein, often a catalytic enzyme, involved in a critical metabolic pathway (Figure 76-1). This deficiency leads to a block in the pathway and the accumulation of the enzyme substrate. In this model, three distinct pathogenic mechanisms are possible proximate causes of the symptoms associated with an IEM. The specific pathogenic mechanism involved in any given IEM dictates the appropriate treatment strategy. First, accumulation of the substrate may lead to toxic effects at very high levels; successful therapy requires effective elimination of the substrate or a method to block its toxic effects. An appropriate example for this mechanism is PKU, in which elevated phenylalanine levels adversely affect neuronal development, and the reduction of tissue phenylalanine content through dietary phenylalanine restriction largely prevents the major clinical features of PKU.⁵ Second, deficiency of the reaction product, should it be a critically important metabolite, may lead to disease. Supplementation with the essential metabolite, if possible, may cure the disease. Biotin is a required cofactor for four distinct carboxylase enzymes. Deficiency of free biotin develops in the face of genetic biotinidase deficiency and leads to symptoms of multiple carboxylase deficiency. Supplementation with oral biotin completely prevents the clinical manifestations of biotinidase deficiency.⁶ The final pathogenic mechanism involves the conversion of the enzyme substrate, through normally quiescent alternative pathways, to toxic secondary metabolites. Elimination or decreased production of these secondary metabolites may improve disease symptoms. For example, tyrosinemia type I (fumarylacetoacetate hydrolase [FAH] deficiency) is associated with recurrent attacks of abdominal pain and paresthesias reminiscent of acute intermittent porphyria. The accumulating substrate, fumarylacetoacetic acid, is converted through secondary pathways to succinylacetone, and succinylacetone in turn inhibits the heme synthetic pathway and causes porphyria-like symptoms. Pharmacologic inhibition of the tyrosine catabolic pathway proximal to the block at FAH decreases the production of fumarylacetoacetic acid and succinylacetone and alleviates the pathology associated with these toxic compounds.⁷

Figure 76–1 Inborn error of metabolism paradigm. Normally, in a given step of intermediate metabolism with intact enzymatic activity, the substrate A is efficiently converted to the product B. In an inborn error of metabolism, deficiency of enzyme activity may lead to excessive accumulation of the substrate; critical deficiency of the product; or production of an alternative, potentially toxic metabolite C through normally quiescent pathways.

Inheritance of Inborn Errors of Metabolism

IEMs are heritable disorders. The majority of diseases are inherited in an autosomal-recessive pattern, yielding a 25% recurrence risk in future offspring. The gene defects associated with several IEMs are located on the X chromosome. These IEMs, such as ornithine transcarbamoylase deficiency and glycerol kinase deficiency, are inherited in an X-linked pattern. These IEMs are most severe in males, but carrier females may be symptomatic, although usually with less severe or late-onset disease as a result of skewed X-chromosome inactivation. Mutations for several mitochondrial disorders are found on mitochondrial deoxyribonucleic acid (mtDNA). Because mtDNA is exclusively passed from mothers to their offspring, these IEMs exhibit a maternal inheritance pattern but often with variable penetrance and expressivity. Prenatal diagnosis is possible for many IEMs. In addition to allowing for appropriate medical therapy, the timely diagnosis of an IEM in a sick infant or child is important for genetic counseling purposes.

Signs and Symptoms of Inborn Errors of Metabolism

Clinical signs and symptoms frequently associated with IEMs are listed in Box 76-1. The symptom repertoire of the critically ill infant is limited, and the clinical presentation of metabolic disorders often is nonspecific. It is for this reason that the diagnosis of an IEM may be easily missed. To maintain maximum diagnostic sensitivity for IEMs, the clinician must maintain a high level of suspicion and be willing to initiate screening metabolic laboratory studies with little provocation. As was true for appendectomies in the era prior to the advent of ultrasound-based diagnosis of appendicitis, a certain number of nondiagnostic metabolic laboratory workups in sick children must be performed to ensure ascertainment of individuals with inherited metabolic disorders. In particular, IEM should be a strong diagnostic consideration in any neonate who has become catastrophically ill following a period of normalcy. This presentation may be clinically indistinguishable from bacterial or viral sepsis, and the nonspecific supportive therapy provided to potentially septic infants (fluid and glucose administration) may alleviate the symptoms and mask the presence of an IEM. Diagnostic metabolic laboratory studies are most likely to provide definitive information if performed on clinical samples obtained at initial presentation and before any therapy is initiated. Failure to obtain the necessary specimens at this time may miss an important diagnostic window of opportunity. Many children with IEM have been saved initially by intensive but nonspecific treatment but then suffered clinical relapse or even death in the absence of the correct diagnosis. Certainly, the possibility of an IEM should be considered in any child for whom the clinical picture suggests sepsis but the laboratory evaluation for sepsis is negative. Unfortunately, bacterial sepsis is often a complicating factor in critically ill children with IEM. For example, Escherichia coli infection (including pyelonephritis, bacteremia, or meningitis) is frequently detected at presentation in infants with galactosemia. The astute clinician remains ever vigilant for the signs and symptoms that may suggest an inherited metabolic disorder.

Recurrent episodes of vomiting and dehydration in response to fasting or intercurrent illness are an important clue to IEM in older infants and children. Feeding difficulties and failure to thrive are common chronic complications. Children with unexplained hypotonia, developmental delay, or movement disorder should be evaluated for possible IEM. Inherited neurodegenerative disorders, such as the lysosomal storage diseases, stereotypically cause developmental regression, specifically loss of previously attained developmental milestones. Several IEMs are associated with major physical anomalies (Table 76-1). When present, these anomalies are exceedingly valuable in suggesting a specific diagnosis and directing the diagnostic evaluation. More commonly, the child with IEM is morphologically normal, and the presenting symptoms are nonspecific. The clinician must then rely upon screening laboratory tests to evaluate the potential for IEM.

Table 76–1 Physical Anomalies Associated with Inborn Errors of Metabolism

Dysmorphic facial features	Peroxisomal disorders Glutaric aciduria type II Smith-Lemli-Opitz syndrome Menkes syndrome Lysosomal storage disorders
Structural brain anomalies	Glutaric aciduria type II (cortical cysts) Pyruvate dehydrogenase deficiency (cortical cysts, agenesis of the corpus callosum) Glycosylation disorders (cerebellar agenesis)
Macrocephaly	Glutaric aciduria type I (with subdural effusions) Canavan disease Alexander disease
Cataracts	Galactosemia Peroxisomal disorders Mitochondrial disorders Lowe syndrome
Lens dislocation	Homocystinuria Sulfite oxidase deficiency Molybdenum cofactor deficiency
Pigmentary retinopathy	Peroxisomal disorders including cherry red spots Lysosomal storage disorders Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Renal cysts	Glutaric aciduria type II, Peroxisomal disorders Mitochondrial disorders
Ambiguous genitalia	Congenital adrenal hyperplasia Smith-Lemli-Opitz syndrome
Skeletal abnormalities	Menkes disease Homocystinuria Peroxisomal disorders Lysosomal storage diseases
Hair or skin abnormalities	Menkes disease Holocarboxylase synthetase deficiency Biotinidase deficiency Argininosuccinic aciduria Phenylketonuria

Laboratory Evaluation of Suspected Inborn Errors of Metabolism

Abnormal results of routine laboratory studies may provide clues to the presence and type of IEM (Table 76-2). Highly informative but sometimes subtle laboratory abnormalities are often overlooked, especially in a busy ICU or hospital ward. For instance, a clinically relevant newborn screening result may have been sent to the primary care provider or birth hospital but not efficiently communicated to the ICU, in a different hospital, to which the now critically ill infant has been admitted. It is imperative to verify the infant’s screening results with the primary care provider or newborn screening laboratory (Box 76-2). Calculation of the anion gap, another example of a routine and highly informative result, is key to the differential diagnosis of metabolic acidosis. The absence of urine ketones in hypoglycemic children older than 2 weeks strongly suggests impaired ketogenesis as a consequence of either hyperinsulinism or fatty acid oxidation disorder. On the other hand, fatty acid oxidation and ketogenesis are incompletely developed in neonates. The presence of ketones in the urine of infants younger than 2 weeks is very unusual even during fasting or hypoglycemia and suggests the presence of an unusual keto acid, such as those excreted in maple syrup disease or the organic acidemias. Keto acids, organic acids, and sugars such as galactose or fructose increase urine specific gravity. Urine specific gravity greater than 1.020 in any neonate or in a well-hydrated older child suggests the unexpected presence of an osmotically active substance. Routine urinalysis at many hospitals may not include use of the Clinitest to detect reducing substances. Urine Chemstrips utilize a colorimetric glucose oxidase-based method to specifically detect glucose. This test does not react with any other sugar (galactose or fructose). However, some bedside glucose monitoring systems do react with galactose or fructose; inappropriately elevated capillary blood “glucose” accompanied by a normal venous glucose as measured by chemistry analyzer suggests the presence of a sugar other than glucose in the blood. A comatose infant with a blood urea nitrogen (BUN) level below the limits of detection may have an inherited defect in the urea cycle. Blood ammonia measurement is crucial to confirming that suspicion. Failure to check the blood ammonia level has caused missed diagnoses, failure to appropriately treat hyperammonemia, and further morbidity and mortality in comatose infants with urea cycle disorders or organic acidemias. Finally, bacterial sepsis and meningitis are more common causes of severe lethargy and coma in infants than is IEM, but bacterial infection may also be a complicating feature in severely ill infants with IEM. Infants with galactosemia, for example, are particularly prone to pyelonephritis, bacteremia, sepsis, or meningitis, often with E. coli, as noted above. Antibiotic therapy without diagnosis and specific treatment of the underlying disorder may be useful in the short term but does not mitigate long-term IEM-specific effects.

Table 76–2 Initial Laboratory Evaluation of Suspected Inborn Errors of Metabolism

Laboratory Test	Abnormality	Disorder
Complete blood count	Neutropenia Macrocytic anemia Pancytopenia	Organic acidemias Glycogenosis type 1b Cobalamin processing defects Congenital lactic acidoses
Serum electrolytes	Metabolic acidosis	Glycogenoses Organic acidemias FAO disorders MSUD Congenital lactic acidoses
Blood gas	Metabolic acidosis Metabolic alkalosis	Same as above Urea cycle disorders
BUN	Low or undetectable BUN (with hyperammonemia)	Urea cycle disorders
Transaminases (ALT, AST)	Liver dysfunction	Galactosemia Fructosemia Tyrosinemia α1-antitrypsin deficiency FAO disorders Organic acidemias Congenital lactic acidoses Congenital disorders of glycosylation
Total and direct bilirubin	Hyperbilirubinemia	Galactosemia Fructosemia Tyrosinemia α1-antitrypsin deficiency Congenital lactic acidoses
Serum uric acid	Hyperuricemia	Glycogenoses Purine disorders
Blood ammonia	Hyperammonemia	Urea cycle disorders FAO disorders Organic acidemias
Blood lactate	Lactic acidemia	Congenital lactic acidoses Glycogenoses Fructosemia Gluconeogenesis disorders
Urinalysis Odor Color pH Specific gravity Ketones Reducing substances	Unusual odor Inappropriately high specific gravity due to metabolites Ketosis Positive reducing substances	PKU, MSUD, organic acidemias Organic acidemias, galactosemia, fructosemia MSUD, organic acidemias Galactosemia, fructosemia

BUN, Blood urea nitrogen; FAO, fatty acid oxidation; MSUD, maple syrup urine disease.

Suspicion of an IEM based upon clinical and routine laboratory findings should initiate specialized biochemical testing (Table 76–3). In the case of severely ill infants or when the clinical suspicion of IEM is very high, consultation with a biochemical geneticist, even if only by phone, is strongly advised to help direct the laboratory investigation and initial therapy. When the clinical presentation is nonspecific, that is, catastrophic illness in a previously well child without signs of any particular IEM, the “shotgun” diagnostic evaluation should minimally include plasma amino acid analysis, urine organic acid analysis by gas chromatography-mass spectrometry, and a so-called urine metabolic screen. The battery of qualitative assays included in a urine metabolic screen differs among laboratories, and the ordering clinician should be aware of which tests and disorders are included in the repertoire of the diagnostic laboratory chosen. Furthermore, although diagnostic laboratories in the United States must meet Clinical Laboratory Improvement Amendments requirements and often are accredited by the College of American Pathologists, the testing methodologies used, the quality of diagnostic testing for IEM, and more problematically, the availability of laboratory-associated consultants with experience in the diagnosis and treatment of IEM vary widely among laboratories. Although the ability of clinicians to direct clinical specimens toward specific diagnostic laboratories may be inhibited by contractual arrangements between the hospital and large referral laboratories, the critically ill patient is best served by diagnostic evaluation carried out in a timely manner by an experienced biochemical genetics laboratory, with laboratory staff available by phone for expert consultation on interpretation of test results.

Table 76–3 Biochemical Genetic Laboratory Studies

Specimen	Test	Disorder
Blood	Plasma amino acid analysis	Aminoacidopathies
	Plasma carnitine	Organic acidemias FAO disorders
	Plasma acylcarnitine profile	Organic acidemias FAO disorders
	Serum transferrin electrophoresis	Congenital disorders of glycosylation
Urine	Metabolic screen Ketones Reducing substances Ferric chloride Dinitrophenylhydrazine 2,4-nitrosonaphthol Cyanide-nitroprusside Mucopolysaccharide screen Qualitative amino acid chromatography	Organic acidemias Galactosemia, fructosemia PKU PKU, MSUD Tyrosinemia Sulfur-containing amino acids Mucopolysaccharidoses Multiple amino acidurias
	Organic acid analysis	Organic acidemias FAO disorders
	Acylglycine profile	Organic acidemias FAO disorders
	Quantitative mucopolysaccharide measurement and electrophoresis	Mucopolysaccharidoses
	Qualitative sulfites (Sulfitest) or quantitative sulfocysteine	Sulfite oxidase deficiency Molybdenum cofactor deficiency
	Quantitative succinylacetone	Tyrosinemia type 1
	Quantitative purines	Purine synthesis disorders

PKU, Phenylketonuria; FAO, fatty acid oxygenation; MSUD, maple syrup urine disease.

The specific clinical presentation or specific screening laboratory findings may direct the intensivist or biochemical geneticist to order other more specialized metabolic tests (see Table 76-3). These analyses may provide diagnostic confirmation for specific disorders and supportive evidence alone for others. For several IEMs, confirmation of diagnosis may require enzyme activity analysis in tissue (red blood cells, lymphocytes, cultured skin fibroblasts, liver, or skeletal muscle depending upon the specific disorder in question) or molecular DNA testing for a specific gene defect. In general, these tertiary tests, which are often difficult, labor-intensive, and expensive, should be ordered following consultation with a biochemical geneticist. In some instances, confirmatory diagnostic biochemical or molecular tests are available only through specialized research laboratories.