Inborn Errors of Metabolism
Michael Wilhelm
Wendy K. Chung
KEY POINTS
General Approach to Inborn Errors of Metabolism
Although individually rare, inborn errors of metabolism (IEMs) are collectively common in pediatrics.
There should be a high index of suspicion of an IEM in patients with encephalopathy, (cardio) myopathy, hyperammonemia, hypoglycemia, or refractory metabolic acidosis.
Prompt initiation of specific therapy can prevent irreversible brain injury.
Patients with IEMs may have a number of nonmetabolic complications requiring pediatric intensive care.Disorders Associated with Lactic Acidosis
Primary lactic acidemia should be suspected when a source of tissue hypoperfusion cannot be determined.
In disorders of oxidative phosphorylation, lactate levels may fluctuate significantly in the blood, or only be elevated in the cerebrospinal fluid.
In diseases of energy metabolism or hypoperfusion, the lactate-adjusted anion gap is normal while it is elevated in the organic acidemias due to the presence of other anions besides lactate.
A lactate-to-pyruvate ratio of greater than 25:1 suggests a defect in oxidative phosphorylation.Metabolic Acidosis without Increased Lactate
These disorders should be suspected with intoxication syndromes exhibiting encephalopathy and vomiting associated with marked ketosis.
Extracorporeal toxin removal with hemodialysis or hemofiltration may be beneficial with severe presentations that do not respond to conservative therapies.
Specific supplemental vitamin/cofactor therapies are indicated in many of these disorders in addition to general management.
Liver (and in rare cases renal) transplantation may be beneficial in many of these disorders.Hypoglycemia
Hypoglycemia (<50 mg/dL or <40 mg/dL in neonates) must be promptly treated to prevent permanent brain injury.
Critical samples should be obtained at the time of hypoglycemia.
The absence of ketones suggests inappropriate hyperinsulinism or a defect in fatty acid oxidation.
Hypoglycemia with fasting (often as infants begin sleeping through the night) suggests glycogen storage disorders.
C-peptide distinguishes endogenous hyperinsulinism from administered insulin.Hyperammonemia
Hyperammonemia is one of the most critical metabolic conditions as ammonia is extremely toxic to the brain.
Prophylactic intubation is indicated with levels >500 µmol/L due to the risk of rapid progression to coma and respiratory depression.
Levels >500 µmol/L should be treated with some form of hemodialysis.
The more severe cases (>300 µmol/L) are typically due to urea cycle defects.
Initial treatment consists of making the patient NPO and making them anabolic with an appropriate glucose and electrolyte infusion.
In suspected urea cycle defects, L-arginine, sodium benzoate, and phenylacetate should be added empirically.Liver Failure
Hepatomegaly may help distinguish metabolic causes of liver failure from infectious causes initially.
Initial presentation with hepatomegaly, hepatocellular injury, conjugated hyperbilirubinemia, or unconjugated hyperbilirubinemia can suggest the specific metabolic disorder.
Associated myopathy and cardiomyopathy suggest a defect of long-chain fatty acid oxidation.Nonmetabolic Critical Illness in IEMs
IEMs can affect hepatic, renal, pulmonary, cardiovascular, and hematologic systems.
Certain IEMs are contraindications to specific anesthetic agents.
Storage diseases (i.e., the mucopolysaccharidoses) may make endotracheal intubation extremely difficult.Inborn errors of metabolism (IEMs) result from the deficiency of any one of over 400 enzymes involved in 
intermediary metabolism. Although individually rare, collectively they are common in pediatrics. Many children with previously diagnosed IEMs will come to the PICU postoperatively following procedures or during an acute metabolic decompensation and will require specialized cardiorespiratory and metabolic management dictated by their underlying IEM. Other children with previously unrecognized IEMs will present in a variety of ways, including change in mental status, shock, metabolic acidosis, vomiting, failure to thrive, developmental delay, intractable seizures, liver failure, and cardiomyopathy. Therefore, pediatric intensivists must have a fundamental understanding of these conditions, including when to suspect an IEM and how to initially manage these patients. This chapter provides a basic framework for approaching the patient with a suspected IEM with particular attention given to management issues that may confront the pediatric intensivist. Because of the large number of IEMs, we present some general concepts initially followed by specific discussions of the more important individual diseases, their presentation, and treatment.
intermediary metabolism. Although individually rare, collectively they are common in pediatrics. Many children with previously diagnosed IEMs will come to the PICU postoperatively following procedures or during an acute metabolic decompensation and will require specialized cardiorespiratory and metabolic management dictated by their underlying IEM. Other children with previously unrecognized IEMs will present in a variety of ways, including change in mental status, shock, metabolic acidosis, vomiting, failure to thrive, developmental delay, intractable seizures, liver failure, and cardiomyopathy. Therefore, pediatric intensivists must have a fundamental understanding of these conditions, including when to suspect an IEM and how to initially manage these patients. This chapter provides a basic framework for approaching the patient with a suspected IEM with particular attention given to management issues that may confront the pediatric intensivist. Because of the large number of IEMs, we present some general concepts initially followed by specific discussions of the more important individual diseases, their presentation, and treatment.GENERAL APPROACH TO INBORN ERRORS
Pathophysiology of IEMs
Inborn errors often present with nonspecific manifestations that may culminate in critical illness, particularly in young infants or neonates. Because these disorders result from enzyme deficiencies for which 50% of normal activity is usually adequate, they are inherited predominantly in an autosomal recessive fashion. The mitochondrial genome, however, is maternally inherited and thus some mitochondrial disorders are matrilineally transmitted. Furthermore, many mitochondrial diseases depend upon the percentage of the mitochondrial population that carries the mutation (heteroplasmy) and therefore manifestations depend on the load of mutant mitochondria in each tissue. Thus, a given mutation may produce varying manifestations in different family members. Specific disorders with X-linked inheritance predominantly affecting males are identified in the appropriate sections.
These diseases manifest as a result of the lack of products of the deficient enzyme, accumulation of upstream metabolites, shunting of accumulated metabolites into other pathways, or some combination of the above. The pathophysiology of IEMs presenting in the PICU can be categorized into one of the following processes: (a) intoxication from metabolites such as ammonia, amino acid derivatives, or ketoacids, (b) reduced fasting tolerance, (c) derangements of energy metabolism, (d) derangement of neurotransmission, or (e) storage of nonmetabolizable substrates in vital organs or tissues. Table 113.1 lists disorders associated with each of these categories.
TABLE 113.1 CATEGORIES OF INBORN ERRORS OF METABOLISM WITH ACUTE PRESENTATIONS | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||
Clinical Presentation and Differential Diagnosis
Historical Clues
The history and physical examination may provide clues that a patient has an IEM, though IEMs can masquerade as other causes of critical illness. Commonly, IEMs present with changes in mental status (lethargy, irritability, seizures, and coma) with or without overt cardiorespiratory compromise and can be easily confused with sepsis. Hypothermia may be associated with metabolic decompensation, especially in the urea cycle defects. Furthermore, infection often exacerbates metabolic derangements and precipitates metabolic decompensation owing to increased energy requirements and the frequent association with decreased food intake. Finally, certain IEMs make patients more susceptible to infection (Escherichia coli sepsis in galactosemia or neutropenia associated with organic acidurias). Therefore, empiric treatment for suspected sepsis should be initiated after obtaining appropriate cultures.
The child’s history may reveal decreased oral intake, due to an intercurrent infection or fasting as an infant begins to sleep through the night. Neonates may present with failure to regain birth weight by the second week of life. The older child may present with recurrent episodes of lethargy and difficulty recovering from minor illnesses. Children of all ages often demonstrate failure to thrive. In rare cases, the specific dietary intake may suggest the diagnosis. Particular foods such as a high-protein meal may induce symptoms, including nausea in urea cycle defects. Ingestion of fruits or sweet foods containing sucrose may trigger decompensation in hereditary fructose intolerance. Children with partial enzymatic deficiencies and milder disorders may even unknowingly alter their diet to avoid foods that make them feel lethargic or ill.
A history of developmental delay, hypotonia, and/or seizures is associated with many of the IEMs. A history of developmental regression is particularly concerning and should prompt a careful search for an IEM, particularly the lysosomal storage and mitochondrial disorders.
TABLE 113.2 ODORS ASSOCIATED WITH METABOLIC DISEASES | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Features of the family history may suggest a metabolic disease, including parental consanguinity, ethnicity of the patient (hepatorenal tyrosinemia in French Canadians and maple syrup urine disease in Pennsylvania Amish), fetal demise, unexplained deaths or sudden infant death syndrome, developmental delay, seizures, failure to thrive or other unexplained chronic illness. Although the prenatal history is often unremarkable, a history of maternal liver disease or HELLP syndrome may suggest a long-chain fatty acid oxidation disorder. The sex of the patient is relevant in a small number of IEMs that are X linked, such as the urea cycle defect ornithine transcarbamylase deficiency, the carbohydrate defect pyruvate dehydrogenase deficiency E1α, and the defect of the nucleotide salvage pathway Lesch-Nyhan disease.
Physical Examination Findings
On physical examination, the presence of an unusual body or urine odor might suggest a specific organic acidemia (Table 113.2), but these odors can be subtle and their absence should not dissuade pursuit of an IEM. Careful attention should be paid to the respiratory pattern (tachypnea may herald sepsis with acute respiratory distress syndrome, Kussmaul respirations occur with metabolic acidosis). It is important to remember, that Kussmaul respirations can be difficult to discern in neonates and other patients with restrictive lung disease.
Progressive hepatosplenomegaly occurs in a number of IEMs as nonmetabolizable substrate accumulates in glycogen storage disorders and lysosomal storage disorders. Dysmorphic features are present at birth in a number of peroxisomal biogenesis disorders, fatty acid oxidation disorders, congenital disorders of glycosylation, and pyruvate dehydrogenase deficiency while they develop progressively over time in the mucopolysaccharidoses (MPSs) as storage material accumulates in the soft tissues and bones. Smith-Lemli-Opitz syndrome, a defect in sterol biosynthesis, may present with ambiguous genitalia and 2/3 toe syndactyly. Ophthalmologic examination may also provide clues to an IEM with cataracts observed in galactosemia and retinal pigmentary changes in Tay Sachs disease and in some of the mitochondrial disorders.
TABLE 113.3 LABORATORY EVALUATION OF A SUSPECTED INBORN ERROR OF METABOLISM | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
Myopathy demonstrated by hypotonia or cardiomyopathy (hypertrophic or dilated) possibly detected by a heart murmur or signs of heart failure may herald a disorder of fatty acid oxidation, mitochondrial derangement, glycogen storage disorder, or rarely a congenital disorder of glycosylation. IEMs are important causes of cardiomyopathy to exclude in children since these can be treated and in some cases cured such as in the case of Pompe disease.
Laboratory Findings
Routine laboratory test results may suggest an IEM (Tables 113.3 and 113.4). A primary respiratory alkalosis may be found with hyperammonemia caused by a urea cycle defect. A metabolic acidosis, particularly with an elevation in anion gap (AG) or in lactate occurs in certain IEMs, though this may also occur in other diseases such as sepsis or hypoperfusion. Children with elevated lactate due to hypoperfusion usually appear quite ill, whereas patients with an IEM may have lactate elevations out of proportion to their degree of illness. The lactate-adjusted AG
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
