Inborn Errors of Metabolism

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121 Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) are a subgroup of genetic disorders in which biochemical pathways are blocked or have significantly decreased activity, often leading to abnormal accumulation of a substrate or deficiency of a product of an enzyme reaction. In this chapter, a general discussion of IEM is followed by more detailed descriptions of individual categories of disorders.

Individually, IEM are rare, but they collectively make up a significant source of disease, particularly in infants and children. Most diseases are autosomal recessive, but autosomal dominant, X-linked, and mitochondrial inheritance patterns exist (see Chapter 115).

Although metabolic physicians typically manage disorders with abnormal biochemical findings in body fluids that include plasma amino acid and urine organic acid profiles, the true definition of IEM includes a wide array of diseases. Many of these, such as α-1-antitrypsin (AAT) deficiency and congenital adrenal hyperplasia, affect a specific organ system and are often followed by specialists in other specialties. This chapter focuses on pediatric IEM typically managed by metabolic specialists that should be considered in the differential diagnoses of common pediatric presentations.

The advent of newborn screening (NBS) methods has facilitated early detection and management of many of these disorders, with dramatically improved outcomes. The earliest NBS efforts included bacterial inhibition assays for phenylketonuria (PKU), but recent technology such as tandem mass spectrometry, permits highly sensitive rapid detection of metabolites. The challenge of NBS currently lies in deciding which diseases to screen based on available technology, detection rates, cost of follow-up, and the clinical benefits of early management.

The survival rate and quality of life for many patients with IEM is improving, and there is greater recognition of later-onset variants of diseases; thus, physicians who treat both pediatric and adult patients have more contact with affected individuals than in the past. Although management is frequently coordinated by specialists, generalists should be prepared to identify potential new cases, initiate therapy, and assist in general medical management. Even in metabolic disorders for which few therapeutic options exist, making an accurate diagnosis is important for anticipatory guidance, reproductive counseling, and improved decisions about the care of the patient.

Clinical Presentation

Although variations in genotype, diet, and lifestyle choices can lead to variable presentations for many IEM, illness or fasting typically exacerbates the disease process because of increased catabolism. Hence, a significant portion of IEM presents in infants, who have both increased metabolic demands associated with growth and a limited capacity to respond to illness. Clinical features can include nonspecific sepsis-like presentations such as poor feeding and growth, vomiting, lethargy, hypothermia, seizures, and irritability, and before NBS, undiagnosed IEM probably contributed to a significant proportion of unexplained infantile deaths. In older children with metabolic disorders associated with intellectual disabilities or behavioral problems, affected patients may not be able to convey the nature of their symptoms. Therefore, because of potential nonspecific presentations, IEM should be considered in all critically ill newborns or children with developmental delays, seizures, persistent vomiting, severe liver disease, metabolic acidosis, ketosis, hypoglycemia, hyperammonemia, or disease-specific findings common to a particular disorder.

To accomplish this, a thorough history and physical examination will narrow the differential diagnosis before diagnostic testing. A complete dietary history may reveal symptoms instigated by certain food types or fasting. Food preferences or aversions may also be instructive. Other important information includes the frequency of and severity of response to illness, pattern of developmental delays, presence of consanguinity, and distinct body fluid odors. Although there are many physical examination and laboratory findings characteristic of specific disorders (Figure 121-1), several findings help to indicate general categories. For example, Kussmaul’s respirations may be found with metabolic acidosis or hyperventilation with hyperammonemia or cerebral edema. Organomegaly may also be evident as the result of a storage defect or organ dysfunction. Several disorders, such as the peroxisomal disorder Zellweger’s syndrome, have characteristic patterns of dysmorphia.

Evaluation And Management

Diagnostic Testing

When an IEM is suspected, it is often important to initiate treatment measures while an investigative workup is underway because a delay in therapy may affect the clinical outcome. Blood, urine, and cerebrospinal fluid (CSF) can be useful in the laboratory evaluation, and several laboratory studies are particularly helpful when an IEM is suspected in an ill child (Box 121-1). Serum electrolytes and blood gas analysis evaluate the acid-base status and anion gap. Ketone levels in urine, and sometimes blood, should be determined. Serum ammonia, lactate, and pyruvate, which can be tested in most hospitals, can also be informative, particularly in ill newborns. Metabolic laboratory studies such as plasma amino acids, plasma acylcarnitines, and urine organic acids, which provide important diagnostic information, must often be sent to specialized centers. Finally, one should consider other disease-specific testing, such as complete blood counts, to evaluate for bone marrow suppression in some organic acidurias. Molecular DNA testing and enzyme assays may require biopsy of specific tissues.

Key to interpretation of testing, some laboratories require special collection methods. For example, blood for ammonia for lactate levels should be drawn from a free-flowing vessel, transported to the laboratory on ice, and tested soon after collection or values may be falsely elevated. The metabolic workup is most appropriately performed in a focused, tiered fashion, starting with testing for the most likely and treatable disorders.

Special efforts are necessary to arrive at a diagnosis in patients suspected of having IEM who are dying or recently deceased because clear confirmation of an IEM greatly assists with genetic and reproductive counseling for families. In a dying patient, consider collection and freezing of urine and separated plasma as well as a skin biopsy to be stored in tissue culture medium at room temperature for isolation of skin fibroblasts. One may also consider a liver biopsy (frozen sample for enzyme assays and fresh tissue for electron microscopy).

Common Presentations

Although IEM have a broad range of manifestations, common presentations and laboratory findings can lead one to consider a metabolic disorder. Because IEM are individually rare, a practical, generalized approach to common presentations is valuable.


Ammonia is a product of protein metabolism that, in elevated levels, is toxic to the central nervous system (CNS), resulting in cerebral edema. Normally, ammonia is converted to urea in the liver via the urea cycle and is excreted in the urine. When the nitrogen load exceeds the clearance capacity of the liver, ammonia accumulates. The nitrogen load increases with dietary protein intake and endogenous protein breakdown, both of which can cause hyperammonemia in patients with primary or secondary urea cycle defects. Symptoms of hyperammonemia include vomiting, seizures, lethargy, coma, and hyperventilation associated with respiratory alkalosis. Nonspecific episodes of headache, vomiting, and mental status changes may be the only signs in later-onset cases. For extremely high ammonia levels, such as during neonatal presentations of urea cycle disorders (UCDs), dialysis to rapidly reduce the toxic levels may be necessary in addition to less invasive therapies. Nonmetabolic causes of hyperammonemia include sepsis; liver failure; use of medications such as valproate; and transient hyperammonemia of the newborn, a disorder associated with severe neonatal hyperammonemia that resolves perinatally, although residual neurologic sequelae may result. Classic metabolic causes of hyperammonemia include UCDs, organic acidurias, FAODs, hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, pyruvate carboxylase deficiency, and hyperammonemia-hyperinsulinemia syndrome. Several of these disorders, including organic acidurias and FAODs, cause secondary urea cycle inhibition. Whereas hyperammonemia without metabolic acidosis and hypoglycemia is suggestive of UCD, an anion gap metabolic acidosis should arouse suspicion for an organic aciduria. Diagnostic pathways for biochemical causes of hyperammonemia are depicted in Figure 121-4.