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Pediatrics, Inborn Errors of Metabolism

Author: Debra L Weiner, MD, PhD, Attending Physician, Division of Emergency Medicine, Children's Hospital, Boston; Assistant Professor, Department of Pediatrics, Harvard Medical School
Contributor Information and Disclosures

Updated: Mar 30, 2009

Introduction

Background

Inborn errors of metabolism (IEMs) individually are rare but collectively are common. Presentation is usually in the neonatal period or infancy but can occur at any time, even in adulthood. Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. An understanding of the major clinical manifestations of inborn errors of metabolism provides the basis for knowing when to consider the diagnosis. A high index of suspicion is most important in making the diagnosis.

For patients with suspected or known inborn errors of metabolism, successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization. Asymptomatic neonates with newborn screening results positive for an inborn error of metabolism may require emergent evaluation including confirmatory testing, and as appropriate, initiation of disease-specific management.

Pathophysiology

Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. Most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, or a combination of these metabolic deviations. Nearly every metabolic disease has several forms that vary in age of onset, clinical severity, and, often, mode of inheritance.

Categories of inborn errors of metabolism, or IEMs, are as follows:

• Disorders that result in toxic accumulation
  • Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects)
  • Disorders of carbohydrate intolerance
  • Lysosomal storage disorders
• Disorders of energy production, utilization
  • Fatty acid oxidation defects
  • Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis)
  • Mitochondrial disorders
  • Peroxisomal disorders

For more information, see eMedicine's articles in the Genetic and Metabolic Disease section of the eMedicine Pediatrics volume.

Frequency

United States

The incidence, collectively, is estimated to be approximately 1 in 4000 live births. The frequencies for each individual inborn error of metabolism vary, but most are very rare. Of term infants who develop symptoms of sepsis without known risk factors, as many as 20% may have an inborn error of metabolism.

International

The overall incidence and the frequency for individual diseases varies based on racial and ethnic composition of the population and on extent of screening programs. Overall rates are in a range similar to that of the United States.

Mortality/Morbidity

• Mortality can be very high for certain inborn errors of metabolism (IEMs), particularly those that present in neonates, but initial presentation of IEM even in adults may result in death. Prompt treatment of acute decompensation can be life-saving and is critical to optimizing outcome.
• Inborn errors of metabolism (IEMs) can affect any organ system and usually affect multiple organ systems resulting in morbidity due to acute and/or chronic organ dysfunction.
• Progression may be unrelenting with rapid life-threatening deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades.

Race

The incidence within different racial and ethnic groups varies with predominance of certain inborn errors of metabolism (IEMs) within particular groups (eg, cystic fibrosis, 1 per 1600 people of European descent; sickle cell anemia, 1 per 600 people of African descent; Tay-Sachs, 1 per 3500 Ashkenazi Jews).

Sex

• The mode of inheritance determines the male-to-female ratio of affected individuals.
• Many inborn errors of metabolism (IEMs) have multiple forms that differ in their mode of inheritance.
• The male-to-female ratio is 1:1 for autosomal dominant and autosomal recessive transmission. It is also 1:1 for X-linked dominant if transmission is from mother to child.

Age

Age for presentation of clinical symptoms varies for individual inborn errors of metabolism (IEM) and variant forms within the IEM. The timing of presentation depends on significant accumulation of toxic metabolites or on the deficiency of substrate.

• The onset and severity may be exacerbated by environmental factors such as diet and intercurrent illness.
• Disorders of protein or carbohydrate intolerance and disorders of energy production tend to present in the neonatal period or early infancy and tend to be unrelenting and rapidly progressive. Less severe variants of these diseases usually present later in infancy or childhood and tend to be episodic.
• Fatty acid oxidation defects, glycogen storage, and lysosomal storage disorders tend to present in infancy or childhood. Disorders manifested by subtle neurologic or psychiatric features often go undiagnosed until adulthood.

Clinical

History

• The history varies with age at presentation and is a function of the age at which various inborn errors of metabolism (IEMs) manifest clinically.
• The patient’s history may include the following:
  • Symptoms that range from abrupt in onset and episodic to chronic and progressive
  • Poor feeding, vomiting, failure to thrive, lethargy
  • Developmental delay, sometimes with loss of milestones
  • Onset of symptoms with change in diet and unusual dietary preferences, particularly protein or carbohydrate aversion
  • Decompensation out of proportion to what would be expected from intercurrent infection
  • Similar findings of unexplained neonatal or sudden infant deaths in siblings or maternal male relatives (A negative family history does not rule out IEM.)
  • Possible parental consanguinity (increases the likelihood of autosomal recessive IEM)
• Neonate
  • Consider an inborn error of metabolism (IEM) in any critically ill neonate.
  • Frequently, the most important clue is a history of deterioration, often life-threatening, after an initial period of apparent good health ranging from hours to weeks, usually following an uncomplicated pregnancy and delivery in a term infant.
  • In term infants without risk for sepsis who develop the symptoms of sepsis, metabolic disease may be nearly as common as sepsis. A negative newborn screen result does not exclude diagnosis of metabolic disease.
  • Nearly all states and many countries test newborns for a core set of 29 diseases, and many test for more than 50 diseases, most of which are IEMs using tandem mass spectrometry. Tests screened for by each state are provided by the National Newborn Screening and Genetics Resource Center (see National Newborn Screening Status Report).¹ It usually takes a few days and sometimes weeks until results are available. False-negative findings can result from screening too early, from medications, from transfusions, and from sample collection and handling. For every true positive newborn screen result, 12-60 false-positive results occur depending on the inborn error of metabolism (IEM).² Cut-off values have been deliberately set to yield a low rate of false-negative results.
• Infants and young children (1 mo to 5 y)
  • Onset of symptoms may coincide with what are normally developmentally appropriate changes in diet that result in increased intake of protein and carbohydrates or with increased duration of fasting as infants begin sleeping through the night.
  • A history of recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, or fulminant (Reye syndrome–like) hepatoencephalopathy.
  • Infants may appear and act normal between episodes or have a history of poor feeding, failure to thrive, fussiness, decreased activity and/or developmental delay, sometimes with loss of milestones.
  • With routine illnesses, infants with an inborn error of metabolism (IEM) may become more severely symptomatic, develop symptoms more rapidly, or require longer to recover than unaffected children.
• Older children (>5 y), adolescents
  • Undiagnosed metabolic disease should be considered in older children (>5 y), adolescents, or even adults with subtle neurologic or psychiatric abnormalities.
  • Many individuals previously diagnosed as having birth injury or atypical forms of psychiatric disorders or medical diseases, such as multiple sclerosis, migraines, or stroke, actually have an undiagnosed inborn error of metabolism.

Physical

• The physical examination findings are nonspecific in most patients with inborn errors of metabolism (IEM), and examination findings may be normal. When present, physical findings provide important clues to the presence of an inborn error of metabolism, the category, and, occasionally, the specific metabolic disease (see Table 1 in Workup).
  • Examination finding usually relate to major organ dysfunction or failure, most commonly hepatic and/or neurologic, and less commonly, cardiac or pulmonary.
  • Abnormalities include failure to thrive; dysmorphic features; abnormalities of hair, skin, skeleton, or all three; abnormal odor; organomegaly; and abnormal muscle tone.
  • Finding may be indistinguishable from those of sepsis, respiratory illness, cardiac disease, GI obstruction, renal disease, and CNS problems. Presence of these conditions does not rule out the possibility of an inborn error of metabolism.
• Neonate
  • Symptoms for inborn errors of metabolism of substrate and intermediary metabolism develop once a significant amount of toxic metabolites accumulate following the initiation of feeding and may include the following: poor feeding, vomiting, diarrhea, and/or dehydration; temperature instability; tachypnea; apnea; bradycardia; poor perfusion; irritability; involuntary movement; posturing; abnormal tone; seizures; and altered level of consciousness.
  • Certain inborn errors of metabolism (including galactosemia during the newborn period) and certain organic acidopathies may be associated with an increased risk of sepsis.
  • For neonates with inborn errors of substrate and intermediary metabolism, the physical examination findings are usually unremarkable.
  • For inborn errors of metabolism (IEMs) of energy deficiency, symptoms usually develop within 24 hours of birth and are often present at birth. Neonates with inborn errors that result in defects in energy production and use often have dysmorphic features, skeletal malformations, cardiopulmonary compromise, organomegaly, and severe generalized hypotonia.
  • Inborn errors of metabolism most likely to cause acute decompensation in the neonate include certain forms of the tyrosinemia, organic acidemias, urea cycle defects, fatty acid oxidation defects, and galactosemia.
• Infants and young children
  • Recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, fulminant hepatoencephalopathy, or a combination
  • Dysmorphic or coarse features, skeletal abnormalities, and abnormalities of the hair or skin
  • Poor feeding, failure to thrive
  • Dilated or hypertrophic cardiomyopathy, hepatomegaly, jaundice, and liver dysfunction
  • Developmental delay, occasionally with loss of milestones
  • Ataxia, hypotonia or hypertonia, and visual and auditory disturbances
• Older children, adolescents, and adults
  • Common findings include mild to profound mental retardation, autism, learning disorders, behavioral disturbances, hallucinations, delirium, aggressiveness, agitation, anxiety, panic attacks, seizures, dizziness, ataxia, exercise intolerance, muscle weakness, and paraparesis.
  • Some manifestations may be intermittent, precipitated by the stress of illness, changes in diet, exercise and/or hormones, or progressive, with worsening over time.
  • While most inborn errors of metabolism (IEMs) diagnosed in this age group are not immediately life threatening, partial ornithine transcarbamylase (OTC) deficiency, a urea cycle defect, can manifest at this time as a life-threatening metabolic catastrophe. This is observed particularly in adolescent females with a history of protein aversion, abdominal pain, and migrainelike headaches.

Causes

Diet or stress (ie, from intercurrent illness, trauma, surgery, or immunization) may precipitate episodic decompensation.

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