Pediatric Article
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Inborn Errors of Metabolism

By Santa J. Bartholomew M.D. FAAP, FCCM & Betsy Kastak, DNP, RN, C-PNP

See Corresponding Case Study: Inborn Errors Of Metabolism

Inborn Errors of Metabolism (IEMs), or metabolic disorders, represent a group of inherited diseases caused by the absence or deficiency of a substance critical to cellular metabolism, called an enzyme. When the normal metabolic process is interrupted by a missing enzyme, the final product is either absent or takes an alternate path.

This derangement leads to illness in children or death in some cases if not diagnosed. Most IEMs are characterized by abnormal:  protein, carbohydrate, or fat metabolism. IEMs are generally inherited as autosomal recessive or X-chromosomal traits. Autosomal recessive diseases are inherited from both mother and father who are both carriers of the disease.  An X-linked recessive inheritance pattern is when the abnormal gene is on the X chromosome only. 

inborn errors of metabolism


Inborn errors of metabolism are rare but improved testing and greater awareness of these diseases have shown that the prevalence is much greater than previously thought.

Inborn errors of metabolism are rare but improved testing and greater awareness of these diseases have shown that the prevalence is much greater than previously thought. In all states and US territories, a heel-stick blood test is typically done within the first 24 hours of a baby’s life and sent to a state lab that looks for the most common of these diseases. Although, newborn screening for IEMs varies from state to state every state has some form of newborn screening.

The infants blood sample is tested for at least 30 disorders and in some states as many as 70 disorders. Newborn screening programs have certainly increased the detection of IEMs however they cannot be trusted to be 100% accurate. False-positive and negative tests occur, usually because of technical error (i.e., before the newborn has eaten an appropriate amount of protein or carbohydrates), medications that interfere with testing, or blood transfusions. If detected via screening, the diagnosis is confirmed by further analysis of the blood or urine. Thirteen states use the two-screen model of newborn screening. In the two-screen model, all babies are screened at 24 hours and again at 1 to 2 weeks. The second test occurs in the primary provider’s office. State labs occasionally request that tests be repeated if drawn improperly or the screening is “borderline.” 

Screening immediately after birth provides the best chance for children with an IEM to be identified early and to minimize injury to the child. To get the infant diagnosed and treated when therapy is available for the disease identified. Best outcomes rely on prompt recognition of the signs and symptoms of a metabolic disease or a positive screen, followed by evaluation and referral to a pediatric center. Confirmation of diagnosis of specific disorders typically requires specialized testing. This testing should be performed in consultation with a genetic or metabolic medicine specialist.  

Symptoms: are typically non-specific making them less valuable except as related to a positive metabolic screen result. Poor feeding, nausea, vomiting, lethargy, seizures in some cases.

However, despite the lack of specificity of symptoms a delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death. 

The perinatal history for many common IEMs is usually typical since the mother generally compensates for impaired fetal metabolism.

In certain disorders, however, there may be problems with the pregnancy and abnormalities at birth, such as:

  • Low maternal serum estriol on routine maternal serum screening.
  • Decreased fetal movement.
  • HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).
  • Acute fatty liver of pregnancy.
  • Hyperemesis (excessive, prolonged vomiting)
  • Prolonged labor due to decreased placental estrogen production.
  • Non-immune hydrops fetalis (Dysregulation of fluid movement between the vascular and interstitial spaces of the fetus)   

Types of Inborn Errors of Metabolism

  • More than 1000 IEMs have been described to date.
  • Approximately 50% of them affect the central nervous system, causing mild to severe mental disabilities.
  • Many IEMs have a specific treatment that can prevent or at least lessen neurobiological damage and disability.


  • Amino acid disorders are caused by a flaw in the metabolic pathways of amino acids. Symptoms result from accumulating a substance that cannot be metabolized.
  • Organic acidemias are characterized by the accumulation of abnormal, toxic organic acid metabolites in the urine. Affected children develop a life-threatening episode of metabolic decompensation with poor feeding, vomiting, and lethargy.
  • Urea cycle disorders are an error in the metabolic pathway that transforms nitrogen to urea for excretion from the body through the urine. A deficiency of any of the enzymes in the pathway causes a Urea Cycle Disorder.
  • Carbohydrate disorders can lead to hypoglycemia, liver dysfunction, myopathy, and cardiomyopathy. These disorders include deficiencies of enzymes in the pathways of the metabolism of sugars.
  • Fatty acid oxidation disorder disrupts mitochondrial β-oxidation or fatty acid metabolism when stored energy is needed.
  • Mitochondrial disorders occur when the part of the cell known as the “mitochondria” (the energy center of the cell) cannot convert food into energy. Mitochondrial disorders can affect muscles, the brain, or multiple systems involving major organs.
  • Peroxisomal disorders are a group of IEMs that result in the impairment of peroxisome function. Multiple functions of cellular metabolism occur in peroxisomes.
  • Lysosomal storage disorders are caused by defective metabolism or distribution of naturally occurring compounds in the cell. This leads to the accumulation of substances within the tissues.
  • Purine and pyrimidine disorders involve impaired metabolism of these two substances. They may entail frequent bouts of kidney stones, neurologic dysfunction, developmental delays, self-mutilation, hemolytic anemia, and immune deficiency.
  • Porphyrias are genetic deficiencies in the activity of enzymes in the biosynthesis of blood.
  • Metal metabolism disorder is an impaired intestinal heavy metal absorption (i.e. zinc, copper, iron) represented by an overload or a deficiency and, ultimately, neurological or organ damage. 
  • Congenital disorders of glycosylation– Many essential body components require glycosylation to function normally. This process of attaching sugars to proteins occurs in the cell and requires multiple enzymes. Congenital disorders of glycosylation (CDGs) are caused by genetic errors that misdirect the enzymes necessary to synthesize these substances.
  • Congenital disorders of creatine metabolism affect the formation of adenosine triphosphate (ATP), an energy source for several intracellular metabolic processes.

Unfortunately, IEMs can present as acute metabolic emergencies resulting in significant morbidity, progressive neurologic injury, or death. An acute presentation with multisystem involvement is strongly suggestive of an IEM. The initial clinical manifestations of acute metabolic decompensation include vomiting, lethargy that can progress to coma, seizures, rapid, deep breathing, and low core temperature.

An abnormal laboratory value may be the first finding that suggests an IEM. In some disorders, these laboratory abnormalities are only present during the episode of metabolic decompensation. Testing in patients with a history and physical exam findings suggestive of an IEM should be performed at the time of presentation or when symptoms are most pronounced because laboratory values may be normal when the patient is well. Metabolic acidosis for example, (low serum bicarbonate and low blood pH) is usually present in organic acidemias. This finding also may be present in multiple disorders but only during an acute episode of acidosis. 

The detection of IEM begins a high index of suspicion. Infants with specific critical presentations, such as hypoglycemia, abnormal chemistry or elevated ammonia, should be evaluated for IEM. Infants with life-threatening illness should undergo concurrent evaluation for sepsis and cardiac failure as well as IEM’s since they often present similarly.

Infants with a significant metabolic crisis require immediate management to prevent further deterioration and sequelae, in the form of respiratory support, fluids, and, if necessary, toxin removal before confirmation of the diagnosis may be lifesaving or prevent or reduce the long-term neurologic consequences or even death in some of these conditions.