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  1. List clinical symptoms that prompt further workup for an inborn error of metabolism (IEM).

  2. Define the utility of common laboratory tests in the diagnosis of children with an IEM.

  3. Distinguish the features of laboratory test results in the setting of an IEM from those in other pathologic conditions.

  4. Describe the indications and limitations of specialized metabolic techniques used in the diagnosis and monitoring of children with an IEM.


Countless biological processes are required to sustain human life, including the synthesis and catabolism of proteins, carbohydrates, and lipids. The bulk of this activity is performed by a tightly regulated network of enzymes and transport proteins, each of which is responsible for performing a specific step in one of many metabolic pathways. These metabolic pathways are highly dynamic and interrelated, allowing individual cells to turn some pathways on and others off during normal growth and aging, following changes in nutritional status and in response to stress. In states of normal health, enzyme activity is continuously turned up or down to maintain cellular concentrations of pathway intermediates within an acceptable range. Deficiencies in any of these enzymes caused by inborn errors of metabolism (IEMs) result in pathway dysregulation, leading to excesses of certain pathway intermediates and deficiencies in others. Depending on the enzyme deficiency, certain IEMs are asymptomatic, others cause significant impairment in the absence of appropriate treatment, while others are incompatible with life.

Because IEMs often cause clinical symptoms during the first days, months, or years of life, patients with IEMs are most frequently encountered in a pediatric setting. Unfortunately, due to the wide range of enzyme deficiencies and phenotypic clinical presentations, IEMs are often difficult to recognize, diagnose, and treat in a timely manner, thus representing a unique set of challenges for the pediatric physician. Metabolic abnormalities observed in many patients with IEMs can cause irreversible damage to the brain, liver, and other essential organ systems if left untreated. Fortunately, neurological damage and other morbidities caused by some IEMs may be avoided if the correct diagnosis is made and treatment initiated in a timely fashion. The goal of this chapter is to provide an introduction to IEMs, describe the role of metabolic genetics in the diagnostic process, and discuss the laboratory techniques most commonly used in diagnosis and disease management.

Newborn Screening

To date, greater than 500 IEMs have been characterized, each of which is associated with a distinct pattern of metabolic abnormalities. Because of the importance of rapidly diagnosing patients with IEMs, newborn screening (NBS) for selected IEMs is now standard practice in all 50 states and many countries around the world. The American College of Medical Genetics (ACMG) has recommended the measurement of biomarkers that strongly suggest the presence of 29 IEMs (Table 4-1).1 It is likely that this panel will expand to include ...

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