Inborn Errors of Metabolism: From Preconception to Adulthood

 

Am Fam Physician. 2019 Jan 1;99(1):25-32.

  Patient information: Handouts on this topic are available at https://familydoctor.org/newborn-screening-tests/ (newborn screening overview, including metabolic disorders) and https://familydoctor.org/condition/phenylketonuria-pku (PKU).

Author disclosure: No relevant financial affiliations.

Inborn errors of metabolism (IEM), although individually rare, occur in 1 out of every 1,500 births. The first opportunity to detect IEM occurs during preconception counseling, when pregnant women and couples considering future pregnancies can undergo carrier screening. For individuals of all ethnic backgrounds, the screening includes testing for a variety of IEM and non-IEM. For individuals of Ashkenazi Jewish descent, carrier screening, per the American College of Medical Genetics and Genomics, also includes testing for Tay-Sachs disease and four other IEM. Inborn errors of metabolism can present in utero; in newborns; or in children, adolescents, and adults. Some IEM can be detected in utero with the use of ultrasonography. Most commonly, IEM are detected at newborn screening. Expanded newborn screening, which now includes 34 core conditions, allows for diagnosis in the newborn period and provides the opportunity for early institution of available treatments. However, some newborns present with symptoms consistent with an IEM before the availability of pending newborn screening results or present with symptoms attributable to an IEM not detectable with screening. Such situations are medical emergencies requiring immediate consultation with a metabolic specialist. If a delay occurs in obtaining consultation, initial treatment involves discontinuing feeding and providing high-rate glucose infusions. Some IEM present later in life. Children may develop and present with dysmorphic facial features. In some cases, symptoms may not appear until adolescence or adulthood when patients have residual enzyme activity that allows for slow accumulation of toxic molecules over time. Long-term treatments are effective for some IEM. Treatments include dietary restrictions and enzyme-replacement therapies.

Inborn errors of metabolism (IEM) are genetic conditions that block metabolic pathways involved in the breakdown of nutrients and the generation of energy. Perturbation of these metabolic pathways results in a spectrum of clinical findings affecting multiple organ systems. The diagnosis of IEM is challenging because the clinical presentation is often nonspecific; however, more IEM are now included in recommended newborn screening, which helps for early diagnosis. Therefore, knowledge of IEM has become essential for physicians. Although individual IEM are rare, the combined incidence is 1 out of every 1,500 births.1 This review discusses IEM disorders from preconception to adulthood.

WHAT IS NEW ON THIS TOPIC

The American College of Obstetricians and Gynecologists has classified expanded carrier screening as an acceptable pre-pregnancy and prenatal screening strategy for all patients. Expanded screening refers to concurrently screening for as many as several hundred conditions, including both IEM and non-IEM.

The initial treatment for all newborns and children with a suspected IEM comprises ending the buildup of toxic metabolites by discontinuing feeds and by preventing catabolism by giving glucose at a high infusion rate (5 to 10 g per kg per hour).

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationStrength of recommendationReferencesComments

The option of carrier screening for IEM should be discussed when providing preconception counseling to women considering pregnancy.

C

7

Consensus

Newborn screening is recommended for 34 disorders, including 25 IEM.

C

14, 15

Consensus

An IEM disorder should always be considered in the differential diagnosis in infants being evaluated or treated for suspected infection, especially if the infant does not respond to antibiotics as expected.

C

24, 25

Expert opinion

Physicians should consult with a metabolic specialist on an emergency basis upon diagnosis of IEM in a newborn.

C

16, 18

Expert opinion

The ACMG ACTion (ACT) sheets and algorithms should be used to further determine appropriate action after a positive newborn screen, particularly if there is a delay in contacting a metabolic specialist.

C

16, 18

Expert opinion


ACMG = American College of Medical Genetics and Genomics; IEM = inborn errors of metabolism.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationStrength of recommendationReferencesComments

The option of carrier screening for IEM should be discussed when providing preconception counseling to women considering pregnancy.

C

7

Consensus

Newborn screening is recommended for 34 disorders, including 25 IEM.

C

14, 15

Consensus

An IEM disorder should always be considered in the differential diagnosis in infants being evaluated or treated for suspected infection, especially if the infant does not

The Authors

show all author info

PAUL KRUSZKA, MD, MPH, is a clinical geneticist at the National Human Genome Research Institute at the National Institutes of Health, Bethesda, Md....

DEBRA REGIER, MD, PhD, is an assistant professor of pediatrics at George Washington University and director of education in the Division of Genetics at Children's National Health System, Washington, DC.

Address correspondence to Paul Kruszka, MD, MPH, National Human Genome Research Institute, 35 Convent Dr., Bldg. 35, Rm 1B207, Bethesda, MD 20892 (e-mail: paul.kruszka@nih.gov). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

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