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 (newborn screening overview, including metabolic disorders) and (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.


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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Clinical recommendationStrength of recommendationReferencesComments

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




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


14, 15


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.


24, 25

Expert opinion

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


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.


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


Clinical recommendationStrength of recommendationReferencesComments

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




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


14, 15


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

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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: Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


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1. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics. 2000;105(1):e10....

2. Vallance H, Ford J. Carrier testing for autosomal-recessive disorders. Crit Rev Clin Lab Sci. 2003;40(4):473–497.

3. Kaback M, Lim-Steele J, Dabholkar D, et al. Tay-Sachs disease—carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. JAMA. 1993;270(19):2307–2315.

4. Committee on Genetics. Committee Opinion No. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41–e55.

5. Gross SJ, Pletcher BA, Monaghan KG; Professional Practice and Guidelines Committee. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008;10(1):54–56.

6. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider. Obstet Gynecol. 2015;125(3):653–662.

7. Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129(3):e35–e40.

8. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32:338–343.

9. Poustie VJ, Wildgoose J. Dietary interventions for phenylketonuria. Cochrane Database Syst Rev. 2010;(1):CD001304.

10. Chace DH, Sherwin JE, Hillman SL, et al. Use of phenylalanine-totyrosine ratio determined by tandem mass spectrometry to improve newborn screening for phenylketonuria of early discharge specimens collected in the first 24 hours. Clin Chem. 1998;44(12):2405–2409.

11. Millington DS, Kodo N, Norwood DL, Roe CR. Tandem mass spectrometry. J Inherit Metab Dis. 1990;13(3):321–324.

12. Lund AM, Hougaard DM, Simonsen H, et al. Biochemical screening of 504,049 newborns in Denmark, the Faroe Islands and Greenland. Mol Genet Metab. 2012;107(3):281–293.

13. Vilarinho L, Rocha H, Sousa C, et al. Four years of expanded newborn screening in Portugal with tandem mass spectrometry. J Inherit Metab Dis. 2010;33(suppl 3):S133–S138.

14. Kemper AR, Green NS, Calonge N, et al. Decision-making process for conditions nominated to the recommended uniform screening panel. Genet Med. 2014;16(2):183–187.

15. Advisory Committee on Heritable Disorders in Newborns and Children. Recommended Uniform Screening Panel. Accessed July 1, 2017.

16. Zschocke J, Hoffmann GF. Vademecum Metabolicum: Diagnosis and Treatment of Inborn Errors of Metabolism. 3rd ed. Accessed August 31, 2018.

17. Perrin JM, Knapp AA, Browning MF, et al. An evidence development process for newborn screening. Genet Med. 2010;12(3):131–134.

18. Weismiller DG. Expanded newborn screening: information and resources for the family physician. Am Fam Physician. 2017;95(11):703–709.

19. Gimovsky AC, Luzi P, Berghella V. Lysosomal storage disease as an etiology of nonimmune hydrops. Am J Obstet Gynecol. 2015;212(3):281–290.

20. Vianey-Saban C, Acquaviva C, Cheillan D, et al. Antenatal manifestations of inborn errors of metabolism: biological diagnosis. J Inherit Metab Dis. 2016;39(5):611–624.

21. Mendez-Figueroa H, Lamance K, Sutton VR, Aagaard-Tillery K, Van den Veyver I. Management of ornithine transcarbamylase deficiency in pregnancy. Am J Perinatol. 2010;27(10):775–784.

22. Walter JH. Inborn errors of metabolism and pregnancy. J Inherit Metab Dis. 2000;23(3):229–236.

23. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstet Gynecol. 2007;110(6):1459–1467.

24. Saudubray JM, Garcia-Cazorla À. Inborn errors of metabolism overview. Pediatr Clin North Am. 2018;65(2):179–208.

25. Cook P, Walker V. Investigation of the child with an acute metabolic disorder. J Clin Pathol. 2011;64(3):181–191.

26. Klouwer FC, Berendse K, Ferdinandusse S, et al. Zellweger spectrum disorders. Orphanet J Rare Dis. 2015;10:151.

27. Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmoglobulinemia D syndrome. Orphanet J Rare Dis. 2006;1:13.

28. Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol. 2012;11(5):453–466.

29. Campos D, Monaga M. Mucopolysaccharidosis type I. Metab Brain Dis. 2012;27(2):121–129.

30. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377–e386.

31. Gray RG, Preece MA, Green SH, et al. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiatry. 2000;69(1):5–12.

32. Pastores GM, Hughes DA. Gaucher Disease. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; July 27, 2000 [updated June 21, 2018]:1993–2018.

33. Singh RH, Rhead WJ, Smith W, et al. Nutritional management of urea cycle disorders. Crit Care Clin. 2005;21(4 suppl):S27–S35.

34. Chapman KA, Gropman A, MacLeod E, et al. Acute management of propionic acidemia. Mol Genet Metab. 2012;105(1):16–25.

35. Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician. 2006;73(11):1981–1990.



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