Guidance for primary care clinicians receiving a positive newborn screen result
Other Names
Hyperphenylalaninemia
Phenylalanine hydroxylase deficiency
PKU
Disorder Category
Amino acidemia
Screening
Abnormal Finding
Elevated phenylalanine, elevated phenylalanine/tyrosine ratio
Tested By
Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=99.95%
Description
PKU is caused by a deficiency of phenylalanine hydroxylase (PAH), the enzyme responsible for converting phenylalanine to tyrosine. This results in the accumulation of phenylalanine (Phe) and related metabolites, which can negatively impact growth and neurodevelopmental outcomes, particularly in infants and children. Classic PKU is the most common and well-known hyperphenylalaninemia condition, though biopterin synthesis and recycling impaired disorders and DNAJC12 deficiency should be considered until other confirmatory testing has been performed. DHPR accounts for about 2% of those with elevated phenylalanine levels and notably has a different therapeutic approach and outcomes than PKU.
Hyperphenylalaninemia is defined as a Phe level ranging from 120 to 360 mmol/L and generally does not require treatment, though regular monitoring may still be necessary as some patients will have Phe levels that cross that threshold as they get older. PAH deficiency refers to a plasma Phe level of >360 µmol/L at any point while not receiving treatment and not caused by a biopterin defect, necessitating intervention to reduce the excess Phe. Classic PKU historically describes individuals with Phe levels >1,200 µmol/L.
Maternal PKU refers to pregnant individuals with elevated Phe (not related to the fetus having PKU). The toxicity of the maternal elevation of Phe can significantly impact fetal growth and development, causing microcephaly, developmental disability, intrauterine growth restriction, and congenital heart defects.
Clinical Characteristics
With treatment, normal IQ and development can be expected. The landscape of therapeutic options for PKU is constantly growing, of which dietary restriction of Phe has been the mainstay (Camp et al., 2014). This typically means using specialized metabolic formulas and restricting protein intake. However, there remains an increased risk of developing neuropsychological problems like anxiety, depression, panic attacks, reduced attention span, and slow motor reaction time compared to unaffected siblings (Bilder et al., 2013; Burton et al., 2013). Life-long therapy is recommended to reduce such risks and protect against maternal PKU in those considering pregnancy.
Some patients, but not all, respond to therapy with sapropterin, a synthetic form of the cofactor tetrahydrobiopterin that stimulates residual PAH enzyme activity. Pegvaliase is a bacterial-derived enzyme (phenylalanine ammonia lyase) that can metabolize excess phenylalanine into non-toxic metabolites independently of PAH. Injectable pegvaliase has been approved for the treatment of PKU in adults.
Without treatment, patients with classic PKU have no signs or symptoms at birth to suspect the condition. However, classic PKU’s features typically become more apparent by early infancy.
Initial symptoms may include:
- A musty or “mousy” odor of the body and urine
- Developmental delays
- Microcephaly
If left untreated, patients progress to develop:
- Decreased skin and hair pigmentation
- Eczema
- Failure to thrive
- Profound intellectual disability
Incidence
PKU affects all races and ethnicities, with an overall estimated incidence of 1:23,080 births in the US. However, it is relatively less common in African Americans (incidence of 1:50,000 births) and even more rare in people with Japanese and Ashkenazi Jewish ancestry (Therrell et al., 2014).
Inheritance
Autosomal recessive
Primary Care Management
Next Steps After a Positive Screen
- Contact the family and evaluate the infant for any of the above symptoms.
- Provide urgent treatment/referral for any significant symptoms or seizures even though newborns with classic PKU are asymptomatic. See the ACT Sheet for Increased Phenylalanine (ACMG) ( 351 KB).
- Obtain confirmatory testing.
Confirming the Diagnosis
- To confirm the diagnosis of PKU, work with Newborn Screening Services.
- Order quantitative plasma amino acid analysis to confirm the diagnosis.
- A red blood cell DHPR assay and urine neopterin profile (two tests to exclude defects in tetrahydrobiopterin synthesis or recycling) should be performed, although this should be coordinated with a geneticist.
- DNA testing for PAH gene variants should also be coordinated with a geneticist to confirm the diagnosis and exclude DNAJC12 deficiency, another cause of hyperphenylalaninemia not identified by biopterin screening.
If the Diagnosis is Confirmed
- For evaluation and ongoing collaborative management, consult Medical Genetics.
- Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill.
- Support initiation and maintenance of phenylalanine-restricted diet and supplementation of tyrosine and essential amino acids. Breastfeeding may continue in certain cases under guidance of a metabolic specialist and dietitian.
- Avoid the sugar substitute aspartame (“NutraSweet,” “Equal,” “Sweet Mate,” and Canderel”) in diet drinks and medications.
- Regular blood and urine tests should be performed to monitor Phe levels and diet as indicated.
- Assist in management of outcomes as necessary, particularly with developmental and educational interventions.
Specialty Care Collaboration
A dietician may work with the family to devise an optimal approach to dietary management.
Clinical Tools
ACT Sheet for Phenylketonuria (ACMG) ( 226 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.
Confirmatory Algorithm for Phenylalanine Elevated ( 178 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.
Bibliography
Bilder, D. A., Burton, B. K., Coon, H., Leviton, L., Ashworth, J., Lundy, B. D., Vespa, H., Bakian, A. V., & Longo, N. (2013). Psychiatric symptoms in adults with phenylketonuria. Molecular Genetics and Metabolism, 108(3), 155–160. https://doi.org/10.1016/j.ymgme.2012.12.006
Burton, B. K., Leviton, L., Vespa, H., Coon, H., Longo, N., Lundy, B. D., Johnson, M., Angelino, A., Hamosh, A., & Bilder, D. (2013). A diversified approach for PKU treatment: Routine screening yields high incidence of psychiatric distress in phenylketonuria clinics. Molecular Genetics and Metabolism, 108(1), 8–12. https://doi.org/10.1016/j.ymgme.2012.11.003
Camp, K. M., Parisi, M. A., Acosta, P. B., Berry, G. T., Bilder, D. A., Blau, N., Bodamer, O. A., Brosco, J. P., Brown, C. S., Burlina, A. B., Burton, B. K., Chang, C. S., Coates, P. M., Cunningham, A. C., Dobrowolski, S. F., Ferguson, J. H., Franklin, T. D., Frazier, D. M., Grange, D. K., … Young, J. M. (2014). Phenylketonuria Scientific Review Conference: State of the science and future research needs. Molecular Genetics and Metabolism, 112(2), 87–122. https://doi.org/10.1016/j.ymgme.2014.02.013
Therrell, B. L., Lloyd-Puryear, M. A., Camp, K. M., & Mann, M. Y. (2014). Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning. Molecular Genetics and Metabolism, 113(1–2), 14–26. https://doi.org/10.1016/j.ymgme.2014.07.009
Article History
The Medical Home Portal last published this article in April 2024, and Topical Reviews in Pediatrics (TRIP) reprinted it in November 2024. The Medical Home Portal, retired in July 2024, provided diagnosis and management information for pediatric conditions, guidance for immediate steps after a positive newborn screen result, and in-depth family education to improve outcomes for children with complex medical care needs. The full archive can be found at Medical Home Portal Archive.
Topical Reviews in Pediatrics (TRIP) includes archival and updated content from the Medical Home Portal and features new, contemporary topics in pediatrics.
Initial publication: March 2015; last update/revision: April 2024
- 2024 update: Brian J. Shayota, MDA, Nancy Rose, MDR
- 2022 update: Christopher Torsitano, MDA; Brian J. Shayota, MD, MPHA; Nicola Longo, MD, Ph.D.R
- 2015 first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer
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