Phenylketonuria (PKU)

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Phenylalanine hydroxylase deficiency

ICD-10 Coding

E70.0, Classical phenylketonuria

Disorder Category

Amino acidemia


Abnormal Finding

Elevated phenylalanine, elevated phenylalanine/tyrosine ratio

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=99.95%


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 compared to 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: 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: 2013] [Burton: 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, typically, the features of classic PKU may 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


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: 2014]


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) (PDF Document 351 KB).
  • Obtain confirmatory testing as below.

Confirming the Diagnosis

  • To confirm the diagnosis of PKU, work with Newborn Screening Services (see RI providers [2]).
  • 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 (see RI providers [4]).
  • Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill. See PKU - Information for Parents (STAR-G).
  • 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.


Information & Support

Related Portal Content
PKU and Pterin Defects
Assessment and management information for the primary care clinician caring for the child with biotinidase deficiency.
Phenylketonuria (PKU) (FAQ)
Answers to questions families often have about caring for their child with biotinidase deficiency.
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Phenylalanine Hydroxylase Deficiency (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

For Parents and Patients

PKU - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology and Research in Genetics.

Phenylketonuria (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

National Urea Cycle Disorders Foundation
Support and information that includes medical lectures on urea cycle disorders, nutrition and medication resources, and information about events and conferences.


RI ACT Sheet for PKU (ACMG) (PDF Document 108 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive, along with resources for consultation and patient education/support; from the American College of Genetics and Genomics

Confirmatory Algorithm for Phenylalanine Elevated (PDF Document 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.

Services for Patients & Families in Rhode Island (RI)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: March 2007; last update/revision: April 2024
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD
Authoring history
2024: update: Brian J. Shayota, MD, MPHA
2022: update: Christopher Torsitano, MDA; Brian J. Shayota, MD, MPHA; Nicola Longo, MD, Ph.D.A
2015: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Bilder DA, Burton BK, Coon H, Leviton L, Ashworth J, Lundy BD, Vespa H, Bakian AV, Longo N.
Psychiatric symptoms in adults with phenylketonuria.
Mol Genet Metab. 2013;108(3):155-60. PubMed abstract

Burton BK, Leviton L, Vespa H, Coon H, Longo N, Lundy BD, Johnson M, Angelino A, Hamosh A, Bilder D.
A diversified approach for PKU treatment: routine screening yields high incidence of psychiatric distress in phenylketonuria clinics.
Mol Genet Metab. 2013;108(1):8-12. PubMed abstract

Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, et al.
Phenylketonuria Scientific Review Conference: state of the science and future research needs.
Mol Genet Metab. 2014;112(2):87-122. PubMed abstract
Though its title suggests a focus on research, this also represents a consensus on best approaches to care.

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text