Phenylketonuria (PKU)

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Hyperphenylalaninemia
Phenylalanine hydroxylase deficiency

ICD-10 Coding

E70.0, Classical phenylketonuria

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

Deficiency of phenylalanine hydroxylase (PAH), the enzyme responsible for converting phenylalanine to tyrosine, results in the accumulation of phenylalanine (Phe) and related metabolites can negatively impact brain development.
PKU generally refers to PAH deficiency resulting in plasma Phe level of >360 µmol/L at any point, necessitating the need for intervention to reduce the excess Phe. Classic PKU historically describes individuals with Phe levels >1,200 µmol/L. Hyperphenylalanemia with Phe levels ranging from 120 to 360 mmol/L does not require treatment and is associated with normal growth/development without treatment but still may need regular monitoring. Elevated Phe levels in pregnant women with PKU can have teratogenic effects on the developing fetus, including intellectual disability, microcephaly, intrauterine growth restriction, and congenital heart malformations.
Elevated phenylalanine levels can also be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential cofactor of phenylalanine hydroxylase. This accounts for about 2% of people with elevated phenylalanine levels and should always be ruled out following an abnormal newborn screen. Tetrahydrobiopterin is also a cofactor of other enzymes involved in neurotransmitter synthesis, so the therapeutic approach and outcomes differ significantly from PKU.

Clinical Characteristics

With treatment by early introduction and maintenance of a specialized diet and potentially other targeted therapies, normal IQ and development can be expected. 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, even in adults, to reduce such risks.
Various therapeutic approaches have become available, of which dietary restriction of Phe has been the mainstay [Camp: 2014] This typically means using specialized metabolic formulas and restricting protein intake. 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 independently of PAH can metabolize excess phenylalanine into non-toxic metabolites. 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 by early infancy, features of classic PKU may become more apparent.
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
  • Seizures
  • Profound intellectual disability

Incidence

The incidence of PKU in the U.S. is approximately 1:23,080 births, although, in the African-American population, the incidence is about 1:50,000. [Therrell: 2014]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

Confirming the Diagnosis

  • To confirm the diagnosis of PKU, work with Newborn Screening Services (see NM providers [1]).
  • Start by ordering quantitative plasma amino acid analysis to confirm the diagnosis.
  • The patient will also need red blood cell DHPR assay and urine neopterin profile (two tests to exclude defects in tetrahydrobiopterin synthesis or recycling), though this should be coordinated with a geneticist.
  • DNA testing for PAH gene mutations should also be coordinated with a geneticist to confirm variants in the PAH gene 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 NM 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.
  • Avoid the sugar substitute aspartame ("NutraSweet," "Equal," "Sweet Mate," and Canderel") in diet drinks and medications.
  • Perform regular blood and urine tests to monitor Phe levels and diet as indicated.
  • Assist in management of irreversible consequences 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.

Resources

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.

Tools

ACT Sheet for Phenylketonuria (ACMG) (PDF Document 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 (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 New Mexico (NM)

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 2022
Current Authors and Reviewers:
Authors: Christopher Torsitano, MD
Brian J. Shayota, MD, MPH
Nicola Longo, MD, Ph.D.
Authoring history
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