Clinical characteristics.

The phenotypes in individuals with PAH deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. Maternal PKU (MPKU) syndrome occurs in offspring of mothers with inadequately treated PAH deficiency during pregnancy and results from the toxic effects of elevated blood phenylalanine (Phe) concentrations on the developing fetus.

PAH deficiency treated from birth is characterized by the following, even with adherence to a low Phe diet: (1) a modest but measurable decrease in intellectual functioning as well variable impairments in executive function, attention, and fine motor functions; (2) an increased prevalence of mental health concerns including anxiety and depression; and (3) neurologic problems (including hypertonia, paraplegia, movement disorders, and seizures), which may improve or resolve with lowering blood Phe concentration.

Late-diagnosed or untreated PAH deficiency is characterized by irreversible neurocognitive impairment (intellectual disability), neurobehavioral/psychological issues, neurologic manifestations (motor disturbances including movement disorders and seizures), and microcephaly. Although lowering blood Phe concentration sometimes improves neurobehavioral/psychological issues and motor disturbances, it does not reduce neurocognitive impairment.

MPKU syndrome is characterized by intellectual disability, neurobehavioral/psychiatric manifestations, congenital heart defects, and other birth defects.

Diagnosis/testing.

The diagnosis of PAH deficiency is established in all neonates following an out-of-range newborn screening result with (1) biochemical testing (plasma amino acid analysis) and (2) molecular genetic testing to identify the causative biallelic PAH pathogenic variants to confirm the biochemical diagnosis of PAH deficiency and inform clinical management and genetic counseling.

Management.

Targeted therapies: Lifelong treatment of all individuals with an untreated blood Phe concentration greater than 360 μmol/L with an age-appropriate Phe-restricted diet and Phe-free protein supplementation with medical foods (amino acid or glycomacropeptide based). In certain individuals, FDA-approved pharmacologic therapies may include the Phe hydroxylase activator/cofactor sapropterin dihydrochloride and/or enzyme substitution therapy (pegvaliase).

Supportive care: Because treatment for affected individuals of all ages can be difficult, the support of an experienced health care team consisting of physicians, metabolic dietitians, genetic counselors, social workers, nurses, nurse practitioners, and psychologists is essential for all individuals with PAH deficiency and their parents/caregivers. Teaching should include information on malnutrition and growth failure, the side effects of dietary treatment. Therapy needs are greater for individuals with late diagnosis and resultant neurodevelopmental deficits. As PAH deficiency is a lifelong disorder with varying age-related implications, smooth transition of care of affected individuals from a pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties.

Surveillance: Regular individualized screening for early identification of the manifestations of PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency is required.

Agents/circumstances to avoid: Aspartame, an artificial sweetener often added to soft drinks, foods, and some medications, is metabolized in the gastrointestinal tract into Phe and aspartate. Persons with PAH deficiency should either (1) avoid products containing aspartame or (2) when using such products calculate total Phe intake in order to adapt diet components accordingly.

Evaluation of relatives at risk: If the PAH pathogenic variants in the family are known, molecular genetic prenatal testing of a fetus at risk can be performed via amniocentesis or chorionic villus sampling to allow for treatment at birth of an infant known to be affected. Any at-risk newborn sib who did not have prenatal testing should be evaluated immediately after birth for PAH deficiency by measuring blood Phe concentration to allow for earliest possible diagnosis and treatment. Older at-risk sibs – even those who are apparently asymptomatic – should be evaluated for PAH deficiency given the significant variability in the clinical manifestations of previously undiagnosed PAH deficiency.

Preconception, pregnancy, and postpartum care: Preconception: achieve and maintain maternal blood Phe concentration at <360 µmol/L for three months prior to conception; provide genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus. Pregnancy: maintain maternal blood Phe concentration at 120-360 µmol/L during pregnancy and monitor dietary intake to ensure that dietary nutrients are adequate. Postpartum: monitor blood Phe concentrations of mother and infant as needed.

Genetic counseling.

PAH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PAH pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial PAH pathogenic variants. Children born of one parent with PAH deficiency and one parent with two normal PAH alleles are obligate heterozygotes. If the mother is the affected parent, MPKU syndrome is a critical issue. Females with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (i.e., MPKU syndrome) when they reach childbearing age. Once the PAH pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for PAH deficiency are possible.

Suggestive Findings

A diagnosis of PAH deficiency should be suspected due to an out-of-range newborn screening (NBS) result prior to onset of suggestive findings (see Scenario 1) or manifestations of PAH deficiency (see Scenario 2).

Establishing the Diagnosis

The diagnosis of PAH deficiency is established in all neonates following an out-of-range NBS result with (1) biochemical testing (plasma amino acid analysis) and (2) molecular genetic testing [Smith et al 2025]. Molecular genetic testing is strongly recommended to confirm the biochemical diagnosis of PAH deficiency, inform clinical management, and allow genetic counseling.

Clinical Description

The phenotypes in individuals with phenylalanine hydroxylase (PAH) deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. In addition, maternal PKU (MPKU) syndrome is important to consider in offspring of mothers with inadequately treated PAH deficiency during pregnancy, as elevated blood phenylalanine (Phe) concentrations are toxic to the developing fetus [Smith et al 2025].

Genotype-Phenotype Correlations

Although genotype can be predictive of sapropterin dihydrochloride responsiveness (see Management, Targeted Therapies), genotype-phenotype correlations to date are imperfect; thus, all individuals with PAH deficiency except those with biallelic null PAH pathogenic variants should be offered a trial of sapropterin dihydrochloride therapy to assess responsiveness [Adams et al 2023]. Muntau et al [2019] reviewed 23 studies of sapropterin trials and noted a high level of sapropterin responsiveness in individuals classified as having mild or moderate PAH deficiency, and low levels of responsiveness in individuals with classic PAH deficiency.

Nomenclature

"Traditional" PAH terminology is not used in the 2023 ACMG practice guideline for PAH deficiency diagnosis and management [Smith et al 2025] but is often utilized in historical publications.

• "Phenylketonuria (PKU)" refers specifically to severe PAH deficiency associated, in an untreated state, with plasma Phe concentrations >1,000 µmol/L [Kayaalp et al 1997].
• "Non-PKU hyperphenylalaninemia (non-PKU HPA)" describes plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but <1,000 µmol/L when an individual is on a normal diet [Kayaalp et al 1997].
• "Variant PKU" refers to individuals who do not fit the description for either PKU or non-PKU HPA [Kayaalp et al 1997].
• "Mild hyperphenylalaninemia (HPA)" refers to individuals with an untreated blood phenylalanine concentration of 360-600 µmol/L.

The term "classic PKU" is most often used to refer to severe PAH deficiency associated with a complete or near-complete deficiency of PAH activity [Guldberg et al 1998].

Prevalence

Hillert et al [2020] estimated the incidence of PAH deficiency worldwide at 1:23,930 newborns. The highest incidence is described in the Karachay-Cherkess region of Russia (1:850), with relatively higher incidences in Europe and some Middle Eastern countries (approximately 1:4,000 to 1:10,000). Incidence is somewhat lower in Asia outside of China (1:125,000 in Japan). Incidence in the United States is estimated at 1:25,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PAH deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Newborns with an out-of-range newborn screening (NBS) result. Refer to a metabolic specialty center that includes a metabolic physician / biochemical geneticist and metabolic dietitian to establish the diagnosis and begin an age-appropriate low-phenylalanine (Phe) diet as soon as elevated blood Phe concentrations have been documented (see Establishing the Diagnosis). If a referral is not immediately practical, see Treatment of Manifestations for treatment guidelines. Ideally the low-Phe diet should be initiated within the first week of life, with a goal of having blood Phe concentration in the treated range within the first two weeks of life [Smith et al 2025].

Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of PAH deficiency to facilitate medical and personal decision making is recommended.

Assess the need for family support and resources including community or online resources such as Parent to Parent and National PKU Alliance (NPKUA); social work involvement for parental support; and home nursing referral.

Individuals with late-diagnosed or untreated hyperphenylalaninemia (HPA). Refer to a metabolic specialty center that includes a metabolic physician / biochemical geneticist and metabolic dietitian to begin appropriate treatment based on the specific diagnosis, age of the individual, and other extenuating circumstances.

Individuals in this group need to be evaluated for the medical issues associated with untreated PAH deficiency such as epilepsy, intellectual disability, neurobehavioral/psychiatric manifestations, and movement disorders. These evaluations and their management follow standard medical practice and are not discussed further in this GeneReview.

Individuals with benign HPA (i.e., untreated blood Phe concentration between 120 and 360 µmol/l). Although immediate treatment is not recommended for these individuals, their blood Phe concentration should be measured regularly while on a non-protein-restricted diet until at least age two years to ensure that blood Phe concentrations do not reach the threshold for which treatment would be recommended. See Surveillance for recommended follow up after age two years.

Treatment of Manifestations

There is no cure for PAH deficiency. However, gene therapy trials are currently under way (see Therapies Under Investigation).

ACMG guidelines recommend lifelong treatment of all individuals with untreated blood Phe concentrations >360 μmol/L [Smith et al 2025].

Surveillance

For those with untreated blood Phe concentrations >360 µmol/L, the ACMG recommendations for monitoring of blood Phe concentration and nutritional status are summarized in Table 4 [Vockley et al 2014].

For those with untreated blood Phe concentrations >120 µmol/L, the recommendation is monitoring blood Phe concentration at least until age two years [Vockley et al 2014]. The frequency of monitoring depends on blood Phe concentrations and may extend beyond age two years as needed. If treatment is not required before age two years, monitoring annually or every two years is adequate for subsequent assessment.

Other manifestations. Although most individuals with PAH deficiency will have normal development if blood Phe concentrations are appropriately controlled, developmental, neuropsychological, and psychosocial concerns merit careful attention to assure that needs are being met across the life span. Assessment by the appropriate specialists involved in providing supportive care should be considered when concerns arise, including: (1) acquisition of developmental milestones and overall developmental progress; (2) educational needs; (3) neuropsychologic issues; (4) neurologic abnormalities; (5) osteopenia and bone health; and (6) family need for social work support, care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

Agents/Circumstances to Avoid

Aspartame, an artificial sweetener that is often added to soft drinks, foods, and some medications, is metabolized in the gastrointestinal tract into Phe and aspartate. Persons with PAH deficiency should either avoid products containing aspartame or calculate total Phe intake when using such products in order to adapt diet components accordingly [Maler et al 2023].

Note: Some medications (such as antibiotics) contain aspartame. Depending on the condition being treated, antibiotic treatment might need to be altered if no other alternatives are readily available.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If the PAH pathogenic variants in the family are known, molecular genetic prenatal testing of a fetus at risk can be performed via amniocentesis or chorionic villus sampling to allow for treatment at birth of an infant known to be affected.

Newborn sib of a proband with PAH deficiency. If prenatal testing has not been performed, each at-risk newborn sib should be evaluated immediately after birth for PAH deficiency by measuring blood Phe concentration to allow for earliest possible diagnosis and treatment.

The initial newborn screening (NBS) measurement of blood Phe concentration is collected when the newborn is on a normal formula / breast milk diet.

In most circumstances, the results of NBS blood Phe concentration will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with an out-of-range NBS result. Note that molecular genetic testing in this circumstance is most informative if the familial PAH pathogenic variants are known. It should also be noted that if molecular testing is performed, carrier status will also be determined; thus, appropriate genetic counseling when testing a minor should also be included in any discussion.

Older at-risk sibs. Because of the significant variability in the clinical manifestations of previously undiagnosed PAH deficiency, even apparently asymptomatic sibs of an individual with PAH deficiency could be affected. If the at-risk sib underwent NBS, review of the sib's NBS result is recommended to clarify the status of at-risk sibs; if NBS was not performed, the following evaluations are recommended [Smith et al 2025]:

• Measure blood Phe concentrations;
• Perform molecular genetic testing if the PAH pathogenic variants in the family are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Multiple modalities are now in clinical trials or being prepared for clinical trial, including gene therapy (NCT04480567, NCT06332807), mRNA therapy (NCT06147856), Phe uptake receptor blocker (NCT05781399), sepiapterin (NCT06302348), and multiple diet and dietary supplement studies. It is expected that multiple options for treatment of PAH deficiency will be available in coming years.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Phenylalanine hydroxylase (PAH) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a PAH pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PAH pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a PAH pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial PAH pathogenic variants.
• Significant intrafamilial variability has been observed in PAH deficiency; thus, the clinical phenotype observed in the proband might not be consistent with or predicative of the clinical phenotype in affected sibs [Camp et al 2014].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Children born of one parent with PAH deficiency and one parent with two normal PAH alleles are obligate heterozygotes.
• If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected.
• If the mother is the affected parent, maternal PKU (MPKU) syndrome is a critical issue (see Clinical Description, MPKU Syndrome).

Other family members. Each sib of the proband's unaffected parents is at a 50% risk of being a carrier of a PAH pathogenic variant.

Carrier Detection

Molecular genetic testing for at-risk relatives requires prior identification of the PAH pathogenic variants in the family. American College of Medical Genetics and Genomics (ACMG) guidelines recommend the use of molecular genetic testing to identify carriers in a family with a known PAH pathogenic variant [Smith et al 2025].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• Young women with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (e.g., MPKU syndrome) when they reach childbearing age (see Management, Preconception Care).
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Partners of an individual affected with PAH deficiency or known to be a carrier of a PAH pathogenic variant may be interested in carrier testing. Molecular genetic testing of PAH can be offered, with appropriate counseling about limits of sensitivity. Founder variants have been identified in the Bukharan Jewish, Sephardic Jewish, Ashkenazi Jewish, Amish, Romani, and Mennonite populations.
• The ACMG includes PAH deficiency among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PAH pathogenic variants have been identified in an affected family member, molecular genetic prenatal and preimplantation genetic testing for PAH deficiency are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Phenylalanine hydroxylase (PAH) is the rate-limiting step in the conversion of phenylalanine (Phe) to tyrosine (Tyr), a reaction that requires the cofactor tetrahydrobiopterin (BH₄). PAH deficiency is an inborn error of Phe metabolism caused by biallelic PAH pathogenic variants resulting in reduced activity of the enzyme PAH. The main consequences of PAH deficiency are: (1) accumulation of alternative products of Phe metabolism, including phenylacetic, phenylpyruvic, and phenyllactic acid, which are toxic to brain development; and (2) reduction of Tyr, resulting in deficiency of the neurotransmitters dopamine, adrenaline, and norepinephrine, which affects the conversion to thyroxine in the thyroid gland and melanin in melanocytes.

Mechanism of disease causation. Loss-of-function PAH variants

Author History

Georgianne Arnold, MD (2025-present)
Carol L Greene, MD, FAAP, FACMG; University of Maryland School of Medicine (2016-2025)
John J Mitchell, MD; McGill University, Montreal (2005-2016)
Debra S Regier, MD, PhD, FAAP, FACMG; Children's National Medical Center (2016-present)
Shannon Ryan, MSc; Montreal Children's Hospital (2000-2005)
Charles R Scriver, MD; Montreal Children's Hospital (2000-2013)
Jerry Vockley, MD, PhD (2025-present)

Revision History

• 13 March 2025 (bp) Comprehensive update posted live
• 20 October 2016 (ma) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 4 May 2010 (me) Comprehensive update posted live
• 29 March 2007 (me) Comprehensive update posted live
• 8 July 2004 (me) Comprehensive update posted live
• 13 August 2002 (me) Comprehensive update posted live
• 10 January 2000 (me) Review posted live
• 16 July 1999 (dsr) Original submission

Published Guidelines / Consensus Statements

• Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. The Canadian Guide to Clinical Preventive Health Care. Available online. 1994. Accessed 11-17-20.
• Committee on Genetics. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria). American College of Obstetricians and Gynecologists Committee Opinion April 2020. Number 802. Available online. 2020. Accessed 11-17-20.
• Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121-31. [PubMed]
• Smith WE, Berry SA, Bloom K, Brown C, Burton BK, Demarest OM, Jenkins GP, Malinowski J, McBride KL, Mroczkowski HJ, Scharfe C, Vockley J; ACMG Board of Directors. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27:101289. [PubMed]
• van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12:162. [PubMed]
• Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. [PubMed]

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