Phenylketonuria – PKU (PAH gene)

Hyperphenylalaninemia, non-PKU mild (HPA)

– Phenylketonuria, maternal, included

  • Also known as: Phenylalanine Hydroxylase Deficiency; PAH Deficiency; Classical PKU; Oligophrenia Phenylpyruvica; Folling Disease; Hyperphenylalaninemia, non-PKU mild (HPA); Phenylketonuria, maternal, included; Hyperphenylalaninemia due to BH4 defects
  • OMIM#261600

– Hyperphenylalaninemia, Mild, non-BH4-deficient (DNAJC12 gene)

– Hyperphenylalaninemia, BH4-deficient A (PTS gene)

  • Also known as: Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to PTS Deficiency; 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency; PTSD;
    PTS Deficiency
  • OMIM#261640

– Hyperphenylalaninemia, BH4-deficient B (GCH1 gene)

  • Also known as: Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to GTP Cyclohydrolase I Deficiency; GTP Cyclohydrolase I Deficiency; Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive
  • OMIM#333910

– Hyperphenylalaninemia, BH4-deficient C (QDPR gene)

  • Also known as: Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to DHPR Deficiency; Dihydropterine Reductase Deficency; DHPR deficiency; Quinoid Dihydropterine Reductase Deficency; QDPR Deficency
  • OMIM#261630

– Hyperphenylalaninemia, BH4-deficient D (PCBD1 gene)

  • Also known as: Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to Pterin-4-Alpha-Carbinolamine Dehydratase Deficiency; Hyperphenylalaninemia with primapterinuria; CADH deficiency; PCBD deficiency
  • OMIM#264070

1. The Disease

Hyperphenylalaninemia (HPA) is the most common amino acid metabolic disease involving phenylalanine hydroxylase deficiency or coenzyme tetrahydrobiopterin (BH4) deficiency. Patients with severe HPA often have a difficult life. Early diagnosis of HPA before the development of symptoms is possible via neonatal screening, facilitating appropriate treatment and reducing mortality and disability rates.

This group of rare inborn error of amino acid or BH4 metabolism characterized by elevated blood phenylalanine and low levels or absence of different enzymes with a common aspect: if not detected early or left untreated, the disorder manifests with mild to severe mental disability due to neurotoxity.

2. The Symptoms

Infants are usually initially asymptomatic at birth and in the neonatal period. Lack of early signs or symptoms does not exclude the diagnosis.

  • Infants present with irritability, seizures, vomiting, excessive restlessness, increased deep tendon reflexes, and a musty odor of the body or urine in the first weeks of life (less seen nowadays due to neutralizing odors diapers).
  • Left untreated, PKU and other HPA result in mild to severe developmental delay, motor dysfunction and mental retardation. Early detection and treatment of HPA is necessary to prevent mental retardation.
  • Women with untreated PKU who become pregnant are at high risk for having newborns with neurological damage, as high phenylalanine levels in the untreated mother cross the placenta and are toxic to the developing fetus. As such, it is critical that women of childbearing age who are diagnosed with PKU or hyperphenylalaninemia are on strict dietary control prior to conception and throughout pregnancy to avoid the toxic effects to the fetus.

3. Actions to take in case of early diagnosis

  • Infants with a positive genetic test (having 2 mutations or 2 copies of a single mutations in one of the 6 referred genes) should continue breastfeeding.
  • Patient phenotypes are on a continuous spectrum from mild hyperphenylalaninemia to mild PKU, moderate PKU, and severe classic PKU. There is a good correlation between the biochemical phenotype and the patient’s genotype. It is possible to even predict the BH4 responsiveness trough mutation combinations in patients, see the link
  • Biochemical correlation is essential for diagnosis confirmation through NBS with tandem mass spectrometry (MS/MS) for the detection of elevated phenylalanine. Laboratories cutoffs for treatment vary between 360 (6.0 mg/dL) and 600 (10.0 mg/dL), but are usually significantly higher. A Phe/Tyr molar ratio of greater than 2.5 provides additional evidence of a metabolic defect in the conversion of Phenylalanine (Phe) to Tyrosine (Tyr), indicative of a hyperphenylalaninemia due to BH4 deficiency.
  • It is also possible to determine the Phe and Tyr concentration by plasma amino acid chromatography and pterins analysis in plasma and CSF. Pterins assay in dried blood spots is easier and can help in defining the diagnosis together with molecular results.
  • Genetic HPA (PKU or BH4 defect) is a lifelong disease that requires lifetime compliance to dietary management and regular follow-up with a metabolic disease specialist and a multidisciplinary approach to care, including pediatrics, genetics and nutrition.
  • Early treatment, through phenylalanine restriction or/ and BH4 suplementation, is essential in preventing developmental delays. The BH4-responsiveness test should be performed following the guidelines recommendation.
  • The prognosis for PKU and related disorders is very favorable with lifetime compliance to a low phenylalanine diet and oral Sapropterin (KuvanÒ) when indicated. Current treatment is not curative and does not prevent all morbidity.
  • Future gene therapy is under investigation.
  • Pegvaliase injections (PalynziqÒ) in adult patients may also be considered.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

4. For more information



  • van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162. Published 2017 Oct 12. doi:10.1186/s13023-017-0685-2. PMID:29025426.
  • Muntau AC, Adams DJ, Bélanger-Quintana A, et al. International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria. Mol Genet Metab. 2019;127(1):1-11. doi:10.1016/j.ymgme.2019.04.004. PMID: 31103398.
  • Blau N, Martinez A, Hoffmann GF, Thöny B. DNAJC12 deficiency: A new strategy in the diagnosis of hyperphenylalaninemias. Mol Genet Metab. 2018;123(1):1-5. PMID: 29174366.
  • Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104 Suppl:S2-S9. PMID: 21937252.