National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Tetrahydrobiopterin deficiency


Other Names:
BH4 deficiency; Hyperphenylalaninemia caused by a defect in biopterin metabolism; Hyperphenylalaninemia, non-phenylketonuric; BH4 deficiency; Hyperphenylalaninemia caused by a defect in biopterin metabolism; Hyperphenylalaninemia, non-phenylketonuric; Non-phenylketonuric hyperphenylalaninemia; Hyperphenylalaninemia due to tetrahydrobiopterin deficiency; Hyperphenylalaninemia due to BH4 deficiency See More
Categories:
Subtypes:
Tetrahydrobiopterin (BH4) deficiency is a neurological condition caused by an inborn error of metabolism. BH4 is a substance in the body that enhances the action of other enzymes. Deficiency of BH4 leads to abnormally high blood levels of the amino acid phenylalanine, and low levels of certain neurotransmitters.[1] Signs and symptoms can range from very mild to severe.[2] Affected newborns appear normal at birth, but may begin to experience neurological symptoms such as abnormal muscle tone; poor sucking and coordination; seizures; and delayed motor development. Without early, appropriate treatment, the condition can cause permanent intellectual disability and even death.[1] BH4 deficiency is caused by mutations in any one of several genes including the GCH1, PCBD1, PTS, and QDPR genes. It is inherited in an autosomal recessive manner.[3]Treatment depends on the genetic cause and severity, and may include a low phenylalanine diet; oral BH4 supplementation; and neurotransmitter replacement.[1]
Last updated: 11/2/2012
Infants with tetrahydrobiopterin (BH4) deficiency typically appear normal and healthy at birth.[1][2] Neurological signs and symptoms usually become apparent over time, and can range from mild to severe.[3][2] These may include abnormal muscle tone; poor sucking and coordination; seizures; and delayed motor development.[1] Other manifestations may include decreased spontaneous movements and difficulty swallowing.[3][2]

Without early and appropriate treatment, signs and symptoms progress and affected individuals may experience irreversible intellectual disability, behavioral problems, an inability to control body temperature, and even death in severe cases.[3][1]
Last updated: 11/2/2012

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Newborn Screening

  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
  • The Newborn Screening Coding and Terminology Guide created by the National Library of Medicine (NLM) at the National Institutes of Health (NIH) promotes and facilitates the use of electronic health data standards in recording and transmitting newborn screening test results. The Web site includes standard codes and terminology for newborn tests and conditions for which they screen, and links to related sites. Click on the links to view details for this condition.
    Disorders of biopterin biosynthesis
    Disorders of biopterin regeneration

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Tetrahydrobiopterin deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Organizations Providing General Support

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Tetrahydrobiopterin deficiency. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Tetrahydrobiopterin deficiency. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • Can hyperphenylalaninemia caused by tetrahydrobiopterin (BH4) deficiency cause failure to thrive and problems with eating solids in babies? See answer


  1. Tetrahydrobiopterin Deficiency. NORD. May 23, 2008; http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/438/viewAbstract. Accessed 10/31/2012.
  2. Noah S Scheinfeld. Tetrahydrobiopterin Deficiency. Medscape Reference. June 27, 2012; http://emedicine.medscape.com/article/949470-overview. Accessed 11/2/2012.
  3. Tetrahydrobiopterin deficiency. Genetics Home Reference. July 2011; http://ghr.nlm.nih.gov/condition/tetrahydrobiopterin-deficiency. Accessed 11/2/2012.