Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
Age of Onset
Autosomal dominant ?A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease
Autosomal recessive ?Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype
X-linked dominant ?X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.
X-linked recessive ?Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder
Mitochondrial or multigenic ?Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.
Multigenic or multifactor ?Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.
Other Names (AKA)
BH4 deficiency; Hyperphenylalaninemia caused by a defect in biopterin metabolism; Hyperphenylalaninemia, non-phenylketonuric;
Tetrahydrobiopterin (BH4) deficiency causes the body to build up an abnormally high level of phenylalanine, one of the building blocks of
- Low muscle tone or increased muscle tone
- Speech delay
- Slow, rigid movements
Seizures Developmental delay Intellectual disability
Infants with tetrahydrobiopterin (BH4) deficiency typically do not have any symptoms at birth. Symptoms usually become apparent over time, and can range from mild to severe. The way the BH4 deficiency changes over time depends on when the condition is diagnosed and when treatment is started. Without treatment, signs and symptoms may get worse and can result in permanent damage to the nervous system.
- 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 screeningresult. 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
screeningresult. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
Specialists involved in the care of someone with tetrahydrobiopterin deficiency may include:
Neurologist Medical geneticist/metabolic geneticist
nutritionist Physical therapist Speech therapist
- Developmental and behavioral
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.
American Association on Intellectual and Developmental Disabilities
501 3rd Street NW
Washington, DC 20001
Toll-free: (800) 424-3688
Telephone: (202) 387-1968
Fax: (202) 387-2193
The Society for Developmental and Behavioral Pediatrics
6728 Old McLean Village Drive
McLean, VA 22101
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.
- MedlinePlus Genetics 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.
- 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.
- Tetrahydrobiopterin Deficiency. NORD. Updated 2018; https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/.
- Kuseyri O, Weisbach A, Bruggemann N, Klein C, Gizewska M, et al. Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders. J Inherit Metab Dis. Sep 2018; 41(5):849-863. https://pubmed.ncbi.nlm.nih.gov/29594647/.
- Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, et al. International Working Group on Neurotransmitter related Disorders (iNTD). Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis. May 26, 2020; 15(1):126. https://pubmed.ncbi.nlm.nih.gov/32456656/.
- Souza CAA, Alves MRA, Soares RDL, Kanufre VC, Rodrigues VM, Norton RC, et al. BH4 deficiency identified in a neonatal screening program for hyperphenylalaninemia.. J Pediatr (Rio J). 2018 Mar-Apr;94(2):170-176.. Mar-Apr 2018; 94(2):170-176. https://pubmed.ncbi.nlm.nih.gov/28801146/.