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Disease Profile

Tetrahydrobiopterin deficiency

Prevalence
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.

1-9 / 1 000 000

US Estimated

Europe Estimated

Age of onset

Neonatal

ICD-10

E70.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

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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.

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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.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

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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.

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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.

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Not applicable

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Other names (AKA)

BH4 deficiency; Hyperphenylalaninemia caused by a defect in biopterin metabolism; Hyperphenylalaninemia, non-phenylketonuric;

Categories

Newborn Screening

Summary

Tetrahydrobiopterin (BH4) deficiency causes the body to build up an abnormally high level of phenylalanine, one of the building blocks of proteins. In addition, BH4 deficiency leads to low levels of certain neurotransmitters, chemical messengers that control many body functions. Symptoms can range from very mild to severe. Babies with BH4 deficiency appear normal at birth but may develop neurological symptoms such as abnormal muscle tone, poor head control, seizures, and delayed motor development. Without treatment, the condition can cause permanent intellectual disability. BH4 deficiency is caused by pathogenic variants in any one of several genes including the GCH1, PCBD1, PTS, and QDPR genes. It is inherited in an autosomal recessive pattern. Diagnosis is based on the symptoms, clinical exam, and blood and urine tests. BH4 deficiency is sometimes diagnosed based on the results of an abnormal newborn screening test. Treatment depends on the genetic cause and severity, and may include a low phenylalanine diet, oral BH4 supplementation, and neurotransmitter replacement.[1][2][3][4]

Symptoms

The following list includes the most common signs and symptoms in people with tetrahydrobiopterin (BH4) deficiency. These features may be different from person to person. Some people may have more symptoms than others, and they can range from mild to severe. This list does not include every symptom that has been described in the condition.

Symptoms of untreated BH4 deficiency may include:[1][2][3] 

  • Low muscle tone or increased muscle tone
  • Speech delay
  • Slow, rigid movements
  • Tremor
  • 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.[3]

Cause

Tetrahydrobiopterin deficiency occurs when the GCH1, PCBD1, PTS, or QDPR gene is not working correctly. DNA changes known as pathogenic variants are responsible for making genes work incorrectly or sometimes, not at all.[1][2]

Diagnosis

Diagnosis of tetrahydrobiopterin deficiency is based on the symptoms, clinical exam, and specific diagnostic testing. Testing may include blood and urine tests, and a spinal tap (lumbar puncture). The results of genetic testing may help confirm the diagnosis. Tetrahydrobiopterin deficiency is sometimes diagnosed due to an abnormal newborn screen.[3]

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.

    Treatment

    Treatment of tetrahydrobiopterin deficiency is focused on managing the symptoms and preventing long-term nervous system damage. Treatment may include a low-phenylalanine diet, supplementation with tetrahydrobiopterin and neurotransmitters, and other medications to help treat symptoms.[2][3]

    Specialists involved in the care of someone with tetrahydrobiopterin deficiency may include: 

    • Neurologist
    • Medical geneticist/metabolic geneticist
    • Dietician/nutritionist
    • Physical therapist
    • Speech therapist
    • Psychologist
    • Developmental and behavioral pediatrician

    Organizations

    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

        Learn more

        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

        • 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.

          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.

            References

            1. Tetrahydrobiopterin Deficiency. NORD. Updated 2018; https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/.
            2. 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/.
            3. 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/.
            4. 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/.

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