• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
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Tetrahydrobiopterin Deficiency

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Last updated: 8/10/2023
Years published: 1987, 1990, 1995, 1999, 2003, 2015, 2018, 2023


Acknowledgment

NORD gratefully acknowledges Prof. Dr. Nenad Blau, Senior Consultant in Biochemical Genetics, Professor emeritus of Clinical Biochemistry, University Children’s Hospital Zurich, for assistance in the preparation of this report.


Disease Overview

Summary


Tetrahydrobiopterin (BH4) deficiencies is a general term for a group of disorders characterized by abnormalities in the creation (biosynthesis) or regeneration of tetrahydrobiopterin, a naturally occurring compound that acts as a cofactor. A cofactor is a non-protein substance in the body that enhances or is necessary for the proper function of certain enzymes. When tetrahydrobiopterin is deficient, the chemical balance within the body is upset. In most of these disorders, there are abnormally high levels of the amino acid phenylalanine (hyperphenylalaninemia). Amino acids such as phenylalanine are chemical building blocks of proteins and are essential for proper growth and development. Most of these disorders also cause abnormally low levels of neurotransmitters. Neurotransmitters are chemicals that modify, amplify or transmit nerve impulses from one nerve cell to another, enabling nerve cells to communicate. These chemical imbalances can ultimately cause a wide variety of symptoms and physical findings including progressive neurological abnormalities, lack of muscle tone (hypotonia), overproduction of saliva (hypersalivation), loss of coordination, abnormal movements and/or delayed motor development. The specific symptoms can vary dramatically from one person to another and can range from mild to severe. Prompt diagnosis and treatment of these disorders can prevent potentially severe, irreversible neurological damage. Tetrahydrobiopterin deficiency is caused by changes (variants or mutations) in specific genes that encode enzymes required for the biosynthesis or regeneration of tetrahydrobiopterin. Most of these gene variants are inherited in an autosomal recessive pattern.

Introduction


There are four main forms of tetrahydrobiopterin deficiency sometimes referred to as ‘classical’ tetrahydrobiopterin deficiency. They are guanosine triphosphate cyclohydrolase I (GTPCH) deficiency; 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency; pterin-4-alpha-carbinolamine dehydratase (PCD) deficiency and dihydropteridine reductase (DHPR) deficiency. The first two disorders are defects in tetrahydrobiopterin synthesis and the latter two are defects in tetrahydrobiopterin regeneration. Sepiapterin reductase deficiency is a related disorder affecting the third step of tetrahydrobiopterin biosynthesis; it differs from the other disorders in that elevated levels of phenylalanine do not develop. GTPCH deficiency can be broken down in the autosomal dominant form, also known as Segawa syndrome or autosomal dominant dopa-responsive dystonia, or the autosomal recessive form, which is covered in this report. NORD has separate, individual reports on sepiapterin reductase deficiency and Segawa syndrome.

In the past, disorders of tetrahydrobiopterin deficiency were referred to as atypical phenylketonuria or malignant phenylketonuria because physicians believed they were forms of phenylketonuria that did not respond to the standard therapy for that disorder. These terms are now considered obsolete because disorders of tetrahydrobiopterin deficiency are now known to be distinct disorders that are treatable with different therapies.

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Synonyms

  • BH4-deficient hyperphenylalaninemia
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Subdivisions

  • 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency
  • dihydropteridine reductase (DHPR) deficiency
  • autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency
  • pterin-4alpha-carbinolamine dehydratase (PCD) deficiency
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Signs & Symptoms

Although researchers have been able to establish distinct syndromes with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and the possibility of other genes influencing the development and progression of these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis.

Disorders of tetrahydrobiopterin deficiency can be classified as transient, mild or severe, which is extremely important in determining specifics of therapy, such as the need for neurotransmitter precursors during treatment (see Standard Therapies below). The specific symptoms and severity associated with tetrahydrobiopterin deficiencies can vary greatly from one person to another, even among individuals with the same subtype or among individuals from the same family. Overall, the symptoms of GTPCH deficiency, PTPS deficiency and DHPR deficiency are extremely similar. Generally, PCD deficiency is less severe than the other disorders and affected infants often only exhibit temporary abnormalities of muscle tone and delays in motor development. They are, however, at risk for developing type 2 diabetes (MODY) after the age of 9 years.

Tetrahydrobiopterin deficiencies usually present within the first six months of life and can be detected upon newborn screening because of elevated levels phenylalanine. Infants usually appear normal at birth, although some newborns, particularly in PTPS deficiency, may have a low birth weight. Failure to grow and gain weight (failure to thrive) may occur. Microcephaly, a condition defined as having a head circumference smaller than normally would be expected based on age and gender, is a common finding.

In the severe forms, common, but variable symptoms include neurological dysfunction including convulsions or seizures, swallowing difficulties, poor muscle tone of the trunk of the body (truncal hypotonia) and excess muscle tone of the arms and legs so that they may be stiff and difficult to move (limb hypertonia). Abnormal movements are common and can include abnormal slowness of movement (bradykinesia), rapid, involuntary, purposeless (chorea), slow, involuntary, writhing movements (athetosis), a type of spasm in which the head and feet bend the backward and the back arches (opisthotonus).

Affected children may also exhibit delays in reaching developmental milestones (developmental delays), delays in acquiring skills that require the coordination of mental and physical activities (psychomotor delay), and, in some children, intellectual disability.

Neurological dysfunction is progressive and, during the school years, affected individuals may appear uncoordinated or clumsy such as having an abnormal manner of walking (gait abnormalities). In some children, this clumsiness is due, in part, to involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (dystonia).

Some affected individuals may develop abnormal movements of the eyes that can range from brief upward rolling of the eyes to oculogyric crises, in which the eyes roll upward for a sustained period. Sometimes, the eyes may roll downward or move toward each other (converge). Severe oculogyric crises can be associated with additional symptoms including the formation of tears (lacrimation), eye blinking, widening (dilation) of the pupils, drooling, backward flexion of the neck, restlessness or a general feeling of poor health (malaise).

Additional symptoms that have been reported include excessive production of saliva, lethargy and irritability. Recurrent episodes of elevated body temperature (hyperthermia) that are not associated with infection may also occur. Certain symptoms may become noticeably worse or more pronounced in the afternoon and evening than in the morning (marked diurnal fluctuation). Swallowing difficulties and poor sucking ability in infants can result in poor feeding during infancy.

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Causes

Tetrahydrobiopterin deficiencies are caused by variants (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.

GTPCH deficiency is caused by variants in the GCH1 gene; PTPS deficiency is caused by variants in the PTS gene; DHPR deficiency is caused by variants in the QDPR gene; PCD deficiency is caused by variants in the PCBD1 gene.

The GCH1 gene provides information for creating (encoding) an enzyme called guanosine triphosphate cyclohydrolase I, which is essential in the first of three steps necessary for the creation (biosynthesis) of tetrahydrobiopterin. The PTS gene encodes an enzyme known as 6-pyruvoyl tetrahydropterin synthase, which is essential for the second step in tetrahydrobiopterin biosynthesis. The QDPR gene encodes an enzyme called quinoid dihydropteridine reductase, which is essential for the proper regeneration of tetrahydrobiopterin. The PCBD1 gene encodes for a double-function protein; an enzyme known as pterin-4-alpha-carbinolamine dehydratase, which is also essential for the proper regeneration of tetrahydrobiopterin and for the dimerizing cofactor of hepatocyte nuclear factor 1 (DCoH1).

Variants in these genes result in low amounts of functional copies of the enzyme that is produced by the specific gene. Consequently, the synthesis or regeneration of tetrahydrobiopterin is affected, resulting in tetrahydrobiopterin deficiency. Because a PCBD1 gene variant is rarely associated with severe complications, researchers believe that other enzymes make up for the reduced activity of pterin-4-alpha-carbinolamine dehydratase.

Tetrahydrobiopterin has several functions within the body including breaking down or processing certain amino acids, particular phenylalanine. Phenylalanine is a chemical building block of proteins and is essential for proper growth and development. Tetrahydrobiopterin deficiency results in abnormally elevated levels of phenylalanine (known as hyperphenylalaninemia) in various cells of the body including brain cells. Hyperphenylalaninemia can damage the affected cells, especially brain cells which are particularly sensitive to excess phenylalanine.

Tetrahydrobiopterin is also necessary for the proper biosynthesis of amine neurotransmitters such as catecholamines (i.e., dopamine, norepinephrine, and epinephrine) and serotonin. Catecholamines are essential for the proper function of certain processes of the brain, especially those that control movement. Serotonin helps to regulate mood, appetite, memory, sleep cycles, and certain muscular functions. Lack of tetrahydrobiopterin results in a lack of these essential neurotransmitters.

The variants that cause the forms of tetrahydrobiopterin deficiency discussed in this report are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Tetrahydrobiopterin deficiencies affect males and females in equal numbers and have been diagnosed in a diversity of ethnic groups worldwide. In the United States, these disorders are estimated to affect 1% to 3% of infants diagnosed with high levels of phenylalanine (hyperphenylalaninemia) by newborn screening. Tetrahydrobiopterin deficiencies are estimated to affect approximately 1-2 in 1,000,000 individuals in the general population. Some cases, particularly mild or transient cases, may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these disorders in the general population.

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Diagnosis

A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Disorders of tetrahydrobiopterin deficiency are often found by newborn screening that detects elevated levels of phenylalanine. Further testing is required to distinguish these disorders from other causes of hyperphenylalaninemia such as phenylketonuria, and to determine the specific type of tetrahydrobiopterin deficiency present. Additionally, phenylalanine levels may be normal when a newborn screening is done and can be formal during early infancy, therefore an evaluation for tetrahydrobiopterin deficiencies should be considered in any infant with unexplained neurological symptoms, particularly in parents who are related by blood.

Biochemical Testing and Workup


Evaluation of urine and dried blood spots (DBS) can measure the levels of pterin metabolites, specifically biopterin and neopterin. Biopterin and neopterin are byproducts of the metabolism of tetrahydrobiopterin. In GTPCH deficiency, levels of biopterin and neopterin are abnormally low or even not detectable. In PTPS deficiency, neopterin is highly elevated and biopterin is very low or absent. In DHPR deficiency, biopterin is highly elevated and neopterin is normal or slightly elevated, but in some patients both metabolites can be normal (see below). In PCD deficiency, neopterin is initially very high, biopterin is slightly reduced, and primapterin (7-biopterin) is present.

A BH4 (sapropterin dihydrochloride) loading test, in which infants suspected of tetrahydrobiopterin deficiency are administered BH4, may also be performed. These tests help to distinguish BH4-deficient disorders from the more common PKU. Elevated phenylalanine levels will drop following a BH4 challenge. In PKU, this drop is minimal to moderate (BH4-responsive PKU). Infants with DHPR deficiency can be missed with urinary or DBS pterins or a BH4 loading test. The activity of the enzyme, DHPR, is therefore an essential part of laboratory testing and can be measured (enzyme assay) in DBS taken during newborn screening. Reduced activity levels can indicate or confirm a diagnosis of DHPR deficiency. Pterins, neurotransmitter metabolites and folates can be measured in cerebrospinal fluid (CSF). These tests can help to distinguish tetrahydrobiopterin deficiencies from one another and to assess the potential severity of the disease.

Molecular genetic testing can confirm a diagnosis of these disorders. Molecular genetic testing can detect variants in the specific genes known to cause tetrahydrobiopterin deficiency. DNA testing is necessary to confirm a diagnosis of a disorder of tetrahydrobiopterin deficiency.

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Standard Therapies

Treatment
Prompt recognition and early treatment of tetrahydrobiopterin deficiency is critical in reducing or preventing the potentially severe, irreversible neurologic damage that can occur in severe cases. For GTPCH deficiency, PTPS deficiency and DHPR deficiency the focus of treatment is to control the level of phenylalanine in the body and restore the proper balance of neurotransmitters in the brain. PCD deficiency may not require any treatment or may require treatment with synthetic BH4 (sapropterin dihydrochloride) temporarily in symptomatic infants or children. Many affected individuals are treated in a specialty metabolic clinic, where they are seen by physicians with experience in treating these types of disorders.

A diet that limits phenylalanine intake is recommended only in DHPR deficiency but may not be sufficient on its own in other BH4 disorders. Treatment for individuals with GTPCH deficiency and PTPS deficiency requires oral doses of synthetic tetrahydrobiopterin (sapropterin dihydrochloride). Individuals with DHPR deficiency may require additional therapy with folinic acid to prevent central nervous system folate deficiency.

Treatment will also require restoring neurotransmitter balance. Affected individuals may be treated with a regimen of amine neurotransmitter precursors, which are substances that are converted into specific neurotransmitters by enzymes in the blood and brain. Specific precursors used to treat tetrahydrobiopterin deficiency are 5-hydroxytryptophan and levodopa (L-dopa) along with carbidopa. In most patiensts, supplemental therapy with neurotransmitter precursors is required for life.

Maternal BH4 deficiency


Pregnancy care of patients with tetrahydrobiopterin deficiencies is a challenge for clinicians since knowledge about the risk of pregnancy and drug treatment are scarce. Data on 16 pregnancies in seven patients did not present any association between standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or pediatric outcome. Intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is, however, essential.

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Clinical Trials and Studies

Some affected individuals require high levels of neurotransmitter precursor treatment, which can be associated with adverse side effects. Positive results from using a selective monoamine oxidase (MAO) B inhibitor or non-ergot dopamine agonist pramipexole as an adjunct therapy have been described in the medical literature. This use of such an inhibitor can allow for lower doses of neurotransmitter precursor to be used. However, the long-term safety (e.g., effects on neonatal brain development) and effectiveness of this therapy is unknown, and more research is required to determine what role, if any, selective monoamine oxidase B inhibitors play in the treatment of individuals with tetrahydrobiopterin deficiency.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

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References

TEXTBOOKS
Blau, N. Phenylketonuria and BH4 deficiencies, 4th Ed. 2021 Uni-Med Publisher, Bremen-London-Boston.

Burlina, A, van Spronsen FJ. Blau, N, Disorders of phenylalanine and tetrahydrobiopterin metabolism. In: Physician’s Guide to the Diagnosis, Treatment, and Follow-up of Inherited Metabolic Diseases. Blau N, Dionisi-Vici C, Ferreira, CR, Vianey-Saban, C, van Karnebeek, CDM, editors. 2022 Springer-Verlag, Berlin-Heidelberg. 2nd Ed, Pp. 331-352.

Nyhan WL, Bishop BA, Al-Aqeel AI. Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin. In: Atlas of Inherited Metabolic Diseases, 3rd ed. Nyhan WL, Bishop BA, Al-Aqeel AI, editors. 2012 Hodder Arnold, London, UK. Pp. 123-135.

Walter JH, Lachmann RH, Burgard P. Hyperphenylalaninaemia. In: Inborn Metabolic Diseases. Saudubray JM, van den Berghe G, Walter JH, editors. 2012 Springer Medizin, Berlin, Germany. Pp. 251-264.

Thony B, Blau N. Tetrahydrobiopterin Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:502.

JOURNAL ARTICLES
Manti F, Nardecchia F, Banderali G, et al. Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients. Mol
Genet Metab. 2020;131(1-2):155-162. doi: 10.1016/j.ymgme.2020.06.009Simaite

Kuseyri O, Weissbach A, Bruggemann N, et al. Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders. J Inherit Metab Dis. 2018 Mar 28. doi: 10.1007/s10545-018-0169-0. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29594647

Simaite D, Kofent J, Gong M, et al. Recessive mutations in PCBD1 cause a new type of early-onset diabetes. Diabetes. 2014;63(10):3557-3564. doi:10.2337/db13-1784

Opladen T, Hoffman GF, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis. 2012;35:963-973. https://www.ncbi.nlm.nih.gov/pubmed/22729819

Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104:S2-S9. https://www.ncbi.nlm.nih.gov/pubmed/21937252

Niu DM. Disorders of BH4 metabolism and the treatment of patients with 6-pyruvoyl-tetrahydropterin synthase deficiency in Taiwan. Brain Dev. 2011; 33:847-855. https://www.ncbi.nlm.nih.gov/pubmed/21880449

Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009;32:333-342. https://www.ncbi.nlm.nih.gov/pubmed/19234759

Jaggi L, Zurfluh MR, Schuler A, et al. Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab. 2008;93:295-305. https://www.ncbi.nlm.nih.gov/pubmed/18060820

Himmelreich N, Blau N, Thony B. Molecular and metabolic bases of tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 133,2021: 123-136. https://www.ncbi.nlm.nih.gov/pubmed/33903016

Opladen T, Lopez-Laso E, Cortes-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, Garcia-Cazorla A, Honzik T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thony B, Scholl-Burgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhanek J, Kuseyri Hubschmann O, International Working Group on Neurotransmitter related D. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis 15,2020: 126. https://www.ncbi.nlm.nih.gov/pubmed/32456656

INTERNET
Blenda AV. Tetrahydrobiopterin Deficiency. Medscape. Updated: Sept 28, 2018. Available at: https://emedicine.medscape.com/article/949470-overview Accessed August 9, 2023.

BIODEFdb: International Database of Tetrahydrobiopterin Deficiencies. https://www.biopku.org/home/biodef.asp Accessed August 9, 2023.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:261640, Last Update: 04/03/2023. Available at: https://omim.org/entry/261640 Accessed August 9, 2023.; Entry No:233910, Last Update: 02/24/2014. Available at: https://omim.org/entry/233910 Accessed August 9, 2023; Entry No:261630, Last Update: 05/24/2016. Available at: https://omim.org/entry/261630 Accessed August 9, 2023; Entry No:264070; Last Update: 04/26/2017. Available at: https://omim.org/entry/264070 Accessed August 9, 2023.

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