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Tetrahydrobiopterin Deficiency

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NORD is grateful to David H. Tegay, DO, Assistant Professor in the Division of Medical Genetics at Stony Brook University Hospital, for assistance in the preparation of this report.

Synonyms of Tetrahydrobiopterin Deficiency

Disorder Subdivisions

General Discussion

Tetrahydrobiopterin Deficiency is a rare genetic, neurological disorder present at birth. It is caused by an inherited inborn error of metabolism. Tetrahydrobiopterin is a natural substance (coenzyme) that enhances the action of other enzymes. When Tetrahydrobiopterin is deficient, an abnormally high blood level of the amino acid phenylalanine, along with low levels of certain neurotransmitters, usually occurs. To avoid irreversible neurological damage, diagnosis and treatment of this progressive disorder is essential as early as possible in life.

The subdivisions of Tetrahydrobiopterin Deficiency are as follows:
Tetrahydrobiopterin Synthesis
GTP Cyclohydrolase I (GTPCH) Deficiency
6-Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency
Tetrahydrobiopterin Regeneration
Pterin-4-alpha-Carbinolamine Dehydratase (PCD) Deficiency
Dihydropteridine Reductase (DHPR) Deficiency


Generally, Tetrahydrobiopterin Deficiency first manifests with neurological problems despite appearing normal at birth, including abnormal muscle tone, poor sucking and coordination, seizures, and delayed motor development. Without appropriate treatment, irreversible neurologic deterioration invariably occurs, including mental retardation, seizures and even death.


Tetrahydrobiopterin Deficiency results from mutations (changes) in any one of multiple genes that are responsible for enzymes that help maintain adequate levels of tetrahydrobiopterin (I.e., the enzymes GTP-cyclohydrolase, 6-pyruvoyl tetrahydropterin synthase, pterin-4-alpha-carbinolamine dehydratase, and dihydropteridine reductase). Mutations that decrease enzyme activity sufficiently result in inadequate levels of tetrahydrobiopterin. Tetrahydrobiopterin is an essential cofactor for multiple enzymes involved in the metabolism of the amino acid phenylalanine, and the production of brain neurotransmitters. Deficiency leads to elevated levels of phenylalanine, and decreased levels of brain neurotransmitters, resulting in disease. Unlike PKU, treatment with phenylalanine restricted diet alone is insufficient because brain neurotransmitter deficiencies would still remain.

Tetrahydrobiopterin Deficiency is inherited in a fashion known as "autosomal recessive". Normally we receive two copies of every gene, one from our mother and one from our father. In order for a person to develop an autosomal recessive disease such as Tetrahydrobiopterin Deficiency, that individual must inherit a defective copy of the disease-causing gene from both his or her mother and father. Individuals who have one working copy and one defective copy of such a gene will usually not develop symptoms and are therefore called "carriers". A carrier is unaffected, but may pass on the defective copy to his children. For two people who are both carriers of a recessive disorder such as Tetrahydrobiopterin Deficiency, there is a 25% chance with each pregnancy that their child will inherit both defective copies and will thus be affected. There is a 50% chance with each pregnancy that their child will inherit one defective copy and one working copy and will thus be unaffected but a carrier. There is a 25% chance with each pregnancy that their child will inherit no defective copies and will thus be both unaffected and also not a carrier. This risk remains the same with each pregnancy. Consultation is recommended with a clinical geneticist for genetic counseling.

Affected Populations

Tetrahydrobiopterin Deficiency has been diagnosed in a diversity of ethnic groups worldwide. In the United States, it is estimated to affect one to three percent of infants diagnosed with high levels of phenylalanine by newborn screening. Phenylketonuria (PKU) occurs at a rate of approximately 1:15,000 live births in the United States. Tetrahydrobiopterin Deficiency therefore, in comparison, occurs with a much lower frequency of approximately 1:1,000,000 live births in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of Tetrahydrobiopterin Deficiency. Comparisons may be useful for a differential diagnosis:

Hyperphenylalaninemia is identified by the presence of abnormally high blood levels of the amino acid phenylalanine in newborns. It may or may not be associated with elevated levels of another amino acid, tyrosine, in these children. This disorder may be a symptom of Phenylketonuria (PKU) or it can be linked with short-term deficiencies of either phenylalanine hydroxylase or p-hydroxyphenylpyruvic acid oxidase.

Phenylketonuria (PKU) is a hereditary metabolic disorder characterized by the inability to metabolize the amino acid phenylalanine. Uncontrolled accumulations of phenylalanine in the blood during childhood results in progressive, severe, irreversible mental retardation. A phenylalanine restricted diet can prevent brain damage if the disorder is identified early in infancy. Unlike PKU, a phenylalanine restricted diet does not prevent brain damage in patients with tetrahydrobiopterin deficiency. (For more information on this disorder, choose "PKU" as your search term in the Rare Disease Database.)

Standard Therapies

Tetrahydrobiopterin Deficiency is usually diagnosed through laboratory analysis of blood phenylalanine levels, urine pterin levels, and blood spot DHPR enzyme activity. Occasionally a special test is done which involves drinking a solution containing tetrahydrobiopterin, followed by obtaining frequent blood levels of phenylalanine. Once the diagnosis is made, more specific studies of enzyme activity, and lumbar puncture to analyze CSF neurotransmitters is essential. Consultation with a doctor experienced in biochemical genetics is recommended for diagnosis and treatment.

Treatment of Tetrahydrobiopterin Deficiency should be started as early as possible to attempt to reduce or prevent irreversible complications such as brain damage. Dietary phenylalanine restriction alone is not sufficient to prevent complications related to neurotransmitter deficiency. However, a low phenylalanine diet may be a part of the prescribed regimen. Treatment options will differ depending on the precise enzyme deficiency responsible for the disease, and its severity. This may involve a regimen of dietary phenylalanine restriction, and/or oral tetrahydrobiopterin supplementation alone or in combination with neurotransmitter replacement (plus oral vitamin supplementation with folinic acid in DHPR deficiency).

Investigational Therapies

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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

Tetrahydrobiopterin Deficiency Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:


Blau N, et al. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriber CR, et al., eds. The Metabolic and Molecular Bases of Inherited Diseases. New York:McGraw-Hill;2001:1725-76.

Fukuda K, et al. Hyperphenylalaninaemia due to impaired dihydrobiopterin biosynthesis: leukocyte function and effect of tetrahydrobiopterin therapy. J Inherited Metab Dis. 1985;8:4952.

Kaufman S. Hyperphenylalaninaemia caused by defects in biopterin metabolism. J Inherited Metab Dis. 1985;1:20-27.

Neiderweiser A, et al. Hyperphenylalaninaemia due to impaired dihydrobiopterin differential diagnosis of tetrahydrobiopterin deficiency. J Inherited Metab Dis. 1985;8:34-38.

Scheinfeld N, et al. Tetrahydrobiopterin deficiency. Emedicine Journal [serial online] (2003). Available at: http://www.emedicine.com

Report last updated: 2008/05/23 00:00:00 GMT+0