Information on the following diseases can be found in the Related Disorders section of this report:

• Hyperphenylalaninemia
• Phenylketonuria (PKU)

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.
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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.
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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.
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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.)

Diagnosis
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
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).
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Pharmacological therapy with 5-hydroxytryptophan and tetrahydrobiopterin is still under investigation. Neither long term benefits, nor adverse effects of 5-hydroxytryptophan and/or tetrahydrobiopterin administration have been fully established. Some studies have reported efficacy in certain cases. Synthetic forms of tetrahydrobiopterin are also under study for use in treating this disorder. Clinical research studies continue to be conducted to determine appropriate treatment and effectiveness.

Information on obtaining tetrahydrobiopterin can be found through the Internet at the Tetrahydrobiopterin Home Page (www.bh4.org). IND approval is mandatory prior to its use for medical therapy in the United States.

Information on obtaining L-5-hydroxytryptophan can also be found through the Internet at the Tetrahydrobiopterin Home Page (www.bh4.org). This compound currently has orphan drug status through the FDA. IND approval is mandatory prior to its use for medical therapy in the United States. (For more information inside the United States, you may contact: Circa Pharmaceuticals, 33 Ralph Avenue, PO Box 30, Copiague, NY 11726-0030, (516) 842-8383, or Watson Laboratories, Inc., 311 Bonnie Circle, PO Box 1900, Corona, CA 91718-1900, (909) 270-1400)

Phenylalanine Ammonia-Lyase also has orphan drug status through the FDA. It is designated for the treatment of Hyperphenylalaninemia. Studies are needed to determine its effectiveness and long-term safety for Tetrahydrobiopterin Deficiency. IND approval is mandatory prior to its use for medical therapy in the United States. (For more information, contact: IBEX Technologies, Inc., 5485 Pare, Montreal, Quebec, Canada)

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