Tetrahydrobiopterin Deficiency

National Organization for Rare Disorders, Inc.

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It is possible that the main title of the report Tetrahydrobiopterin Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


  • BH4-deficient hyperphenylalaninemia

Disorder Subdivisions

  • None

General Discussion

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), the 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 in expression. Prompt diagnosis and treatment of these disorders can prevent potentially severe, irreversible neurological damage. Tetrahydrobiopterin deficiency is caused by mutations in specific genes that encode enzymes required for the biosynthesis or regeneration of tetrahydrobiopterin. Most of these mutations are inherited as autosomal recessive traits.

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 creation 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.

Supporting Organizations

American Dystonia Society

17 Suffolk Lane
Suite 1
Princeton Junction, NJ 08550
Tel: 310-237-5478
Fax: 609-275-5663
Email: info@dystonia.us
Website: http://www.dystonia.us

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building
176 Nantwich Road
Crewe, CW2 6BG
United Kingdom
Tel: 4408452412173
Fax: 4408452412174
Email: enquiries@climb.org.uk
Website: http://www.CLIMB.org.uk

Dystonia Medical Research Foundation

1 East Wacker Drive, Suite 2810 East Wacker Drive
Suite 2810
Chicago, IL 60601-1905
United States
Tel: (312)755-0198
Fax: (312)803-0138
Tel: (800)377-3978
Email: dystonia@dystonia-foundation.org
Website: http://www.dystonia-foundation.org

Dystonia Society

89 Albert Embankment, 2nd Floor
London, SE1 7TP
United Kingdom
Tel: 8454586211
Fax: 8454586311
Tel: 8454586322
Email: angie@dystonia.org.uk
Website: http://www.dystonia.org.uk

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
Website: http://rarediseases.info.nih.gov/GARD/

NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801
Bethesda, MD 20824
Tel: (301)496-5751
Fax: (301)402-2186
Tel: (800)352-9424
Website: http://www.ninds.nih.gov/

Pediatric Neurotransmitter Disease Association

28 Prescott Place
Old Bethpage, NY 11804
Tel: (603)733-8409
Email: pndassociation@aol.com
Website: http://www.pndassoc.org

The Arc

1825 K Street NW, Suite 1200
Washington, DC 20006
Tel: (202)534-3700
Fax: (202)534-3731
Tel: (800)433-5255
Email: info@thearc.org
Website: http://www.thearc.org

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders (NORD). A copy of the complete report can be downloaded free from the NORD website for registered users. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational therapies (if available), and references from medical literature. For a full-text version of this topic, go to www.rarediseases.org and click on Rare Disease Database under "Rare Disease Information".

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.

It is possible that the title of this topic is not the name you selected. Please check the Synonyms listing to find the alternate name(s) and Disorder Subdivision(s) covered by this report

This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

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Last Updated:  1/13/1970
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