NORD gratefully acknowledges Prof. Dr. Nenad Blau, Senior Consultant in Biochemical Genetics, Professor of Clinical Biochemistry (UZH), Dietmar-Hopp Metabolic Center, University Children's Hospital for assistance in the preparation of this report.
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.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 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.
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