Tetrahydrobiopterin (BH4) is a naturally occurring molecule within the human body that functions as a cofactor, working alongside specific enzymes to facilitate biochemical reactions. Present in virtually every cell and tissue, BH4 supports numerous processes fundamental for overall health.
Biological Functions of Tetrahydrobiopterin
BH4 serves as a cofactor for several hydroxylase enzymes, which are responsible for converting amino acids into other compounds. One primary role involves the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine into tyrosine. This conversion is a step in the breakdown of phenylalanine obtained through diet.
BH4 is also involved in the creation of monoamine neurotransmitters. It acts as a cofactor for tyrosine hydroxylase and tryptophan hydroxylase, enzymes involved in the biosynthesis of dopamine, norepinephrine, epinephrine, and serotonin. These neurotransmitters are important for regulating mood, sleep, movement, and other neurological functions.
Beyond its role in amino acid metabolism and neurotransmitter synthesis, BH4 also participates in the production of nitric oxide. Nitric oxide is a signaling molecule involved in various bodily processes, including the regulation of blood pressure and blood flow. It supports the activity of nitric oxide synthases, the enzymes responsible for its formation.
Tetrahydrobiopterin Deficiency Disorders
When the body cannot produce or properly recycle enough BH4, it leads to rare metabolic conditions known as BH4 deficiency disorders. These conditions are typically inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated gene from each parent. The underlying problem can stem from issues with the enzymes involved in BH4 synthesis or its regeneration after it has been used.
A common consequence of BH4 deficiency is elevated phenylalanine in the blood, a condition called hyperphenylalaninemia. This occurs because the phenylalanine hydroxylase enzyme, which requires BH4 to function, cannot adequately convert phenylalanine into tyrosine. Excessive phenylalanine can accumulate in the bloodstream and other tissues, potentially damaging nerve cells in the brain.
In addition to phenylalanine buildup, BH4 deficiency also results in a shortage of essential neurotransmitters like dopamine, serotonin, norepinephrine, and epinephrine. The enzymes responsible for synthesizing these neurotransmitters also depend on BH4. This dual chemical imbalance significantly disrupts normal brain function.
Symptoms of BH4 deficiency vary widely, from mild to profound. Infants may appear healthy at birth, but problems usually emerge over time. Common symptoms include:
Developmental delays
Intellectual disability
Movement disorders
Seizures
Difficulty swallowing
Behavioral issues
Challenges with controlling body temperature
Diagnostic and Treatment Approaches
The early identification of BH4 deficiency is important to prevent severe and irreversible neurological damage. Diagnosis often begins with newborn screening programs, which may detect elevated phenylalanine levels in the blood. If high phenylalanine is found, further tests are conducted, including blood tests to measure phenylalanine and tyrosine levels, and urine analysis to check for specific biopterin metabolites. Measuring dihydropteridine reductase (DHPR) enzyme activity in blood can also help confirm certain forms of the deficiency.
Primary treatment for many forms of BH4 deficiency involves supplementation with sapropterin dihydrochloride, a synthetic form of BH4. This medication works by providing the body with the missing cofactor, helping restore enzyme function like phenylalanine hydroxylase. Sapropterin can reduce phenylalanine levels in the blood and improve some neurological symptoms. Dosage typically ranges from 5 to 20 mg/kg per day, adjusted based on biochemical response.
Beyond sapropterin, other supportive therapies are often necessary to manage the complex symptoms of BH4 deficiency. A controlled low-phenylalanine diet may be recommended to help prevent buildup in the body. Furthermore, medications that replace missing neurotransmitters, such as levodopa (L-dopa) with carbidopa for dopamine, and 5-hydroxytryptophan (5-HTP) for serotonin, are frequently administered. In some cases, particularly with dihydropteridine reductase deficiency, folinic acid supplementation may also be required to address cerebral folate deficiency.