Tetrahydrobiopterin (BH4) deficiency is a rare genetic disorder characterized by a shortage of the BH4 molecule. This condition disrupts the body’s ability to process certain substances, including the amino acid phenylalanine, leading to a range of metabolic and neurological issues. When the body cannot produce or recycle enough of it, development and overall health can be affected.
Biological Role and Causes of Deficiency
Tetrahydrobiopterin functions as a cofactor, a “helper molecule,” for several enzymes. It is required for phenylalanine hydroxylase to process the amino acid phenylalanine and is also involved in producing neurotransmitters like dopamine and serotonin. Without sufficient BH4, phenylalanine can accumulate to harmful levels, while the production of these key neurotransmitters is impaired.
This deficiency is an inherited disorder caused by mutations in genes responsible for synthesizing or regenerating BH4. A mutation in any of the following genes, which provide instructions for making enzymes in BH4 metabolism, can disrupt the process:
- GCH1
- PCBD1
- PTS
- QDPR
The condition is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the mutated gene, one from each parent. The parents are carriers who have only one copy of the mutation and do not show signs or symptoms of the condition.
Signs and Symptoms
Infants with tetrahydrobiopterin deficiency appear normal at birth, but symptoms develop over time and can range from mild to severe. One of the first indicators is a high level of phenylalanine detected during routine newborn screening. This can sometimes lead to a misdiagnosis of classic Phenylketonuria (PKU), a more common disorder also characterized by high phenylalanine.
The distinguishing symptoms of BH4 deficiency are neurological, arising from a shortage of neurotransmitters like dopamine and serotonin. Unlike in classic PKU, this shortage can lead to progressive developmental problems, poor muscle tone (hypotonia), and movement disorders.
As the condition progresses without treatment, other symptoms may appear. Children may experience seizures, difficulty swallowing, and behavioral problems. An inability to control body temperature is another possible sign. The combination of these issues can lead to significant neurological challenges if not addressed early.
Diagnosis and Screening Process
Diagnosis for BH4 deficiency begins with newborn screening programs that test for high levels of phenylalanine. While this initial test flags a potential issue, it does not distinguish between classic PKU and BH4 deficiency, requiring further investigation.
To reach a definitive diagnosis, specialized follow-up tests are performed. The primary test is the analysis of pterins, molecules related to BH4, in a patient’s urine or blood. The pterin profile can confirm that high phenylalanine is due to a problem with BH4 metabolism rather than a defect in the phenylalanine hydroxylase enzyme, as seen in PKU.
Another diagnostic tool is the BH4 loading test, where a patient is given a dose of BH4 to see if their phenylalanine levels decrease. A significant drop suggests the body’s enzymes are functional but lack the cofactor. Genetic testing can also identify the specific gene mutation, confirming the diagnosis and the type of deficiency.
Treatment Approaches
Treatment for tetrahydrobiopterin deficiency is a lifelong process aimed at managing both high phenylalanine levels and neurotransmitter deficiencies. The primary goal is to start treatment as early as possible to support normal development and minimize neurological issues.
A central component of treatment is BH4 supplementation. Patients are prescribed a synthetic form of BH4, known as sapropterin dihydrochloride. This helps restore the function of the phenylalanine hydroxylase enzyme, lowering phenylalanine levels in the blood. The dosage can range from 2 to 20 mg/kg per day.
Because BH4 supplementation alone does not always fully restore brain neurotransmitter levels, many patients also require replacement therapy with neurotransmitter precursors. These medications, which the body converts into needed neurotransmitters, include L-dopa/carbidopa to address dopamine deficiency and 5-hydroxytryptophan for serotonin deficiency.
In some cases, dietary management is also a part of the treatment plan. Patients may need to follow a diet that restricts their intake of phenylalanine, similar to the diet used for classic PKU. This approach helps prevent the accumulation of this amino acid and protect the brain.