Which are the causes of Tetrahydrobiopterin Deficiency?

Tetrahydrobiopterin (BH4) deficiency is a rare genetic disorder that affects the production and recycling of a molecule called tetrahydrobiopterin. This molecule is essential for the proper functioning of several enzymes involved in the production of neurotransmitters, such as dopamine, serotonin, and norepinephrine. BH4 deficiency can lead to a range of symptoms, including neurological, psychiatric, and metabolic abnormalities.

Genetic Mutations: The primary cause of BH4 deficiency is genetic mutations in the genes responsible for the production or recycling of tetrahydrobiopterin. These mutations can disrupt the synthesis or recycling pathways, leading to a deficiency of BH4. The most common genes associated with BH4 deficiency are GCH1, PTS, and QDPR.

GCH1 Deficiency: GCH1 gene mutations are the most common cause of BH4 deficiency. GCH1 encodes an enzyme called GTP cyclohydrolase 1, which is involved in the first step of BH4 synthesis. Mutations in this gene can impair the production of BH4, leading to a deficiency.

PTS Deficiency: Mutations in the PTS gene can cause BH4 deficiency by impairing the recycling of BH4. The PTS gene provides instructions for producing an enzyme called 6-pyruvoyltetrahydropterin synthase, which is involved in the regeneration of BH4 from its oxidized form. Mutations in this gene can disrupt this recycling process, resulting in BH4 deficiency.

QDPR Deficiency: QDPR gene mutations can also lead to BH4 deficiency. The QDPR gene provides instructions for producing an enzyme called quinoid dihydropteridine reductase, which is involved in the recycling of BH4. Mutations in this gene can impair the activity of the enzyme, leading to reduced BH4 levels.

Other Causes: In rare cases, BH4 deficiency can also be caused by mutations in other genes involved in the synthesis or recycling of BH4. These include PTPS, PCBD1, and SR. Additionally, certain medications or environmental factors may interfere with BH4 metabolism, leading to a secondary BH4 deficiency.

Conclusion: Tetrahydrobiopterin deficiency is primarily caused by genetic mutations in the genes responsible for BH4 synthesis or recycling. GCH1, PTS, and QDPR gene mutations are the most common causes of BH4 deficiency. Understanding the underlying genetic causes of BH4 deficiency is crucial for accurate diagnosis and appropriate management of this rare disorder.