6-pyruvoyl-tetrahydropterin synthase deficiency

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a rare inherited metabolic disorder and the most common cause of tetrahydrobiopterin (BH4) deficiency, also known as hyperphenylalaninemia due to BH4 deficiency. PTPS is the enzyme responsible for the second step in the biosynthesis of tetrahydrobiopterin, an essential cofactor for phenylalanine hydroxylase and for the hydroxylases involved in the synthesis of the neurotransmitters dopamine and serotonin. When this enzyme is deficient, phenylalanine accumulates in the blood (hyperphenylalaninemia), and neurotransmitter production is severely impaired. The condition is typically detected through newborn screening programs that identify elevated phenylalanine levels. The disease primarily affects the central nervous system. Without treatment, affected infants develop progressive neurological deterioration, including intellectual disability, seizures, dystonia, abnormal movements, microcephaly, and difficulty swallowing. Symptoms typically appear within the first months of life, even when dietary phenylalanine restriction is implemented, because the neurotransmitter deficiency is not corrected by diet alone. Patients may also exhibit temperature instability, excessive salivation, and irritability. Treatment requires a combined approach including oral tetrahydrobiopterin (sapropterin) supplementation to control blood phenylalanine levels, along with neurotransmitter precursor replacement therapy using L-DOPA (with a peripheral decarboxylase inhibitor such as carbidopa) and 5-hydroxytryptophan to restore dopamine and serotonin levels, respectively. Folinic acid supplementation is also often administered, as some patients develop central folate deficiency. Early diagnosis and prompt initiation of treatment are critical to prevent irreversible neurological damage. With appropriate and timely therapy, outcomes can be significantly improved, though lifelong treatment and careful monitoring of neurotransmitter metabolites in cerebrospinal fluid are necessary.

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