Tetrahydrobiopterin deficiencies: an international survey of clinical and biochemical features, treatment strategies and follow-up of 626 patients

Objectives: Tetrahydrobiopterin (BH4) is the essential cofactor for phenylalanine hydroxylation and synthesis of dopamine and serotonin. Inborn errors of BH4 metabolism therefore lead to biogenic amines depletion and progressive neurological dysfunction. The study summarizes clinical and biochemical findings, current treatment strategies, and follow-up.

Methods: We analyzed data of 626 patients with BH4 deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] tabulated in the BIODEF Database.

Results: Up to 57% of neonates with BH4 deficiencies are clinically symptomatic. During infancy, the predominant symptoms are muscular hypotonia and developmental delay. Children develop age-dependent movement disorders. After diagnosis of hyperphenylalaninemia in newborn screening, BH4 deficiency is confirmed by urinary or dried blood spot pterins and the measurement of DHPR activity in the blood. Absence of hyperphenylalaninemia delays diagnosis in patients with sepiapterin reductase and in some with GTPCH deficiency and CSF investigations are the only option. Treatment includes L-dopa, 5-hydroxytryptophan, and BH4 or low-phenylalanine diet. Medications dose vary widely among patients and should be increased slowly. Experiences with dopamine agonists and monoamine catabolism inhibitors are limited.

Conclusion: BH4 deficiencies are treatable pediatric neurotransmitter disorders, characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes are highly variable, early diagnosis and treatment are highly beneficial for the good outcome.