Long-term safety and effectiveness of pramipexole in tetrahydrobiopterin deficiency

Abstract Tetrahydrobiopterin (BH 4 ) deficiencies are inherited neuro-metabolic disorders leading to monoamine neurotransmitters deficiency. An individualized replacement therapy with neurotransmitters precursors is necessary to restore dopaminergic and serotoninergic homeostasis. The correction of dopaminergic tone is complicated, like in Parkinson disease, by l -dopa short half-life and adverse effects. To improve this picture, since 2009 we introduced the non-ergot dopamine agonist pramipexole as an adjunct to l -dopa therapy in the treatment of the most common causes of BH 4 deficiency, 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency and dihydropteridine reductase (DHPR) deficiency. In the short-term period, this approach allowed substantial clinical advantages in affected patients, with amelioration and stabilization of the clinical picture on twice daily treatment administration and no adverse effect. Here we describe the long-term clinical follow-up (83 ± 24 months) of seven patients with BH 4 deficiency treated with pramipexole. After a period of good clinical compensation (34 ± 1 months), different impulse control disorders (gambling, compulsive buying, and hypersexuality) were observed in three patients treated with high-dose pramipexole (0.030–0.033 mg/kg/day) beyond adolescence. These psychiatric adverse effects promptly disappeared after curtailing pramipexole dose by 50–60%. Low-dose pramipexole therapy has been safe and effective in the long-term period in all treated patients (59 ± 9 months). High-dose pramipexole therapy in BH 4 deficiency can be complicated, like in Parkinson disease, by psychiatric adverse effects. Low-dose pramipexole therapy (∼0.010 mg/kg/day) has been safe and clinically effective on long-term follow-up, representing a helpful therapeutic option in patients with BH 4 deficiency.