On-off phenomenon in a child with tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency (BH4 deficiency)

Abstract

Marked fluctuations in mobility, known as the on-off phenomenon, frequently emerge during the course of chronic treatment with levodopa in patients with Parkinson's disease. Similar fluctuations in mobility and mental status have been observed in a 10-year-old Japanese girl with tetrahydrobiopterin deficiency (BH4 deficiency) while receiving neurotransmitter and biopterin supplement. In order to define the underlying mechanisms for the phenomenon in our patient, we studied the temporal relationship between plasma levodopa levels and clinical status during oral (2.0 mg/kg per day) and continuous intravenous (2.0 mg/kg per 12 h) administration of the drug. Following each oral levodopa dose, the plasma concentration of levodopa peaked at 60-90 ng/ml within 60 min and fell to 5-15 ng/ml within 2 h. The clinical state of the patient varied acutely in parallel with the plasma levodopa concentrations. The clinical swings completely disappeared when the plasma levodopa concentrations were stabilized between 120-150 ng/ml by continuous infusion. Paradoxically, on awakening from sleep, she was invariably ambulatory despite very low plasma levodopa levels (less than 10 ng/ml). These observations indicate that the on-off phenomenon in our patient reflect the fluctuations of plasma levodopa levels as demonstrated in Parkinson's disease, but there may be substantial differences in levodopa transport across the blood-brain barrier and/or striatal dopamine-receptor interaction between Parkinson's disease and BH4 deficiency.

Dihydropteridine reductase deficiency in man: From biology to treatment

“…[120][121][122] Unfortunately, higher doses of neurotransmitter precursors are progressively required with age, thus generating in patients diurnal symptoms fluctuations, overdose effects, or on-off phenomena. 123 Aliquoting of the daily dosage into six to eight administrations or concurrent treatment with Dopa agonists such as bromocryptine have been proposed with only partial success, 59,124 whereas some result was obtained in similar cases with the concurrent administration of RL-Deprenyl (Selegiline, phenylisopropylmethylpropynylamine) a selective monoamine oxidase B inhibitor which allows a 10% reduction in the dosage of neurotransmitter precursors by curtailing their catabolism. 113,125,126 Actually, substitutive therapy with L-Dopa represents the most critical aspect in the treatment of DHPR deficiency, as pharmacological disadvantages or adverse effects encompass both its short-term and long-term outcome.…”

Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency

“…While treatment and follow-up of these patients is relatively simple (BH 4 substitution in order to control plasma Phe levels) [21,30,42], infants with severe forms of PTPS de®ciency need a combined therapy with BH 4 and neurotransmitter precursors [4,35]. Several case reports have been published; however, it must be stressed that they dier with regard to the time of diagnosis, treatment, clinical outcome, and mode of follow-up [5,16,23,25,28,38,50].…”

Monitoring treatment in tetrahydrobiopterin deficiency by serum prolactin

“…Recently, all patients were begun on an innovative therapeutic approach with a monoamine oxidase inhibitor, L-deprenyl, at the dose of Spada et al Outcome of patients affected by inherited BH 4 deficiency is often poor despite early treatment. Many failures are consequent on difficulties in managing the neurotransmitter substitutive therapy, mostly because of dopamine fluctuations (Tanaka et al 1989). Actually, clinical monitoring of this treatment is hampered by the composite picture resulting from agonist, antagonist, and side-effects of L-dopa and 5-hydroxytryptophan, which can also mimic the symptoms of deficiency.…”