d,l-threo-3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine beta-hydroxylase deficiency

Abstract

Two patients with congenital dopamine beta-hydroxylase (DBH) deficiency were treated with d,l-threo-3,4-dihydroxyphenylserine (DOPS), 500 mg twice daily. In this orthostatic syndrome the functional integrity of the sympathetic noradrenergic neuron is probably intact, but dopamine instead of noradrenaline is released as the neurotransmitter. In vitro l-DOPS may serve as a substrate for aromatic-l-amino-acid decarboxylase (ALAAD) to form physiological (-)-noradrenaline. During infusion of d,l-threo-DOPS, 400 mg in 4 h, noradrenaline appeared in plasma and blood pressure rose, whereas plasma dopamine and the elevated venous:arterial ratio of plasma dopamine decreased. During chronic treatment supine blood pressure rose from 100-115/55-65 to 140-145/80-85 mmHg and orthostatic hypotension disappeared. After 12 and 6 months of treatment the patients are free of symptoms and they live a normal life. During chronic treatment, d,l-threo-DOPS, like plasma noradrenaline and dopamine, rose after standing, indicating release of the precursor after neuronal stimulation. After administration of tyramine plasma noradrenaline, dopamine and d,l-threo-DOPS and their respective venous:arterial ratios rose; this is further evidence of neuronal release. Thus, in DBH deficiency, dopamine instead of noradrenaline is released as a neurotransmitter, but the integrity of the sympathetic neuron is otherwise intact. Acting as an alternative substrate for ALAAD in the production of noradrenaline, DOPS is taken up by the neuron, restoring sympathetic control and thereby curing the orthostatic hypotension in DBH deficiency.