TOTAL NOREPINEPHRINE SPILLOVER, MUSCLE SYMPATHETIC-NERVE ACTIVITY ANDHEART-RATE SPECTRAL-ANALYSIS IN A PATIENT WITH DOPAMINE-BETA-HYDROXYLASE DEFICIENCY

Dopamine-beta-hydroxylase (D beta H) is the enzyme responsible for int raneural conversion of dopamine to norepinephrine. Its deficiency resu lts in failure of norepinephrine synthesis, excessive dopamine release and orthostatic hypotension. We studied a young patient with this def iciency using the currently available methods to assess sympathetic fu nction namely measurement of norepinephrine kinetics, microneurography to assess muscle sympathetic nerve activity (MSNA), and heart-rate sp ectral analysis. We compared these findings with those in 24 young hea lthy controls, and 4 patients with peripheral autonomic failure (PAF), Recordings were made in our subject before and after 5 months of trea tment with L-threo-3,4-dihydroxyphenylserine (DOPS) (which is converte d directly into L-norepinephrine bypassing the D beta H enzymatic step ); measurements were made at rest in the supine position and after 15 min of 30 degrees head-up tilt. Our subject with D beta H deficiency h ad a high resting nerve firing rate (40.3 bursts/min) compared with th e mean value in normal controls (19.3 bursts/min), and an appropriate increase in nerve firing rate during tilt. Total body norepinephrine s pillover at rest was very low, 38 ng/min, compared with age-matched no rmals (519 +/- 43.3 ng/min, mean +/- SEM), and epinephrine secretion w as undetectable. Conversely, the plasma concentrations of dopamine, DO PAC, HVA and DOPA were raised, At rest, low-frequency heart-rate varia bility (0.1 Hz) was absent with preservation of the respiratory-relate d high-frequency peak. In contrast, the PAF subjects had no detectable muscle sympathetic nerve activity, very low levels of norepinephrine spillover and epinephrine secretion and a reduction in heart rate vari ability at all frequencies. After 5 months treatment with L-threo-3,4- dihydroxyphenylserine (DOPS) in the D beta H deficiency patient there was a dramatic clinical improvement with resolution of the orthostatic symptoms, dramatic reduction in MSNA activity at rest, and return of plasma norepinephrine, norepinephrine spillover, DHPG and MHPG to with in the normal range, indicating intraneuronal production of norepineph rine.