Dopamine-Beta-Hydroxylase Deficiency (DBH)
There is virtual absence of norepinephrine, epinephrine, and their metabolites. However, there is greatly increased dopamine in plasma, cerebrospinal fluid, and urine.
- As children, DBH deficient patients have had a markedly reduced ability to exercise, perhaps because of hypotension engendered by the physical exertion.
- Symptoms have generally worsened in late adolescence and by early adulthood, patients complain of profound orthostatic hypotension, especially early in the day and during hot weather or after alcohol ingestion.
- In addition to drooping of the eyelids, there is a tendency for nasal stuffiness to occur, especially in the supine posture.
- Presyncopal symptoms in these patients have included dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally chest pain.
- The physical examination usually includes a normal or low normal supine blood pressure and a normal heart rate but a standing blood pressure that is less than 80 mmHg systolic.
- Heart rate rises on standing but appears to have an attenuated elevation given the very low blood pressure with upright posture.
- Pupils are somewhat small but respond to light and accommodation. Parasympatholytics dilate the eye appropriately.
- Many specialized tests differentiate these patients from those with familial dysautonomia. Cholinergic sensitivity as assessed by conjunctival methacholine is normal, and intradermal histamine evokes a typical flare reaction in DBH deficiency, whereas this does not occur in familial dysautonomia. Atrial fibrillation, occasionally occurs in adults.
- These patients have no response even to high doses of tyramine, which normally increases blood pressure by releasing neuronal norepinephrine. Dopamine, rather than norepinephrine, levels increase when the patient stands, during sustained handgrip, and after tyramine administration, while they decrease after clonidine administration.
- Muscle sympathetic nerve traffic, as measured by direct intraneuronal recordings, is present in excess under basal conditions but is otherwise normally modulated by baroreflex mechanisms in these patients. Therefore, primary autonomic neuronal pathways are intact and respond to appropriate stimuli, but dopamine instead of norepinephrine is present in noradrenergic nerve terminals.
- Sympathetic cholinergic function is intact, as assessed by normal sweating.
- Parasympathetic function is also preserved, as assessed by intact sinus arrhythmia, normal heart rate increase during Valsalva, and tachycardia after atropine.
- A diagnosis of DBH deficiency is based on the characteristic plasma catecholamine pattern of absent norepinephrine and epinephrine and elevated dopamine.
- Fludrocortisone at relatively high doses has successfully raised blood pressure with some benefit. Indomethacin has also been of modest benefit in raising blood pressure, but one patient had aggressive ideation while receiving this drug.
- The monoamine oxidase inhibitor tranylcypromine also produced paranoid thinking in one patient.
- There has been a reasonable response to phenylpropanolamine (25 and 50 mg), perhaps because of the hypersensitive alpha-adrenoreceptors in these patients.
- Once the specific enzymatic defect had been elucidated, investigators knew that a better treatment for DBH deficiency could be devised.
- Metyrosine significantly reduces urinary and plasma dopamine levels in DBH deficiency.
- A more favorable long-term result has been achieved with L-dihydroxyphenylserine (droxidopa or L-DOPS). The administration of DOPS to these patients results in dramatic increases in blood pressure and in the restoration of plasma and urinary levels of norepinephrine toward normal. Long-term experience with this drug indicates continued effectiveness at 250 mg or 500 mg three times a day.