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  • Updated 10.21.2020
  • Released 03.30.1995
  • Expires For CME 10.21.2023

Dopamine beta-hydroxylase deficiency

Introduction

Overview

Dopamine beta-hydroxylase deficiency is an autosomal recessive genetic form of primary autonomic failure. Dopamine beta-hydroxylase normally converts dopamine to norepinephrine (which can then be further metabolized to epinephrine), so a deficiency or dysfunction of this enzyme causes a profound deficiency of norepinephrine and epinephrine within the central and peripheral nervous systems. Patients with dopamine beta-hydroxylase deficiency have generally been detected in adolescence or adulthood following the onset of severe orthostatic hypotension. Although symptoms are usually diagnosed in adulthood, ptosis, hypothermia, severe orthostatic hypotension, hypoglycemia, and other autonomic abnormalities may have been evident since birth. Testing reveals extremely low levels of norepinephrine, epinephrine, and their metabolites in plasma, CSF, and urine. Treatment with the norepinephrine prodrug droxidopa (dl-dihydroxyphenylserine, L-DOPS) increases plasma and urine norepinephrine to near normal levels, with a consequent increase in blood pressure and amelioration or correction of the symptoms of orthostatic hypotension.

Key points

• Dopamine beta-hydroxylase deficiency is inherited as an autosomal recessive trait.

• Dopamine beta-hydroxylase deficiency leads to a profound deficiency of norepinephrine and epinephrine within the central and peripheral nervous systems.

• Dopamine beta-hydroxylase deficiency leads to a primary autonomic failure.

• Dopamine beta-hydroxylase deficiency has only a minor impact on cognitive function.

• Treatment with the norepinephrine prodrug droxidopa (dl-dihydroxyphenylserine, L-DOPS) increases plasma and urine norepinephrine to near normal levels, with a consequent increase in blood pressure and amelioration or correction of the symptoms of orthostatic hypotension.

Historical note and terminology

Dopamine beta-hydroxylase was discovered in the 1950s (18). Dopamine beta-hydroxylase is a copper-containing, ascorbate-dependent enzyme that synthesizes norepinephrine from dopamine (18). Subsequent methylation of norepinephrine (nonadrenaline) forms epinephrine (adrenaline), and these 2 catecholamine neurotransmitters are the main determinants of vascular tone and, hence, of arterial pressure.

In 1986 and 1987, 2 groups reported a syndrome of autonomic failure characterized by severe orthostatic hypotension, noradrenergic failure, and ptosis of the eyelids but with normal parasympathetic function and normal sympathetic cholinergic function (42; Man in't Veld et al 1987a). The biochemical findings of low or absent norepinephrine and epinephrine and their metabolites in the presence of elevated dopamine concentrations, combined with the clinical data, led to the conclusion that this condition was due to a congenital deficiency of dopamine beta-hydroxylase. Activity of this enzyme was absent in plasma. Earlier cases with a similar syndrome have also been reported, but a definitive diagnosis was not made (02; 35).

Patients with dopamine beta-hydroxylase deficiency have generally been detected in adolescence or adulthood following the onset of severe orthostatic hypotension. The mode of inheritance is autosomal recessive, and several different mutations have been identified (16; 10).

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