The broader view: catecholamine abnormalities.

Norepinephrine (NE), a vital neurotransmitter in both the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) through the oxidation of dopamine (DA) to NE. DBH deficiency is a congenital disorder characterized by severe orthostatic hypotension, ptosis, and retrograde ejaculation. Biochemical features of the syndrome include elevated levels of dopamine, undetectable levels of DBH, undetectable tissue and circulating levels of NE and epinephrine. Molecular genetic analysis studies suggested that DBH deficiency is a Mendelian recessive disorder attributable to heterogenous mutations at the DBH locus. DBH deficiency has been treated effectively with L-threo-3,4-dihydroxyphenylserine (DOPS). DOPS is converted directly to NE through decarboxylation by L-aromatic amino acid decarboxylase (AADC), thereby bypassing DBH. Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, syncope, and postural tachycardia. Biochemical features may include plasma NE concentration that is disproportionately high in relation to sympathetic outflow, decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists. A subset of OI patients has pathophysiologic features that have been associated with a genetic polymorphism. The coding mutation, A457P, occurs in one of the alleles of norepinephrine transporter gene of a proband with OI and her family. Alpha-methyl dopa, beta blockers and clonidine, a partial agonist of alpha2-adrenoceptor that acts centrally to reduce sympathetic outflow and lower blood pressure, have been effective in the treatment of this condition. The identification of the genetic polymorphisms involved in the synthesis, transport, storage, and metabolism of the catecholamines may provide new insights into the diagnosis and management of autonomic, cardiovascular, endocrine and psychiatric disorders.