ELECTRONIC LETTER DBH gene variants that cause low plasma dopamine b hydroxylase with or without a severe orthostatic syndrome

T he enzyme dopamine b hydroxylase (EC 1.14.17.1, MIM 223360) is a monooxygenase that catalyses the conversion of dopamine to norepinephrine. It requires copper as a cofactor and uses oxygen and ascorbate as cosubstrates. Dopamine b hydroxylase is localised within the soluble and membrane fractions of secretory vesicles of neurones of the central nervous system that produce epinephrine and norepinephrine, sympathetic ganglia, and cells of the adrenal medulla. The soluble form of the enzyme is secreted into the circulation, together with norepinephrine, from nerve terminals. 6 The major form of this glycosylated enzyme seems to be a tetramer of 290 kD. Dopamine b hydroxylase continues to receive much attention because of its importance in the synthesis of catecholamines and, hence, its possible involvement in psychiatric disorders such as depression. Concentrations of dopamine b hydroxylase in blood vary considerably in the general population, but intra-individual variation is low. Some 4% of the population have nearly undetectable plasma concentrations, with normal concentrations of norepinephrine and epinephrine. Extremely low plasma concentrations of dopamine b hydroxylase seems to be inherited monogenetically by an autosomal codominant mechanism. Recently, Zabetian et al. provided strong arguments that an allelic variant in the 59 flanking region (21021) is the major quantitative trait locus that determines plasma concentrations of dopamine b hydroxylase. Absence of dopamine b hydroxylase also has been described in conjunction with nearly undetectable concentrations of norepinephrine and epinephrine, hugely elevated concentrations of dopamine, and a syndrome of sympathetic failure. This is compatible with defective conversion of dopamine to norepinephrine by dopamine b hydroxylase, and it therefore can be designated as dopamine b hydroxylase deficiency syndrome. This phenotype seems to be transmitted as a recessive trait, and it can be treated successfully by administration of L-threo-3,4-dihydroxyphenylserine, which can be decarboxylated by aromatic-L-amino acid decarboxylase into norepinephrine. Recently, two mutations associated with dopamine b hydroxylase deficiency syndrome were identified in the DBH gene. We aimed to identify mutations in DBH that cause dopamine b hydroxylase deficiency syndrome in four families with members who had an orthostatic syndrome with undetectable concentrations of dopamine b hydroxylase and high concentrations of dopamine. We related our findings to the 21021 allelic variant of the DBH gene and to low plasma concentrations of dopamine b hydroxylase in these families and in healthy people.