Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency

Abstract

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially.

Keywords: L-DOPS; dopamine beta hydroxylase (DBH) deficiency; epinephrine; hypomagnesaemia; neurogenic orthostatic hypotension; neurotransmitter disorders; norepinephrine.

FIGURE 1

Simplified scheme of catecholamine synthesis and breakdown in DBH‐deficiency. Figure 1 depicts the simplified scheme of the biosynthesis and catabolism of catecholamines (dopamine, norepinephrine, and epinephrine), and shows the metabolic block in DBH‐deficiency (black bar). The artificial compound L‐DOPS can bypass this block because it can be converted to norepinephrine using the enzyme AADC. Breakdown of catecholamines can involve multiple steps (dashed arrows) and differs in different body compartments. HVA is the major stable end‐product of dopamine catabolism in cerebrospinal fluid, blood and urine. MHPG is the major end‐product of (nor)epinephrine catabolism in cerebrospinal fluid. NMET and MET are breakdown products of norepinephrine and epinephrine in the peripheral circulation and urine, VMA is the major common end‐product of (nor)epinephrine catabolism. AADC, aromatic l‐amino acid decarboxylase; ADH, alcohol dehydrogenase; DBH, dopamine beta hydroxylase; DHPG, dihydroxyphenylglycol; COMT: catechol‐O‐methyltransferase; HVA, homovanillic acid; L‐DOPA, L‐3,4 dihydroxyphenylalanine; L‐DOPS: l‐threo‐3,4‐dihydroxyphenylserine; MAO, monoamine oxidase; MET, metanephrine; MHPG, 3‐methoxy‐4‐hydroxyphenylglycol; NMET, normetanephrine; PNMT, phenylethanolamine N‐methyltransferase; VMA, vanillylmandelic acid

FIGURE 2

Schematic representation of pathogenic variants in the dopamine beta hydroxylase gene and pathogenic variants in DBH deficiency. Introns are shown in gray, exons in black and numbered 1 to 12, and UTR's in dark‐gray. Intron lengths are not to scale, while exon sizes are. The coding DNA positions of the first bases of each exon are shown above the schematic. In DBH‐deficiency, 2 intronic pathogenic variants and 8 exonic pathogenic variants have been described sofar, and are depicted under the schematic. The HGVS nomenclature is done using reference sequence NM_000787.4. The respective protein variants are given in Table 1

FIGURE 3

Twenty‐four hours bloodpressure measurements in one patient before and during L‐DOPS treatment. Twenty‐four hours blood pressure measurements in one patient before (left panel) and during (right panel L‐DOPS treatment. The night is shaded in gray. bpm, beats per minute; Dia, diastolic blood pressure; HF, heart frequency; MAP, mean arterial pressure; Sys: systolic blood pressure