D Robertson, V Haile, S E Perry, R M Robertson,... 1991;18:1-8 doi: 10.1161/01.HYP.18.1.1 Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation.

Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation.
D Robertson, V Haile, S E Perry, R M Robertson, J A Phillips, 3rd and I Biaggioni
Hypertension. 1991;18:1-8
doi: 10.1161/01.HYP.18.1.1
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Brief Review
Dopamine /8-Hydroxylase Deficiency
A Genetic Disorder of Cardiovascular Regulation
David Robertson, Virginia Haile, Sharon E. Perry,
Rose Marie Robertson, John A. Phillips III, and Italo Biaggioni
Dopamine /3-hydroxyIase (DBH) deficiency is a genetic disorder in which affected patients
cannot synthesize norepinephrine, epinephrine, and octopamine in either the central nervous
system or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter in
their noradrenergic neurons. Neonates with DBH deficiency have had episodic hypothermia,
hypoglycemia, and hypotension, but survivors sometimes cope relatively well until late
childhood when overwhelming orthostatic hypotension profoundly limits their activities. The
hypotension may be so severe that clonic seizures supervene. Most currently recognized
patients are young or middle-aged adults. The diagnosis is established by the observation of
severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is
much less than one. (Hypertension 1991;18:l-8)
orepinephrine and epinephrine are the most
critical determinants of minute-to-minute
neural regulation of local vascular tone and
thus arterial pressure. Moreover, they are also involved in the regulation of autonomic outflow at the
level of the brain stem and spinal cord. This outflow
has an important influence on cardiac, renal, and
vascular function. In the periphery, the effects of
norepinephrine generally result in the elevation of
blood pressure, but within the central nervous system
this neurotransmitter often depresses sympathetic
outflow, yielding a fall in blood pressure. Thus, any
factor that alters the synthesis of norepinephrine and
epinephrine can perturb blood pressure regulation at
several interacting levels.
The enzyme dopamine /3-hydroxylase (DBH) (EC is required for conversion of dopamine to
norepinephrine (and thus epinephrine), but tyrosine
hydroxylase rather than DBH is the rate-limiting step
in norepinephrine synthesis under almost all circumstances in humans (Figure 1). Even in situations of
high sympathetic activation, such as prolonged treadmill exercise, norepinephrine and epinephrine remain the predominant circulating catecholamines,
with minimal step-up in plasma dopamine levels.1
This indicates that in healthy subjects under ordinary
From the Departments of Pharmacology, Pediatrics, and Medicine, Clinical Research Center, Vanderbilt University, Nashville,
Supported in part by grants HL-36984, HL-44589, and RR
00095 from the National Institutes of Health and by the Vanderbilt
Center for Space Physiology and Medicine.
Address for correspondence: David Robertson, MD, Autonomic Dysfunction Center, AA-3228 MCN, Vanderbilt University,
Nashville, TN 37232-2195.
circumstances, DBH activity is sufficient for the
needs of autonomic cardiovascular regulation.
Recently we and others2-3 have recognized that there
are occasional circumstances in which neuronal DBH
activity is inadequate. The syndrome of severe DBH
deficiency2 is a dramatic example of such a case. The
survival of individuals with an essentially complete
absence of norepinephrine into adulthood strongly
suggests that individuals with partial enzyme deficiency
will also be found. Unlike previously described forms of
autonomic failure, this disorder has been localized to a
discrete enzymatic defect, which has enabled investigators to approach its treatment more rationally than has
heretofore been possible. Recognition of the disorder
has also led to greater understanding of autonomic
control of the circulation.
Dopamine ^-Hydroxylase
DBH catalyzes the conversion of dopamine to
norepinephrine.4-5 It is unique among the catecholamine-synthesizing enzymes in that it is located almost exclusively in the chromaffin granules of the
adrenal medulla and the large dense-core synaptic
vesicles of noradrenergic neurons.6 It is found in both
peripheral and central noradrenergic and adrenergic
neurons. DBH exists in both the dimeric and tetrameric forms, with two copper atoms per monomeric subunit.7-8 The four subunits are linked by
disulfide bridges into two dimers, which are joined to
each other by noncovalent bonds. The copper is
essential for enzyme activity. DBH also requires
molecular oxygen and ascorbic acid for enzyme activity. DBH is not substrate-specific, since it oxidizes
almost any phenylethylamine to its corresponding
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Vol 18, No 1 July 1991
tyroslne Xhydroxylase
NH 2
DOPA | decarboxylase
n u
FIGURE 1. Schematic diagram shows synthesis of norepinephrine and epinephrine. All these enzymatic steps take place
in the cytoplasm except for conversion of dopamine to norepinephrine. Dopamine fi-hydroxylase is confined to the neurotransmitter vesicles.
phenylethanolamine (including the hydroxylation of
tyramine into octopamine) and converts the a-methyldopa metabolite a-methyldopamine to a-methylnorepinephrine. The Km of this enzyme for dopamine
is approximately 5xlO" 3 M.9
Vesicular DBH occurs in both a soluble and a
membrane-bound form.10 These are present in approximately equal amounts. The soluble enzyme is released
into the synaptic cleft at the time of vesicular exocytosis
and is presumably the source of the enzyme present in
blood. Much recent study has gone into the identification of the differences between these two forms.11
Current evidence suggests that both forms of DBH
originate from a single gene and that the soluble form
is derived from the membrane bound form.12 There is
evidence that neither gh/piation13 nor retained signal
peptide14 can account fully for the membrane-binding
characteristic of the enzyme.
The sequence of DBH complementary DNA
(cDNA) was reported by Lamouroux et al15 in 1987.
The cDNA was cloned from a human pheochromocytoma expressing high levels of DBH activity. The
corresponding polypeptide chain contained 603
amino acids corresponding to an unmodified protein
of 64,862 Da, preceded by a cleaved signal peptide of
25 residues. Kobayashi and coworkers16 subsequently
showed that there is a single DBH gene of approximately 23 kb and that it is composed of 12 exons, with
exon 12 providing two alternative polyadenylation
sites. Restriction analysis of the positive DBH clones
revealed two types of DBH cDNA, type A (2.7 kb)
and type B (2.4 kb). The ratio of type A and B
messenger RNAs (mRNAs) in the pheochromocytoma was 5:1. Four clones were selected for further
analysis. Sequencing of the cDNA inserts demonstrated that type A cDNA (DBH-1) differed from
type B cDNA (DBH-2) by an additional 300 nucleotides in the 3' untranslated region, the former set of
clones being 2.7 kb. The clones in each set differed
from each other at six nucleotides found in various
portions of the cDNA (Table 1). This was the first
published data for polymorphism at the DBH locus
at the molecular level, although other restriction
endonuclease restriction fragment length polymorphisms have subsequently been reported. Transcription regulatory sites such as TATA, CCAAT,
CACCC, and GC boxes were identified in the 5'
flanking region as were sequences homologous to
glucocorticoid and cyclic AMP response elements.16
It is not known if the primary structure of DBH
reported by Lamouroux et al15 is Type A or B, but it
cannot be grouped with either set of cDNAs published by Kobayashi et al.16 Furthermore, the nucleotide difference reported at position 910 would cause
an amino acid change (Ala versus Ser), and there is
also a change from Arg to Cys at position 1,642,
which corresponds to Kobayashi's position 1,603.
Serum DBH activity assays have been widely used
during the past 25 years.17 They are based on the
enzymatic conversion of a substrate (e.g., tyramine)
into a corresponding product (e.g., octopamine) by
TABLE 1. Nucleotide Differences Among Published Dopamine /J-Hydroxylase Gene Sequences
Kobayashi 1,2
Kobayashi 3,4
Among the four currently published (presumably normal) dopamine /J-hydroxylase sequences, there are seven
nucleotides at which differences are noted. Only two of these (910 and 1,603) are at sites that result in different amino
acids. Kobayashi 1,2 and Kobayashi 3,4 represent the four clones sequenced by these investigators.16 They also
sequenced the clone from the Maniatis genomic library.16
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Robertson et al
DBH, taking advantage of the non-substrate specificity of the enzyme. Inhibitors of DBH are normally
present in serum but can be inactivated by iV-ethylmaleimide or by copper sulfate.9 In addition to serum
DBH activity measurements, the actual amount of
enzyme present can be determined by radioimmunoassay.18 When antibodies to homologous protein are
used, there is usually an excellent correlation between immunoreactive DBH and DBH enzymatic
It was hoped that measurements of serum DBH
could be used to assess adrenergic and noradrenergic
function in humans. However, it is now recognized
that the wide interindividual variation in enzyme
activity observed in humans is mostly due to a genetic
trait. Furthermore, within individuals, acute changes
in adrenergic function result in changes in DBH
activity that are small in magnitude in comparison
with changes in plasma catecholamine values. These
facts have dampened enthusiasm for the use of serum
DBH as a measure of acute alterations in adrenergic
activity in humans.19
Biochemical genetic studies of the 1970s and early
1980s using these assays documented polymorphism
in DBH in apparently healthy individuals. Serum
DBH enzymatic activity and immunoreactive protein
increase from low levels in young children to high
levels in most adults, but levels of both remain low in
a minority.20 Fifty to seventy percent of the variance
in basal human serum DBH activity results from this
genetic variation in DBH levels. In linkage studies
this trait has been mapped to chromosome 9q34, the
region containing the gene for DBH.21-23 In addition,
approximately 8% of a randomly selected population
was found to have a thermolabile form of serum
DBH that exhibited familial aggregation.24 This thermolability is a characteristic of the DBH molecule
itself and depends on an interaction with oxygen.
Although one would expect such a characteristic to
derive from the structural DBH gene, thermolability
has not been mapped to 9q34.
Although in the vast majority of individuals there is a
good correlation between serum immunoreactive and
enzymatic DBH levels, some persons have a disparity.19
These individuals have much higher amounts of immunoreactive material than enzymatic DBH activity. This
disparity may reflect changes in the active site and
could indicate subclinical impaired function. There is
clearly a familial aggregation of this trait
Clinical Presentation of Dopamine
/J-Hydroxyiase Deficiency
In 1986, we reported a congenital syndrome characterized by severe orthostatic hypotension, noradrenergic failure, and ptosis of the eyelids.2 This
disorder was simultaneously recognized in the Netherlands.3 Based on a battery of biochemical and
physiological tests, it was determined that this disorder was due to a deficiency of DBH. The characteristics of patients with DBH deficiency are distinct
from previously recognized forms of autonomic dys-
Dopamine 0-Hydroxylase Deficiency
Major Forms of Primary Autonomic Failure
Bradbury-Eggleston syndrome (idiopathic orthostatic
Onset late in life
Sympathetic and parasympathetic failure
Absent or minimal other neurological involvement
Plasma norepinephrine/dopamine ratio greater than 1
Shy-Drager syndrome (multiple system atrophy)
Onset in mid to late life
Sympathetic and parasympathetic failure
Other neurological involvement (extrapyramidal, cerebellar,
Plasma norepinephrine/dopamine ratio greater than 1)
Riley-Day syndrome (familial dysautonomia)
Congenital onset and premature mortality
Ashkenazi Jewish extraction
Sympathetic and parasympathetic involvement
Emotional lability
Plasma norepinephrine/dopamine ratio greater than 1
Dopamine /3-hydroxylase deficiency
Congenital onset
Sympathoadrenomedullary failure (orthostatic hypotension)
Intact sweating
Parasympathetic sparing
Plasma norepinephrine/dopamine ratio much less than 1
function (see Table 2) and in some cases the anamnesis may almost provide the diagnosis.
The syndrome differs from familial dysautonomia25
and various other autonomic disorders seen in adults26
in that the peripheral defect can be localized to the
noradrenergic and adrenergic tissues. There is virtual
absence of norepinephrine and epinephrine, coupled
with greatly increased dopamine in plasma, cerebrospinal fluid, and urine.2-3 Furthermore, there is no evidence of other neurological defects, either central or
peripheral.27 The full clinical spectrum of DBH deficiency is still not known because of the limited number
of patients who have been reported. The description
here is based primarily on the data in the first six
published cases2-*-28-31 (Table 3). It is likely that many
features not currently recognized will ultimately be
found to be associated with the disorder as the number
of reported cases increases. Conversely, some abnormalities found in individual patients may ultimately
prove to be fortuitous associations.
Although parents of DBH-deficient patients have
appeared normal,2-31 a history of spontaneous abortions and stillbirths has been noted in mothers of
affected patients.3 The perinatal period in DBHdeficient subjects has sometimes been particularly
difficult.2-3-30 Delay in opening of the eyes (2-week
delay in one case) may occur30 and ptosis of eyelids
has occurred in most infants.2-3-29-30 The infants have
occasionally been so sickly at birth that parents were
advised their survival was unlikely.2 Although records
are incomplete in some cases, it appears that hypo-
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Vol 18, No 1 July 1991
Characteristics of Dopamine 0-Hydroxylase Deficiency
Severe orthostatic hypotension
Impaired ejaculation (n=2)
Plasma dopamine > > > > plasma norepinephrine
Ptosis of eyelids
Complicated perinatal course
Hyperextensible/hyperflexible joints
High palate
Nasal stuffiness
Mild behavioral changes
Seizures (with hypotension)
Sluggish deep tendon reflexes
Weak facial musculature
Hypotonic skeletal muscles
Raised blood urea nitrogen
Atrial fibrillation
T-wave abnormalities (ECG)
Data are taken from the first six published cases.^3-28-31 ECG,
tension, hypoglycemia, and hypothermia have occurred.3 The causes of hypoglycemia and hypothermia are not fully understood at present, but
epinephrine has a well-characterized calorigenic effect in animals, and excessive dopamine may reduce
temperature in animals. Vomiting occurred four
times in the first year of life in one patient.3 The
hypoglycemia and hypothermia have also been seen
primarily in the first year of life. Sometimes seizures
have occurred, probably because of hypoglycemia or
As children, DBH-deficient patients have had a
markedly reduced ability to exercise because of postural hypotension occurring with exertion.2-31 The
syncope associated with this postural hypotension has
led to trials of anticonvulsive medications,2 even
though the electroencephalogram did not suggest a
seizure disorder.
Symptoms have generally worsened considerably
in late adolescence and early adulthood.2-30-31 Patients complain of profound orthostatic hypotension,
especially early in the day and during hot weather or
after alcohol ingestion. There is greatly reduced
exercise tolerance, ptosis of the eyelids, nasal stuffiness,2-30 and prolonged or retrograde ejaculation30-31;
the retrograde ejaculation is recognized by the presence of semen in the postejaculation urine void.
Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally,
chest pain. Some patients have adopted novel strategies for maintaining upright posture. One patient
crossed his legs at a 30° angle and leaned his torso 30°
forward, placing his right hand on his right anterior
thigh for support.30 Sexual maturation has been
normal, with menarche occurring at ages 12-14.2-29-31
The physical examination reveals a low normal
supine blood pressure and a normal heart rate but an
upright blood pressure less than 80 mm Hg systolic.
Heart rate rises on standing, but certainly inadequately when one considers the magnitude of the
hypotension in the upright posture. Patients are
usually unable to stand motionless more than 30
seconds. Pupils are somewhat small but respond to
light and accommodation. Parasympatholytics usually dilate the eye appropriately, but in two patients
homatropine has failed to do so.3-29 There is usually
ptosis of the eyelids. Joints may be hyperflexible29 or
hyperextensible.30 In particular, sweating, a sympathetic nonnoradrenergic function, is normal.
Many specialized tests differentiate these patients
from those with familial dysautonomia (RUey-Day
syndrome). Cholinergic sensitivity, as assessed by the
ophthalmic response to conjunctival administration
of 2.5% methacholine, was normal in that there was
no response. Intradermal histamine evoked a typical
flare reaction, whereas this does not occur in familial
dysautonomia. These patients are further distinguished from familial dysautonomia in that the DBHdeficient patients have 1) normal tearing, 2) intact
corneal and deep tendon reflexes, 3) normal sensory
function, and 4) normal senses of taste and smell.
Also, subjects thus far recognized have not been of
Ashkenazi Jewish extraction.
There have been other clinical abnormalities in
these patients that bear a still uncertain relation to
the pathology as we understand it. Two of six
subjects have evidence of mild renal failure30-31 and
at least two patients have experienced recurrent
hypomagnesemia.27-30 Atrial fibrillation, which
proved remarkably resistant to therapy, developed
in one patient at age 40.30
Dopamine /3-Hydroxylase Deficiency: Diagnosis
The patients with DBH deficiency so far described
have had such striking abnormalities in catecholamine
metabolism that they are readily distinguishable from
patients with all other known disorders. The combination of minimal or undetectable plasma norepinephrine
with a fivefold to 10-fold elevation of plasma dopamine
is probably pathognomonic of the disorder (Table 4).
Indeed, perhaps the only other disorder in which
plasma dopamine exceeds plasma norepinephrine is
Menkes kinky hair disease, a dramatic illness associated
with profound mental retardation.32
The Menkes syndrome is an X-linked recessive
disorder characterized by early growth retardation,
stubby and white hair, hypopigmentation, arterial
rupture and thrombosis, urinary tract diverticulae,
and focal cerebral and cerebellar degeneration. Survival beyond 10 years is rare, and brain damage is
usually severe even in these individuals.
DBH deficiency would probably have been recognized earlier were it not for the fact that most
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Robertson et al
TABLE 4. Autonomlc Maneuvers in Dopamine
0-Hydroxylase Deficiency
Orthostatic hypotension >40 mm Hg systolic
Abnormal Vdlsalva maneuver
Sweating present
Sinus arrhythmia present
Atropine tachycardia >25 bcats/min
Pressor clonidine response
Absent pressor tyramine response
Pressor efficacy of DOPS
Absent pressor isometric handgrip > 10 mm Hg
Absent cold pressor response > 10 mm Hg
DOPS, dihydroxyphenylserine.
medical centers tend to measure norepinephrine and
epinephrine but not dopamine in the evaluation of
patients with autonomic dysfunction. Without comparative details about the levels of norepinephrine
and dopamine and the patterns of their respective
metabolites, the special nature of the enzymatic
defect in this disorder can be entirely missed. Such
patients were probably considered to have an atypical
form of the Bradbury-Eggleston syndrome or idiopathic orthostatic hypotension.33 In addition, commonly used radioenzymatic methods for catecholamine determinations have the disadvantage of a
small, but significant, crossover of dopamine into
epinephrine. Because of normally low levels of dopamine, this is usually of minor practical importance.
However, in a setting of elevated dopamine levels, as
present in DBH deficiency, a proportion of dopamine
may be erroneously measured as epinephrine.2
Plasma dopamine levels in DBH-deficient subjects
approximate plasma norepinephrine levels in normal
subjects, but with greater variability. This is believed
to occur because dopamine, rather than norepinephrine, is being stored and released by noradrenergic
neurons in DBH-deficient subjects. For this reason,
plasma dopamine levels respond to various stimuli
that would elicit an increase in plasma norepinephrine levels in normal subjects. Thus, for example, a
change from supine to upright posture will double or
triple the plasma dopamine level. Likewise, the administration of a central suppressant of sympathetic
activity such as clonidine34 will greatly reduce the
plasma dopamine level. Plasma dopamine levels have
thus been shown to be greatly elevated by insulin
hypoglycemia,3 edrophonium,3 tyramine,2 tilt,3-31 and
upright posture.2 Perhaps because of high levels of
dopamine, plasma prolactin is low in this disorder.3*27
It is noteworthy that plasma dopa levels are also
raised twofold to threefold while the enzyme dopa
decarboxylase is also normal in plasma.3
Metabolites of norepinephrine that have been
measured have been low or absent in plasma, urine,
and cerebral spinal fluid (CSF). Conversely, dopamine metabolites such as homovanillic acid and
3-methoxytyramine are raised. Determination of
Dopamine 0-Hydroxylase Deficiency
whether norepinephrine exists at all in patients with
DBH deficiency must await further investigations
and improvements in assay methodology. A low, but
apparently detectable, level of vanillyl mandelic acid
was found in the urine of three patients,2-31 and a low,
but detectable, level of MHPG was found in the CSF
of another patient.3 In other patients, these metabolites have been beneath the limits of detection of the
assay. Whether these reflect genuine differences in
pathology or the limitations of the respective assays
remains to be seen.
Skin biopsy results reported in three subjects have
not stained for DBH, but tyrosine hydroxylase was
present in all.2'31 In the two subjects in whom data
have been reported, neuropeptide Y, calcitonin
gene-related peptide, substance P, and vasoactive
intestinal peptide have all been present.31
Physiological tests of autonomic function also provide diagnostic information of great specificity. Autonomic tests that measure sympathetic noradrenergic and adrenergic function are uniformly abnormal.
Cold pressor testing (immersion of a hand in ice
water for 1 minute) causes either a fall or no change
in blood pressure. Isometric handgrip exercise (sustained handgrip for 3 minutes) fails to significantly
increase blood pressure. The Valsalva maneuver
results in a profound fall in blood pressure together
with an increase in heart rate reflecting parasympathetic withdrawal. The phase IV overshoot of the
Valsalva maneuver does not occur. Hyperventilation
causes a fall in blood pressure, as is also the case in
patients with the Bradbury-Eggleston syndrome. In
contrast to the absence of sympathetic activation, the
presence of sweating underscores the integrity of
sympathetic cholinergic fibers. Moreover, parasympathetic function is preserved since these patients
have normal sinus arrhythmia. This selective sympathetic noradrenergic impairment is quite characteristic of DBH deficiency. Other forms of autonomic
failure demonstrate both sympathetic and parasympathetic involvement.33-35'36
DBH deficiency shares many pharmacological features of other forms of autonomic failure. There is a
severalfold hypersensitivity to a r adrenergic receptor
agonists and ^-adrenergic receptor agonists. This is
also found in other forms of autonomic failure and
represents a compensatory receptor upregulation as
a result of the chronic relative depletion of catecholamines.37 This phenomenon is analogous to other
forms of "denervation hypersensitivity." Tyramine is
an indirect-acting pressor amine that will induce
norepinephrine release from adrenergic nerve terminals. Tyramine, in intravenous doses of 2-3 mg, will
raise plasma norepinephrine and blood pressure in
normal subjects and in patients with other types of
autonomic failure,37 but no blood pressure elevation
occurred even with 6-8 mg of tyramine in DBHdeficient subjects. Plasma dopamine, instead of norepinephrine, is increased following the administration of tyramine in these patients.
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Vol 18, No 1 July 1991
Propranolol, a £-adrenergic receptor antagonist,
does not lower the basal heart rate in these patients,
but pindolol, a /3-antagonist with sympathomimetic
properties, raises heart rate significantly. Intravenous
atropine raises heart rate by 40-60 beats per minute.
The respiratory arrhythmia that occurs in the baseline state in DBH deficiency disappears with the
administration of atropine. Taken together, these
observations imply normal parasympathetic, but defective sympathetic, control of heart rate. Pindolol, a
^-adrenergic receptor antagonist with some sympathomimetic activity, raises heart rate. It is also of
interest that atropine elicits a much more pronounced pressor effect in DBH-deficient subjects
than in normal subjects.23
Clonidine acts on a2-adrenergic receptors or imidazole receptors in the brain stem to reduce sympathetic outflow and lower blood pressure.34 It can also
exert peripheral pressor effects by stimulation of
vascular a2-adrenergic receptors.38 DBH-deficient
patients have no fall in seated mean arterial pressure
after the administration of clonidine, probably reflecting the fact that in these patients, blood pressure
is not maintained by sympathetic tone. On the contrary, dramatic increases in blood pressure are seen
with higher doses of this agent. It is noteworthy that
the heart rate decreases in DBH-deficient patients
after the administration of clonidine, even though
blood pressure does not fall, consistent with the
postulated central parasympathetic role in clonidineinduced bradycardia.
Finally, direct measurements of sympathetic nerve
traffic to the vasculature of the skeletal muscle have
been carried out using microneurography in a patient
with DBH deficiency.39 They confirm that sympathetic neural traffic is present and regulated in a
qualitatively normal fashion.
Dopamine 0-Hydroxylase Deficiency: Therapy
DBH-deficient patients have been difficult to treat
using standard therapeutic approaches for autonomic failure. Most have failed empirical therapy
with anticonvulsant agents before diagnosis of orthostatic hypotension. Fludrocortisone, at dosages of
0.1-0.8 mg daily, has been used to raise blood
pressure with some benefit,2 but marked orthostatic
hypotension still occurs. Likewise, indomethacin (50
mg four times daily) has been of limited benefit in
raising blood pressure in these subjects; furthermore,
one patient had aggressive ideation on this drug.30
Monoamine oxidase inhibition (tranylcypromine) has
produced paranoid thinking.30 There has been some
pressor response to phenylpropanolamine (25 mg
and 50 mg), presumably owing to the denervation
hypersensitivity of the patients' vascular a-adrenergic
Because both plasma dopa and dopamine levels were
elevated in DBH-deficient patients, the vasodepressor
effects of dopamine, either through direct vasodilatation or by means of a diuretic effect at the level of the
kidney, were proposed as possible explanations for the
striking severity of low blood pressure in these patients.40-41 It was hypothesized that if dopa and dopamine were reducing blood pressure in DBH-deficient
subjects, the administration of metyrosine (a-methyl/wra-tyrosine) might prove therapeutic.28
In normal subjects, metyrosine blocks tyrosine
hydroxylase, the enzyme leading to the synthesis of
dopa. This results in reduced levels of dopamine and
norepinephrine, and therefore blood pressure falls,
particularly when the subject is in the upright posture. We hypothesized that our patients might have
such high dopamine levels that paradoxical pressor
effects might occur. Because metyrosine is a depressor in healthy individuals, a failure of metyrosine to
affect blood pressure, or a reduction in blood pressure with metyrosine, would not support a contribution of dopamine to the low blood pressure in our
patients. Conversely, a rise in blood pressure with
metyrosine would suggest that dopa and dopamine
were indeed exerting depressor effects and that these
effects could be attenuated by an agent that reduced
manufacture and release of dopamine. In the event,
metyrosine given in doses used to treat pheochromocytoma exerted a dramatic pressor effect, which
appeared to correlate with the metyrosine-associated
reduction in urinary dopamine excretion.28
In spite of this initially favorable response to metyrosine, much more experience with it will be required
before it can be recommended for treatment Patients
receiving metyrosine experienced significant sedation;
one patient experienced a marked dystonic reaction,28
but fortunately responded promptly to a 10 mg intravenous dose of diphenhydramine.
In an effort to achieve more specific therapy, we
explored the use of dihydroxyphenylserine (DOPS)
in these patients.42 We administered DOPS in the
hope that it would result in an endogenous conversion (by dopa decarboxylase) of the drug to norepinephrine. We believed this might occur because
DBH is not needed for the conversion of DOPS to
norepinephrine and, thus, this enzyme could be
bypassed in the patients in whom it is defective. We
hypothesized that there would be an increase in
plasma norepinephrine following the administration
of DOPS.
The administration of DOPS to patients with DBH
deficiency has resulted in dramatic increases in blood
pressure and concomitant restoration of plasma and
urinary levels of norepinephrine toward normal.42-43
There has been an associated modest decline in
dopamine levels, as though the provision of norepinephrine to intraneuronal sites might be reducing the
activity of tyrosine hydroxylase through feedback
inhibition. The increase in plasma norepinephrine
was highly correlated with the increase in mean
arterial blood pressure. Standing time was greatly
increased after administration of DOPS.
We could not be certain whether de novo synthesis of
norepinephrine from DOPS occurred in neuronal tissues or in extraneuronal tissues, since dopa decarboxylase activity is present in many extraneuronal tissues.
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Robertson et al Dopamine 0-Hydroxylase Deficiency
However, long-term treatment with DOPS in this disorder is associated with intraneuronaJ restoration of
norepinephrine, which is released on assuming the
upright posture. Thus, DOPS in DBH deficiency appears to be far more effective than any other therapy
for any form of autonomic dysfunction.31-41-42'44
Dopamine /J-Hydroxylase Deficiency: Implications
Although DBH deficiency is probably a rare disease in adults, it could be more common in the
perinatal period. Medical histories of DBH-deficient
patients include near fatal illness during the neonatal
period due to hypotension, hypoglycemia, and hypothermia. We suspect that many DBH-deficient infants succumb undiagnosed at this point, never
reaching childhood and adulthood.
Before recognition of DBH deficiency, it was assumed that humans could not live without norepinephrine. Yet, stretching current assay methodology
to the limit, it is not certain that any norepinephrine
at all is present in the severely affected individuals we
have studied; if it is present in plasma, it is less than
1% of normal.45 Because norepinephrine and its
receptor sites have long been postulated to play a
role in a number of psychiatric disorders, the generally normal29-30 or near-normal31 mood and mental
status of DBH-deficient subjects so far encountered
have elicited great interest among investigators in the
areas of depression and schizophrenia.
Shortly after DBH was recognized as an important
step in catecholamine synthesis, attempts were made
to treat hypertension with DBH inhibitors. Disulfiram (Antabuse, Wyeth-Ayerst Laboratories, Philadelphia, Pa.), a copper chelator, was early recognized
to inhibit DBH.32 Early clinical studies also demonstrated that fusaric acid and its precursor bupicomide
could lower blood pressure in hypertensive subjects
and decrease serum DBH activity.9 However, tachycardia and increased excretion of urinary catecholamines were observed. This apparent contradiction
can be explained by the fact that fusaric acid apparently stimulates the release of catecholamines from
the adrenal gland. More specific and potent DBH
inhibitors are currently being tested as antihypertensive agents. As in our patients, inhibition of DBH
after the administration of SKF 102698 to rats results
in a decrease in plasma and tissue norepinephrine
associated with an increase in dopamine levels.46
Also, as our results with metyrosine suggest, the
hypotensive effects of specific DBH inhibitors may be
related to both a decrease in norepinephrine and an
increase in dopamine with its attendant vasodilatory
and natriuretic effects.
The presence of such a severe deficit in neurotransmitter synthesis encourages us to continue to
search for other disorders of neurotransmitter synthesis.47-48 If DBH deficiency is compatible with life,
it seems likely that phenylethanolamine-Af-methyl
transferase (PNMT) deficiency, a postulated defect
in the synthesis of epinephrine, would also be compatible with life. Indeed, it is possible that in the
adult, PNMT deficiency would be a relatively subtle
abnormality. Because current methods for measuring
epinephrine at most institutions are not sensitive into
the low-normal range, it is likely that PNMT-deficient patients would be easily missed. However,
recognizing them could be important since they
might be subject to significant )3-adrenergic hypersensitivity and hypoglycemia in infancy.
Finally, DBH deficiency provides us with the
unique opportunity to study the role of dopamine not
only in this disorder but also in other forms of
orthostatic hypotension. It also provides a model that
may help us to determine, in general, dopamine's
role in cardiovascular control in humans.40 In normal
subjects, the presence of norepinephrine would obscure the interpretation of any intervention aimed at
modulating dopamine synthesis or action. Our preliminary results suggest that increased endogenous
dopamine is not only a simple marker of the enzymatic defect but that it exerts a tonic depressor
effect, perhaps in relation to its vasodilatory effect, or
more importantly, due to its natriuretic properties.
Most importantly, perhaps, DBH deficiency and its
successful treatment by DOPS encourages us to hope
that other autonomic disorders may one day also
yield to genuinely effective therapeutic interventions.
1. Robertson D, Johnson GA, Robertson RM, Nies AS, Shand
DG, Oates JA: Comparative assessment of stimuli that release
neuronal and adrenomedullary catecholamines in man. Circulation 1979^9:637-643
2. Robertson D, Goldberg MR, Hollister AS, Onrot J, Wiley R,
Thompson JG, Robertson RM: Isolated failure of autonomic
noradrenergic neurotransmission: Evidence for impaired betahydroxylation of dopamine. N EnglJMcd 1986;314:1494-1497
3. Man in't Veld AJ, Boomsma F, Moleman P, Schalekamp
MADH: Congenital dopamine-0-hydroxylase deficiency: A
novel orthostatic syndrome. Lancet 1987;1:183-187
4. Goldstein M: Inhibition of norepinephrine biosynthesis at the
dopamine-beta-hydroxylation stage. Pharmacol Rev 1966;18:
5. Kaufman S, Friedman S: Dopamine-/3-hydroxylase. Pharmacol
Rev 1965;17:71-100
6. Axelrod J: Dopamine-/3-hydroxylase: Regulation of its synthesis and release from nerve terminals. Pharmacol Rev 1972;24:
7. Sabban EL, Goldstein M: Subcellular site of biosynthesis of
the catecholamine biosynthetic enzymes in bovine adrenal
medulla. / Neurochem 1984;43:1663-1668
8. Sabban EL, Kuhn LJ, Levin BE: In vivo biosynthesis of two
subunit forms of dopamine beta-hydroxylation in rat brain. /
Neurosci 1987;7:192-200
9. Nagatsu T: Dopamine beta-hydroxyiase, Boulton RR, Baker
GB (eds): Neuromethods I. Clifton, NJ, Humana, 1986, chap 3,
pp 79-116
10. Sokoloff RL, Frigon RP, O'Connor DT: Dopamine-0hydroxylase: Structural comparisons of membrane-bound versus soluble forms from adrenal medulla and pheochromocytoma. / Neurochem 1985;44:411-420
11. O'Connoar DT, Frigon RP, Stone RA: Human pheochromocytoma dopamine-beta-hydroxylase: Purification and molecular parameters of the tetramer. Mol Pharmacol 1979;16:
12. Dhawan S, Duong LE, Ornberg RL, Fleming PJ: Subunit
exchange between membranous and soluble forms of bovine
dopamine-beta-hydroxyiase. / Bid Chan 1987;262:1869-1875
Downloaded from http://hyper.ahajournals.org/ by guest on September 9, 2014
Vol 18, No 1 July 1991
13. Stewart LC, Klinman JP: Bovine membranous dopamine
beta-hydroxylase is not anchored via covalently attached phosphatidylinositol. / Biol Chan 1988;263:12183-12186
14. Taylor CS, Kent UM, Fleming PJ: The membrane-binding
segment of dopamine beta-hydroxylase is not an uncleaved
signal sequence. / Biol Chan 1989;264:14-16
15. Lamouroux A, Vigny A, Faucon Biguet N, Darmon MC,
Franck R, Henry J-P, Mallet J: The primary structure of
human dopamine-beta-hydroxylase: Insights into the relationship between the soluble and the membrane-bound forms of
the enzyme. EMBO J 1987;6:3931-3937
16. Kobayashi K, Kurosawa Y, Fujita K, Nagatsu T: Human
dopamine beta-hydroxylase gene: Two mRNA types having
different 3'-terminal regions are produced through alternative
poryadenylation. Nucleic Acids Res 1989;17:1089-1102
17. Weinshilboum R, Axelrod J: Serum dopamine-betahydroxylase activity. Cue Res 1971;28:307-315
18. O'Connor DT, Levine GL, Frigon RP: Homologous radioimmunoassay of human plasma dopamine-0-hydroxylase: Analysis of homospecific activity, circulating plasma pool and
intergroup differences based on race, blood pressure and
cardiac function. /Hypertens 1983;l:227-233
19. Weinshilboum R: Catecholamine biochemical genetics, in
Trendelenburg U, Weiner N (eds): Catecholamines II. Berlin,
Springer-Verlag, 1989, chap 19, pp 391-426
20. Weinshilboum RM, Schrott HG, Raymond FA, Weidman
WH, Elveback LR: Inheritance of very low serum dopaminebeta-hydroxyiase activity. Am J Hum Genet 1975;27:573-585
21. Craig SP, Buckle VJ, Lamouroux A, Mallet J, Craig IW:
Localization of the human dopamine beta hydroxylase (DBH)
gene to chromosome 9q34. Cytogenet Cell Genet 1988;48:48-50
22. Goldin LR, Gershon ES, Lake CR, Murphy DL, McGinniss
M, Sparkes RS: Segregation and linkage studies of plasma
DBH: Possible linkage between the ABO locus and a gene
controlling DBH activity. Am J Hum Genet 1981^34:250-262
23. Wilson AF, Elston RC, Siervogel R, Tran LD: Linkage of a
gene regulating dopamine-beta-hydroxylase activity and the
ABO blood group locus. Am J Hum Genet 1988;42:160-166
24. Dunnette J, Weinshilboum R: Family studies of plasma dopamine-beta-hydroxylase thermal stability. Am J Hum Genet
25. Axelrod FB, Pearson J: Congenital sensory neuropathies:
Diagnostic distinction from familial dysautonomia. Am J Dis
Child 1984;138:947-954
26. Robertson D, Biaggioni I (eds): Disorders of the Autonomic
Nervous System. London, Harwood, 1991 (in press)
27. Perry SE, Summar ML, Phillips JA III, Robertson D: Linkage
analysis of the human dopamine-^-hydroxylase gene. Genomics (in press)
28. Biaggioni I, Hollister AS, Robertson D: Dopamine in dopamine-beta-hydroxylase deficiency. N EnglJMed 1987;317:1415
29. Man in't Veld AJ, Boomsma F, Julien C, Lenders J, van den
Meiracker AH, Tulen J, Moleman P, Thien I, Lamberts SJ,
Schalekamp MADH: Patients with dopamine-/3-hydroxylase
deficiency. A lesson in catecholamine physiology. Am J Hypertens 1988;l:231-238
30. Biaggioni I, Goldstein DS, Atkinson T, Robertson D: Dopamine-beta-hydroxylase deficiency in humans. Neurology 1990;
31. Mathias CJ, Bannister RB, Cortelli P, Heslop K, Polak JM,
Raimbach S, Springall DR, Watson L: Clinical autonomic and
therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthe-
size noradrenaline from dopamine because of a deficiency in
dopamine beta hydroxylase. Q J Med 1990;75:617-633
Hoeldtke RD, Cavanaugh ST, Hughes JD, Mattis-Graves K,
Hobnell E, Grover WD: Catecholamine metabolism in kinky
hair disease. Pediatr Neurol 1988;4:23-26
Bradbury S, Eggleston C: Postural hypotension: A report of
three cases. Am Heart J 1925;l:73-75
Robertson D, Goldberg MR, Tung CS, Hollister AS, Robertson D: Use of alpha2-adrenoreceptor agonists and antagonists
in the functional assessment of the sympathetic nervous system. J Clin Invest 1986;78:576-581
Shy GM, Drager GA: A neurological syndrome associated
with orthostatic hypotension. Arch Neurol 1960;2:511-527
Schatz II: Orthostatic Hypotension. Philadelphia, FA Davis,
1986, pp 1-128
Robertson D, Hollister AS, Carey EL, Tung CS, Goldberg
MR, Robertson RM: Increased vascular betaradrenoreceptor
responsiveness in autonomic dysfunction. / Am Coll Cardiol
Robertson D, Goldberg RM, Hollister AS, Wade D, Robertson RM: Clonidine raises blood pressure in severe idiopathic
orthostatic hypotension. Am J Med 1983;74:193-200
Rea RF, Biaggioni I, Robertson RM, Haile V, Robertson D:
Reflex control of sympathetic nerve activity in dopamine
^-hydroxylase deficiency. Hypertension 1990;15:107-112
Kuchel O, Debinski W, Larochelle P: Isolated failure of
autonomic noradrenergic neurotransmission (letter). N Engl J
Med 1986;315:1357-1358
DiBona GF: Neural mechanisms in body fluid homeostasis.
Fed Proc 1986;45:2871-2877
Biaggioni I, Robertson D: Endogenous restoration of norepinephrine by precursor therapy in dopamine-beta-hydroxylase
deficiency. Lancet 1987;2:1170-1172
Man in't Veld AJ, Boomsma F, van den Meiracker AH,
Schalekamp MADH: Effect of an unnatural noradrenaline
precursor on sympathetic control and orthostatic hypotension
in dopamine-/3-hydroxylase deficiency. Lancet 1987;2:
Man in't Veld AJ, Boomsma F, van den Meiracker AH, Julien
C, Lenders J, Schalekamp MA: D,L-threo-3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic
hypotension in dopamine-beta-hydroxylase deficiency. J Hypertens 1988;6(suppl 4)^47-549
Goldstein DS, Polinsky RJ, Garty M, Robertson D, Brown
RT, Biaggioni I, Stull R, Kopin LI: Patterns of plasma levels of
catechols in idiopathic orthostatic hypotension. Ann Neurol
Velasco M, Gilbert CA, Rutledge CO, McNay JL: Antihypertensive effect of a dopamine beta hydroxylase inhibitor, bupicomide: A comparison with hydralazine. Clin Pharm Ther
Kopin D, Polinsky RJ, Oliver JA, Uddershede IR, Ebert MH:
Urinary catecholamine metabolites distinguish different types
of sympathetic neural dysfunction in patients with orthostatic
hypotension. / Clin Endoainol Metab 1983;57:632-637
Polinsky RJ, Kopin IJ, Ebert MH, Weise V: Pharmacologic
distinction of different orthostatic hypotension syndromes.
Neurology 1981;31:l-7
KEYWORDS • dopamine • dopamine ^-hydroxylase • autonomic
nervous system • norepinephrine • genetic hypertension •
catecholamines • sympathetic nervous system • orthostatic
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