Dopamine beta-hydroxylase deficiency (DBHD) is a congenital disorder caused by mutations in the DBH gene. Dysfunctions of the autonomic nervous system manifest in infancy but are not usually related to DBHD until adolescence. Vomiting and dehydration, hypoglycemia, hypothermia, and ptosis may present early on, while the onset of severe orthostatic hypotension is generally delayed until the second decade of life. The disease is well treatable, but rarely considered as a differential diagnosis: Only two dozen patients have been described to date, and awareness is lacking.
Carriers of pathogenic DBH mutations are born healthy, and symptom onset does not usually occur until beyond the neonatal period. What's more, non-specific symptoms are not usually associated with DBHD during infancy or childhood, so the diagnosis is often delayed until adolescence. Only then, deficits in the autonomic regulation of cardiovascular function lead to severe orthostatic hypotension, which significantly reduces the patients' quality of life. When standing up, they experience a sharp drop in blood pressure, may suffer from lightheadedness or blurred vision. Long-term standing may similarly induce dizziness and tends to cause syncopes. Certain environmental conditions, such as hot temperatures and high humidity, may exacerbate these symptoms, although sweating is not affected by DBHD. Symptoms are often worse in the morning and after meals, particularly after meals that are rich in carbohydrates . In the course of time, DBHD patients may learn to recognize nuchal discomfort, chest pain, and dyspnea as prodromal symptoms of syncopes .
Orthostatic hypotension may be accompanied or preceded - by several years - by vomiting and dehydration, hypoglycemia, and difficulties in maintaining body temperature. Anemia has been described in more than half of all cases . These consequences of autonomic insufficiency considerably diminish the patients' resistance to exercise and may even call for hospitalization, though more often than not they are not assigned a definite cause.
DBHD induces ptosis, too. Besides orthostatic hypotension, drooping eyelids are the most relevant clinical finding for diagnosis, but this should not be considered an exclusion criterion. Furthermore, DBHD-related ptosis is generally mild. Additionally, the disease has been related to skeletal muscle hypotonia, hyperextensible joints, sluggish deep-tendon reflexes, nasal stuffiness, polyuria/nocturia, and retrograde or prolonged ejaculation   . Central nervous system disease is generally limited to temporal attention deficits ; seizures have been observed but have been interpreted as a consequence of hypotension rather than a symptom of central deficiency of dopamine β-hydroxylase . In the long term, DBHD may cause renal failure .
The combination of infantile or childhood hypotension and ptosis should raise suspicion as to DBHD, but less severe disease is not usually diagnosed until adolescence. During thorough anamnesis, these patients tend to describe life-long complaints of orthostatic hypotension and reduced physical capacities.
The clinical examination should include measurements of heart rate and blood pressure in the supine, seated, and standing position. While lying down, both parameters are in the lower physiological range or below reference values, and blood pressure falls further when the patient is sitting or standing up. In a small cohort of adolescent patients, mean arterial blood pressures were 90 mm Hg supine, 79 mm Hg sitting, and 46 mm Hg standing . The corresponding elevations
in heart rates were insufficient to maintain cerebral blood flow, which is why the majority of untreated DBHD is unable to stand for more than two minutes. Beyond that, hypotension may be provoked by hyperventilation or the Valsalva maneuver .
An ophthalmological examination should be realized to narrow down the list of potential causes of ptosis, but it may provide valuable hints even in the absence of drooping eyelids. Decreases of the margin reflex distance may be observed irrespective of ptosis, and DBHD patients have also been shown to have markedly decreased intraocular pressure when standing . Furthermore, mydriases may be induced by parasympatholytics, but sympathomimetic amines like hydroxyamphetamine don't exert any effect .
Subsequently, plasma levels of catecholamines norepinephrine, epinephrine, and dopamine should be assessed. While the former are below detection limits irrespective of body posture, the concentration of dopamine is greatly increased  . Interestingly, any movement that should provoke an increase in plasma concentrations of norepinephrine and epinephrine results in a further elevation of the dopamine levels. Due to a broad physiological range, dopamine β-hydroxylase activity levels are not a reliable indicator of DBHD .
In the absence of other conditions that would explain these anomalies, the aforedescribed laboratory findings may suffice to confirm the diagnosis of DBHD. Nevertheless, and in the interest of a familial workup, sequencing of the DBH gene should be carried out.
The administration of L-threo-3,4-dihydroxyphenylserine, which is more commonly referred to as droxidopa, is the cornerstone of DBHD treatment, while standard therapeutic approaches to autonomic failure (e.g., fludrocortisone and indomethacin) are largely ineffective. Droxidopa is a synthetic amino acid that is converted into norepinephrine by the aromatic L-amino acid decarboxylase, the same enzyme that converts L-DOPA to dopamine . Most patients respond well to the application of 100-500 mg droxidopa two or three times a day. During pregnancy and delivery, it may be necessary to increase the therapeutic dose. Furthermore, a general dosage adjustment should be considered in the post-partum period  .
Treatment may be complemented by symptomatic therapy as needed. In this context, 1-deamino-8-D-arginine vasopressin has been recommended to stabilize blood pressure and to treat polyuria and nycturia . The correction of ptosis may require surgery .
Owing to the increased risk of renal failure, patients should undergo regular follow-ups for kidney function .
Most symptoms of autonomic nervous system dysfunction readily decrease under therapy, but they must be expected to return if treatment is ceased . Accordingly, DBHD patients require lifelong therapy. Droxidopa has been shown to be efficient, safe, and well tolerated by DBHD patients  . It restores the patients' tolerance to exercise and improves their quality of life.
Renal failure is a dreaded long-term consequence of DBHD, but its molecular background is incompletely understood, which makes it difficult to predict this detrimental complication. Increased filtered loads and enhanced transport of L-DOPA have been suggested as possible triggers, and these parameters may be reduced to their normal ranges by the administration of droxidopa . In any case, glomerular filtration rates have been shown to improve under droxidopa in at least one patient .
In sum, droxidopa significantly contributes to the approximation of physiological norepinephrine levels and patients may be expected to have a near-to-normal life expectancy. Epidemiological data are scarce, but patients have been reported to have lived beyond the age of 60 years  .
DBHD is caused by mutations in the DBH gene, which is located on the long arm of chromosome 9 and encodes for the enzyme dopamine β-hydroxylase. This enzyme is expressed in neuroscretory vesicles and chromaffin granules of the adrenal medulla and catalyzes the conversion of dopamine to norepinephrine, the main neurotransmitter of postganglionic nerve fibers. Because norepinephrine serves as a precursor of epinephrine, plasma levels of both are decreased in DBHD patients. By contrast, the inadequate conversion of the substrate results in pathologically increased concentrations of dopamine.
The disease is inherited in an autosomal recessive manner, with heterozygous carriers being asymptomatic. Patients may be homozygous for determined mutations in the DBH gene, or compound heterozygous . A number of distinct mutations has been identified, but there are insufficient data to establish correlations between specific genotypes and phenotypes.
DBHD is a very rare disorder. By 2013, about two dozen patients had been described worldwide . Although a review of known cases may suggest female predominance, epidemiological data obtained so far are insufficient to confirm such an assumption. Similarly, all patients identified to date are of Western European descent, but an unknown number of undiagnosed cases is expected in other parts of the world .
DBHD is characterized by dysfunctions of the sympathetic nervous system: While cholinergic functions are preserved, noradrenergic signaling is disturbed . Postganglionic sympathetic neurons secrete norepinephrine onto adrenergic receptors expressed by a myriad of target tissues, which explains the broad spectrum of symptoms of DBHD:
Several questions on DBHD remain unanswered, though. While the enzyme deficiency is congenital, overt orthostatic hypotension does not usually manifest until adolescence. The reason for this relatively late presentation remains unknown . Furthermore, DBHD is a systemic disorder, and alterations of norepinephrine and dopamine levels can be detected in cerebrospinal fluid. Nevertheless, central nervous system dysfunction rarely becomes symptomatic  .
Affected families may benefit from genetic counseling. Those known to harbor mutations in the DBH gene should be offered prenatal diagnosis, which is based on the identification of pathogenic alleles in the unborn child . Alternatively, genetic tests may be conducted within a few days after birth to assure the timely initiation of treatment and prevention of metabolic complications.
DBHD is a very rare, but debilitating disease that can be successfully treated with droxidopa. Patients may present with signs of metabolic decompensation and ptosis during infancy, but the absence of specific symptoms as well as the general lack of awareness of DBHD usually imply diagnostic delays of several years. Hypotension may be identified early on, but it's during adolescence when progressively worsening orthostatic hypotension becomes a major obstacle in daily life. Orthostatic hypotension is the clinical hallmark of DBHD; it has been found in all cases described so far and is the most common motive of a thorough workup.
Clinical symptoms should raise suspicion as to DBHD, and the tentative diagnosis of the disease may be confirmed by laboratory analyses. The measurement of plasma levels of catecholamines norepinephrine, epinephrine, and dopamine yields characteristic, even diagnostic alterations. The final confirmation of DBHD is provided by genetic tests and the identification of the underlying mutation.
Dopamine β-hydroxylase is an enzyme that catalyzes the conversion of dopamine to norepinephrine. Both act as neurotransmitters, but they bind to distinct receptors and fulfill different functions. The inability to produce functional dopamine β-hydroxylase thus interferes with neuronal signaling, and it may be caused by mutations in the gene encoding for the aforementioned enzyme. Affected individuals may be diagnosed with dopamine beta-hydroxylase deficiency (DBHD).
DBHD patients are born healthy but may develop vomiting, dehydration, and hypoglycemia within their first few months of life. Parents of affected infants may also note their difficulties in maintaining body temperature. Additionally, mildly drooping eyelids may be observed. Orthostatic hypotension, i.e., pronounced decreases in blood pressure within moments of standing, may cause dizziness, blurred vision, and fainting. For as-of-yet unknown reasons, orthostatic hypotension exacerbates during adolescence. While this development interferes with the patient's ability to cope with everyday life, it is the most common motive of a thorough workup.
From a biochemical point of view, DBHD is characterized by low plasma levels of norepinephrine and epinephrine, and increased concentrations of dopamine. Because the patient's body is unable to convert dopamine to norepinephrine, any process that should result in an elevation of the latter's concentrations only provokes an additional rise of former's. The diagnosis of DBHD may be confirmed by genetic tests and the identification of the underlying mutation.
The disease is readily treatable, with DBHD therapy being based on the administration of droxidopa. The vast majority of patients experiences significant improvements of orthostatic hypotension and other symptoms, and thus of quality of life. Treatment is required throughout life.