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Dopamine Beta-Hydroxylase Deficiency

Synonym: Norepinephrine Deficiency

, MD and , PhD.

Author Information
, MD
Elton Yates Professor, Departments of Medicine, Pharmacology, and Neurology
Vanderbilt University
Nashville, Tennessee
, PhD
Associate Professor, Department of Medicine
Vanderbilt University
Nashville, Tennessee

Initial Posting: ; Last Update: October 29, 2015.


Clinical characteristics.

Dopamine beta-hydroxylase (DBH) deficiency is characterized by lack of sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function that predispose to orthostatic hypotension. Although DBH deficiency appears to be present from birth, the diagnosis is not generally recognized until late childhood. The combination of ptosis of the eyelids in infants and children, together with hypotension, is suggestive of the disease. In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization; children have reduced exercise capacity. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain. Life expectancy is unknown, but some affected individuals have lived beyond 60 years.


The diagnosis of DBH deficiency is based on clinical findings (including poor cardiovascular regulation, other autonomic dysfunction, and intact sweating), physiologic findings of autonomic function (which reveal failure of sympathetic noradrenergic and adrenomedullary function but intact vagal and sympathetic cholinergic function), and unique biochemical features (minimal or absent plasma norepinephrine and epinephrine AND a five- to tenfold elevation of plasma dopamine, a finding probably pathognomonic of DBH deficiency). DBH deficiency is caused by biallelic pathogenic variants in DBH.


Treatment of manifestations: Administration of L-threo-3,4-dihydroxyphenylserine (droxidopa) alleviates the orthostatic hypotension and other symptoms. Affected individuals do not respond as well to standard therapeutic approaches for autonomic failure. Surgery can correct ptosis.

Prevention of primary manifestations: Droxidopa can improve the orthostatic hypotension and symptoms, but these recur if treatment is stopped.

Surveillance: Renal function (measurement of plasma creatinine and BUN concentrations) is assessed every two years or more often if loss of renal function is evident. Plasma magnesium and potassium should also be assessed.

Agents/circumstances to avoid: Untreated individuals should avoid hot environments, strenuous exercise, standing motionless, and dehydration.

Pregnancy management: Routine blood pressure monitoring during pregnancy and delivery, with adjustment of droxidopa dosage as needed; extra doses of droxidopa may be required during delivery and dose adjustment may be required post partum.

Genetic counseling.

DBH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if both pathogenic variants in the family are known. If the pathogenic variants have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.


Suggestive Findings

Affected individuals are often first encountered during adolescence, complaining of life-long difficulties with lightheadedness and an inability to tolerate standing or exercise. Affected individuals and their parents will report behaviors, such as squatting, used to compensate for the problems with standing. Therefore, dopamine beta-hydroxylase (DBH) deficiency should be suspected in individuals with the following clinical, physiologic, and laboratory findings [Vincent & Robertson 2002, Timmers et al 2004]:

Clinical Findings

  • Poor cardiovascular regulation evident from supine, seated, and standing vital signs:
    • A low-to-normal supine blood pressure and low or normal supine heart rate
    • Systolic blood pressure <80 mm Hg in the upright position
    • An inadequate compensatory rise in heart rate with standing
    • Inability to stand motionless for more than one minute
  • Other autonomic dysfunction evident from an ophthalmic examination:
    • Ptosis in some individuals
    • A marked decrease in intraocular pressure with standing [Phillips et al 2013]
    • Somewhat small pupils that respond to light and accommodation but not to hydroxyamphetamine. Parasympatholytics dilate the pupils appropriately.
  • A comprehensive history and physical examination (including neurologic exam) typically revealing:
    • Intact sweating
    • Skeletal and muscle findings in some affected individuals:
      • Arched palate
      • Hyperextensible joints
      • Sluggish deep-tendon reflexes
      • Mild facial-muscle weakness
      • Hypotonic skeletal muscles

Findings on Physiologic Testing

Physiologic tests of autonomic function, when available, may provide diagnostic information of great specificity. Autonomic function test results (Table 1) indicate that complete DBH deficiency encompasses sympathetic noradrenergic failure and adrenomedullary failure but intact vagal and sympathetic cholinergic function [Biaggioni & Robertson 1987, van den Meiracker et al 1996].

  • 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.
  • Cold pressor testing causes either a fall or no change in blood pressure.
  • Isometric handgrip exercise fails to significantly increase blood pressure.

Note: Click here for results of further physiologic tests of autonomic function.

Table 1.

Results of Autonomic Function Testing in Individuals with Dopamine Beta Hydroxylase Deficiency (DBHD)

DBHD 1Control 1Number:
P Value
Age (years)26±1434±100.033
Sinus arrhythmia ratio1.3±0.211.4±0.218/860.266
Valsalva phase IIDelta SBP (mm Hg)-41±25-7±227/55<0.001
Delta HR (bpm)29±1130±167/530.828
Valsalva phase IVDelta SBP (mm Hg)-22±1823±168/84<0.001
Delta HR (bpm)5±9-8±118/820.001
Valsalva ratio1.3±0.201.7±0.398/79<0.001
HyperventilationDelta SBP (mm Hg)-14±12-7±129/86454
Delta HR (bpm)14±1911±118/860.308
Cold pressorDelta SBP (mm Hg)4±1021±148/830.001
Delta HR (bpm)16±1110±117/830.183
HandgripDelta SBP (mm Hg)2±617±137/830.003
Delta HR (bpm)15±1110±107/830.230

EM Garland, unpublished data from Vanderbilt Autonomic Dysfunction Center

SBP = systolic blood pressure

HR = heart rate


Mean ± SD

Laboratory Findings

Plasma catecholamines. Biochemical features unique to DBH deficiency:

  • Minimal or absent plasma norepinephrine (NE) and epinephrine AND a five- to tenfold elevation of plasma dopamine (DA). This combination is probably pathognomonic of DBH deficiency.
    • Plasma NE concentration should be below the limits of detection (<25 pg/mL or 0.15 nmol/L)
    • Plasma DA concentration is frequently higher than 100 pg/mL (0.65 nmol/L).
      Note: One atypical individual who was not diagnosed until age 73 years was reported to have a plasma DA concentration of 10,000 pg/mL (67 nmol/L) [Despas et al 2010].
  • Note: Although both baroreflex afferent and catecholamine release mechanisms are intact, DA is released in place of NE.

Note: (1) It is essential to assay both NE and DA and to use a procedure with high specificity for these catechols. (2) With some radioenzymatic methods for catecholamine determinations, a proportion of the DA may be erroneously measured as epinephrine [Robertson et al 1986].

The plasma DA concentration responds to various physiologic and pharmacologic stimuli as does NE in normal individuals:

  • A change from supine to upright posture doubles or triples the plasma DA concentration. This observation suggests that sympathetic nerves and reflex arcs are intact, but DA (rather than NE) is stored and released at the sympathetic synapse.

Click here for information pertaining to pharmacologic findings that can be seen in individuals with DBH.

Establishing the Diagnosis

The diagnosis of DBH is established in a proband with the following:

  • Minimal or absent plasma concentration of norepinephrine and epinephrine with a five- to tenfold elevation of plasma dopamine on high performance liquid chromatography and electrochemical detection.
  • Biallelic pathogenic variants in DBH (Table 2). Sequence analysis of DBH should be pursued first, followed by deletion/duplication analysis if only one or no pathogenic variant is found.

A multi-gene panel that includes DBH and other genes of interest (see Differential Diagnosis) may also be considered. The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Table 2.

Molecular Genetic Testing Used in Dopamine Beta-Hydroxylase Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
DBHSequence analysis 350%-100% 4
Gene-targeted deletion/duplication analysis 5Unknown 6

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


No data on detection rate of gene-targeted deletion/duplication analysis are available.

Click here for information on the plasma DBH enzymatic assay.

Clinical Characteristics

Clinical Description

Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function, but apparently only subtle signs of central nervous system dysfunction [Robertson et al 1986, Man in ‘t Veld et al 1987, Timmers et al 2004, Jepma et al 2011].

Although DBH deficiency appears to be present from birth, the diagnosis is not generally recognized until late childhood when orthostatic hypotension becomes more severe.

The full clinical spectrum of DBH deficiency is not known because of the limited number of cases reported. Clinical features reported in 19 affected individuals (12 female, 7 male) are included in Table 3.

In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. Delay in opening of the eyes has occurred and ptosis of the eyelids is seen in most affected infants.

Children with DBH deficiency have markedly reduced exercise capacity, perhaps because of hypotension engendered by physical exertion. The syncope associated with postural hypotension often suggests seizures and prompts trials of anticonvulsive medication despite lack of abnormalities on the electroencephalogram. Mental and physical development are normal.

Symptoms generally worsen in late adolescence. By early adulthood, affected individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Males experience retrograde or prolonged ejaculation.

Clinical features of DBH deficiency are included in Table 3.

Table 3.

Clinical Features of DBH Deficiency

Feature# of Individuals 1
Severe orthostatic hypotension19/19 (100%)
Anemia8/14 (57%)
Ptosis of eyelids11/13 (85%)
Abnormal sexual maturation0/12
Hyperflexible or hypermobile joints6/10 (60%)
ECG abnormalities 22/12 (17%)
Epileptiform symptoms4/12 (33%)
Nasal stuffiness10/10 (100%)
Hypoglycemia3/11 (27%)
Sluggish deep-tendon reflexes3/9 (33%)
Increased plasma creatinine5/10 (50%)
Polyuria/nocturia3/9 (33%)
High palate9/10 (90%)
Increased BUN6/9 (67%)
Muscle hypotonia3/9 (.33%)
Postprandial hypotension3/7 (43%)
Sleep irregularities5/7 (71%)
Impaired ejaculation4/4 (100%)

Number of individuals with the finding/total number evaluated for the finding


ECG = electrocardiogram

Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally chest pain. Symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Occasional bouts of unexplained diarrhea occur.

Elevated blood urea nitrogen has been noted in six affected individuals in the United States [Garland et al 2005a, Garland et al 2009]. This may be evidence of a loss of renal function. The estimated GFR of a 57-year-old affected female was reduced to 18 mL/min/1.73 m2.

Despite the lack of norepinephrine, persons with DBH deficiency apparently have relatively normal mental status. Five affected individuals and ten matched healthy unaffected participants underwent a comprehensive battery of neurocognitive testing in addition to brain MRI, pupillometry, and EEG. Performance of the affected individuals, whether on or off droxidopa treatment, was similar to that of the unaffected individuals in most respects, suggesting that other systems compensate for absent norepinephrine in affected individuals. Brain MRI studies revealed a smaller total brain volume in the affected individuals compared to unaffected individuals, although relative proportions of white and gray matter and cerebrospinal fluid were similar in the two groups. In addition, affected individuals had a temporal-attention deficit when they were not on treatment. During an attentional-blink task, participants were asked to identify two digits, separated by a variable number of letters. Attentional blink refers to the deficit in processing the second digit when it is presented within 200-400 msec of the first. Accuracy in identifying the second digit was impaired in affected individuals not on treatment but performance improved with droxidopa treatment [Jepma et al 2011].

Atrial fibrillation developed in one individual. Another individual had reduced T-wave amplitude, which may reflect an electrolyte abnormality [Man in ‘t Veld et al 1987].

Olfactory function is relatively unaffected in individuals with DBH deficiency, who have intact noradrenergic neurons, in contrast to the marked deficit in individuals with pure autonomic failure, who have peripheral neuronal degeneration [Garland et al 2011].

A 2010 case report described an individual with DBH deficiency who (in addition to features characteristic of this disorder) also had bilateral colobomas, short hands, and high-arched feet. The investigators found a mosaic deletion on chromosome 11p13 that includes PAX6 [Erez et al 2010].

Because so few individuals have been diagnosed with DBH deficiency, it is not known what relationship the less common findings have to the absence of DBH or elevated levels of dopamine; they may be fortuitous findings. However, the investigators [Man in ‘t Veld et al 1987] speculated that hypoglycemia may result from adrenomedullary failure and the T-wave abnormalities from failure of noradrenergic control. In contrast to the report of hypoglycemia during the perinatal period, a girl age 15 years studied with a hyperglycemic clamp had a normal fasting glucose level but insulin resistance [Shibao et al 2014].

Since dopamine inhibits both the synthesis and secretion of prolactin, some degree of hypoprolactemia is not surprising in these individuals.

Four persons with DBH deficiency have died. Three died from natural causes at ages 28, 57, and 63 years. One died at age 20 years, possibly by suicide.

Autopsy of the 28-year old male reported “scattered pyknotic cerebral neurons, isolated microfoci of cortical gliosis, cardiac arteriolar smooth muscle hypertrophy, scattered fibrosis in the cardiac conduction system, and sclerotic renal glomeruli” [Cheshire et al 2006]. In addition, DBH immunostaining was absent in neurons of the ventrolateral medulla.

Genotype-Phenotype Correlations

Because of the small number of individuals diagnosed with DBH deficiency, it is not possible to determine correlations between specific phenotypes and pathogenic variants in DBH.


The prevalence of DBH deficiency is unknown. Only 21 affected individuals, all of western European descent, have been reported in the literature, suggesting that it is a rare disorder.

Differential Diagnosis

The striking catecholamine abnormalities distinguish DBH deficiency from other disorders. Other catecholamine disorders, such as aromatic L-amino acid decarboxylase deficiency (OMIM 608643), have clinical presentations distinct from that of DBH deficiency [Swoboda et al 2003].

Pure autonomic failure/autonomic neuropathy. Pure autonomic failure or Bradbury-Eggleston syndrome is a degenerative disorder of the autonomic nervous system presenting in middle to late life. Like DBH deficiency, it is characterized by severe orthostatic hypotension. It differs from DBH deficiency in that it affects both the sympathetic and parasympathetic nervous systems. Hypohidrosis is common. Individuals with pure autonomic failure have marked hypersensitivity to all pressor and depressor stimuli. Plasma and urinary norepinephrine (NE) concentrations are greatly reduced, sometimes to 10% of normal; plasma dopamine (DA) concentrations are normal or low, rather than elevated as in DBH deficiency.

Systemic illness. Some dysautonomias result from well-characterized autonomic neuropathies secondary to systemic illnesses such as diabetes mellitus.

Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Progressive neuronal degeneration continues throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature, and cardiovascular instability. Approximately 40% of individuals have autonomic crises. An age-related decline in renal function has been noted [Elkayam et al 2006]. Clinically, DBH deficiency is distinguished from FD by normal tearing, intact corneal and deep tendon reflexes, normal sensory function, normal senses of taste and smell, and lack of abnormal cholinergic sensitivity and intradermal histamine response. FD is seen almost exclusively in individuals of Ashkenazi heritage, whereas individuals with DBH deficiency have not to date been of Ashkenazi Jewish descent.

Individuals with familial dysautonomia have high rates of excretion of HVA and low rates of excretion of the NE metabolite 3-methoxy-4-hydroxymandelic acid (VMA). Plasma dihydroxyphenylglycol (DHPG) concentration is low; plasma DOPA (3,4-dihydroxyphenylalanine) and DA concentrations are elevated [Goldstein et al 2008].

Inheritance is autosomal recessive. The diagnosis of FD is established by molecular genetic testing of IKBKAP. Two pathogenic variants account for more than 99% of pathogenic alleles in individuals of Ashkenazi Jewish descent.

ATP7A-related copper transport disorders. Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders of copper transport caused by pathogenic variants in the copper-transporting ATPase gene, ATP7A. DBH is a copper-dependent enzyme, and thus DBH activity is depressed in affected individuals, leading to high plasma and CSF concentrations of DOPA, DOPAC, and DA, low concentrations of DHPG, and approximately normal concentrations of NE. Severe orthostatic hypotension has been reported [Christodoulou et al 1998]. However, individuals with Menkes disease and occipital horn syndrome can be differentiated from those with DBH deficiency by clinical findings. Infants with classic Menkes disease have loss of developmental milestones, hypotonia, seizures, failure to thrive at age two to three months, and characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented). Death usually occurs by age three years. Occipital horn syndrome is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Affected individuals also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Intellect is normal or slightly reduced. Serum copper concentration and serum ceruloplasmin concentration are low.

Inheritance is X-linked. Molecular genetic testing of ATP7A detects pathogenic variants in more than 95% of affected individuals.

Familial transthyretin amyloidosis is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy as well as non-neuropathic changes of nephropathy, cardiomyopathy, vitreous opacities, and CNS amyloidosis. The disease usually begins in the third or fourth decade; onset of symptoms may be later. The cardinal feature of transthyretin amyloid polyneuropathy is slowly progressive sensorimotor and autonomic neuropathy. Autonomic neuropathy may occur as the first clinical symptom of the disease; symptoms include orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence.

Inheritance is autosomal dominant. Molecular genetic testing of TTR detects more than 99% of (amyloidogenic) pathogenic variants.

Multiple system atrophy (MSA, Shy-Drager syndrome, SDS) (OMIM 146500). As in DBH deficiency, signs include orthostatic hypotension, but extrapyramidal or cerebellar findings are also present. Onset of MSA is after age 30 years.


Evaluations Following Initial Diagnosis

To determine the extent of functional disturbance in an individual diagnosed with dopamine beta-hydroxylase (DBH) deficiency, the following are indicated:

  • Assessment of standing time (length of time that the affected individual is able to stand)
  • Medical history
  • Consultation with a medical geneticist or genetic counselor

Treatment of Manifestations

For the most part, treatment for DBH deficiency is supportive and directed at relieving orthostatic symptoms.

The treatment of choice is administration of L-threo-3,4-dihydroxyphenylserine (or droxidopa, marketed in the USA as Northera™). Droxidopa is converted directly to NE by L-aromatic amino acid decarboxylase, thereby bypassing DBH (Figure 1).

Figure 1.

Figure 1.

Synthesis of norepinephrine from dopamine or droxidopa

  • Administration of 100 to 500 mg droxidopa orally twice or three times daily increases blood pressure and concomitantly restores plasma NE to the normal range; however, urinary NE excretion exceeds normal levels.
  • Although NE becomes detectable, plasma epinephrine concentration still remains below a detectable level.
  • Droxidopa administration restores DOPA to within the normal range and reduces DA somewhat, but plasma concentration of DA and its metabolites remains somewhat elevated [Biaggioni & Robertson 1987].
  • This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. An affected female completed a marathon approximately five years after her diagnosis, while taking 1200 mg of droxidopa daily [Garland et al 2005b].

Individuals with DBH deficiency respond somewhat to standard therapeutic approaches for autonomic failure but not nearly as well as they respond to droxidopa.

  • Fludrocortisone, at dosages of 0.1-0.3 mg daily, has been used with some benefit, but marked orthostatic hypotension still occurs.
  • Indomethacin (50 mg 3x/day) has been of limited benefit in raising blood pressure.
  • Metyrosine, a tyrosine hydroxylase inhibitor, raises blood pressure and reduces urinary DA concentration in individuals with DBH deficiency. However, the dose normally used for pheochromocytoma has too much of a pressor effect and has some side effects, including sedation.

Ptosis can be corrected by surgery.

Sinus problems should be treated as needed.

Prevention of Primary Manifestations

Droxidopa can improve the orthostatic hypotension and symptoms, but these recur if treatment is stopped.

Prevention of Secondary Complications

The effect of droxidopa on renal function is unknown.


Renal function should be assessed by BUN and plasma creatinine at a minimum of every two years and more often if a loss of function is evident. Plasma magnesium and potassium should also be assessed.

Individuals on droxidopa should be encouraged to report any adverse events to their physician.

Affected individuals should be queried at least yearly about continued efficacy of droxidopa against orthostatic hypotension and symptoms. Adjustment of dosage may be required.

Agents/Circumstances to Avoid

Untreated individuals with DBH deficiency should avoid hot environments, strenuous exercise, standing still, and dehydration.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

At least two affected women have successfully given birth [Scurrah et al 2002] following uncomplicated deliveries. Based on these experiences, it is recommended that affected pregnant women have their blood pressure monitored regularly throughout the pregnancy and delivery so that the droxidopa dose can be modified as needed. One or two extra doses of droxidopa should be available to be taken as needed at the time of delivery. Dose adjustment may also be required post partum. The effects of maternal droxidopa therapy on the developing fetus have not been studied in humans; however, studies on pregnant animals do not suggest an increased risk for malformations in offspring.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dopamine beta-hydroxylase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one DBH pathogenic variant).
  • Heterozygotes (carriers) appear to be asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a DBH pathogenic variant is 2/3.
  • Heterozygotes (carriers) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment.

Offspring of a proband. The offspring of an individual with DBH deficiency are obligate heterozygotes (carriers) for a pathogenic variant in DBH.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the DBH pathogenic variants in the family.

Biochemical genetic testing. Biochemical testing is not recommended for determining carrier status. There are many individuals without DBH deficiency who have extremely low plasma DBH activity. Parents of at least some individuals with DBH deficiency have normal autonomic function and normal catecholamine levels.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the DBH pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like DBH deficiency) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the DBH pathogenic variants have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Dopamine Beta-Hydroxylase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
DBH9q34​.2Dopamine beta-hydroxylaseDBH databaseDBH

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Dopamine Beta-Hydroxylase Deficiency (View All in OMIM)


Gene structure. DBH is approximately 23 kb and is composed of 12 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Normal allelic variants of DBH correlate with variation in the level of DBH activity in individuals who are neither affected nor carriers. Tenfold differences in serum DBH concentrations are commonly reported in normal controls, with DBH being the major contributor to the variability in activity levels. Heritability of serum DBH concentration is estimated to be 0.98. Oligogenic inheritance accounts for almost all of the large individual variation in serum DBH concentration found in the human population. Several normal allelic variants in DBH that correlate with the level of DBH activity have been identified. The most compelling evidence relates a c.-979T>C variant (T is the minor allele) in the 5' UTR of the gene to low DBH activity [Zabetian et al 2001]. An MspI polymorphic site in intron 9 [Wei et al 1996], a 19-bp insertion/deletion polymorphism in the 5’ UTR (Table 4) [Cubells et al 1998, Robinson et al 2001], a variant at the 3’ end of exon 2 (c.486A>G) [Cubells et al 1998], and a GT microsatellite repeat g.136496870_136496871[11_15] in the 5’ UTR of DBH (Table 4) [Porter et al 1992] have also been associated with DBH activity [Cubells et al 1998].

Some apparently unaffected individuals have consistent levels of very low DBH activity [Zabetian et al 2001]. In European Americans, homozygosity of a T allele at c.-979 predicted very low DBH activity, whereas heterozygosity revealed an intermediate distribution of DBH activity, indicating codominant inheritance. It is noteworthy that while a handful of these individuals with low plasma DBH concentrations have clinical features of DBH deficiency, millions of unaffected individuals also have low plasma DBH concentrations. Some Dutch individuals with DBH deficiency had family members who had undetectable plasma DBH associated with one pathogenic DBH allele and homozygosity for the c.-979T allele but no clinical phenotype (e.g., near-normal plasma concentrations of norepinephrine and epinephrine and no orthostatic symptoms) [Deinum et al 2004]. Recently, the c.-979C allele was found to be associated with increased epinephrine excretion and higher basal blood pressure, as well as enhanced stress-mediated stimulation of blood pressure [Chen et al 2010]. This variant and c.486A>G have been determined to affect mRNA expression [Barrie et al 2014].

Pathogenic allelic variants. DBH gene variants associated with reduced DBH activity in affected individuals were first identified by Kim et al [2002] in two individuals with DBH deficiency: a compound heterozygote for c.[339+2T>C];[342C>A] and a compound heterozygote for c.339+2T>C and an allele with two missense variants c.[301G>A;1033G>A]. These variants have not been reported in other autonomic disorders [Cho et al 2003]. The c.301G>A variant occurs in an area with amino acid variation across species and is not as strong a candidate as the two other missense variants, which are in well-conserved regions [Kim et al 2002]. A third individual who was a compound heterozygote was more recently identified: c.[339+2T>C];[c.1085C>A] [Kim et al 2011].

The c.339+2T>C pathogenic variant and three additional pathogenic variants have been identified in four families with DBH deficiency in the Netherlands [Deinum et al 2004]. The affected individuals were a c.339+2T>C homozygote, a c.806G>T homozygote, and compound heterozygotes for c.[339+2T>C];[617delA] and for c.[339+2T>C];[1667A>G].

Table 4.

Selected DBH Allelic Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
LocationProtein Amino Acid Change
(Alias 1)
Reference Sequences
Benign(19-bp insertion/deletion24.7 kb 5’ to the transcriptional start site--GRCh37​/hg19
(11_15) 3
(444 g/a)
Exon 2 splice donor sitep.Glu162GluNM_000787​.3
c.-979T>C 45' UTR--
(MspI polymorphism4Intron 9
Exon 1p.Val101Met
c.339+2T>C 5
Intron 1--
Exon 2p.Asp114Glu
Exon 3p.Glu206GlyfsTer82
Exon 4p.Cys269Phe
Exon 6p.Asp345Asn
Exon 6p.Ala362Glu
Exon 11p.Tyr556Cys

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


GT dinucleotide repeat sequence that varies between 11 and 15 repeats in a population [Porter et al 1992]


Benign allelic variants that correlate with the level of DBH activity (see Normal gene product)


An allele frequency of 0.001 has been reported for c.339+2T>C in individuals of European American and African American heritage without autonomic dysfunction [Zabetian et al 2003].

Normal gene product. Dopamine-beta-hydroxylase (3,4-dihydroxyphenylethylamine, ascorbate:oxygen oxidoreductase; DBH) is a copper-requiring dimeric or tetrameric enzyme located in central and peripheral noradrenergic neurons and in the adrenal medulla. DBH exists in membrane (of neuronal vesicles) and soluble (intravesicular) forms, depending on the presence or absence, respectively, of a signal peptide. The tetrameric glycoprotein has a molecular weight of approximately 290,000 daltons. The four subunits are linked by disulfide bridges into two dimers, which are joined to each other by non-covalent bonds. There are two to seven moles of copper per mole of DBH, and the copper is essential for enzyme activity. DBH also requires molecular oxygen and ascorbic acid or some other electron source for enzyme activity.

Linkage and association studies have established the DBH locus as the major gene controlling DBH levels in body fluids [Zabetian et al 2001].

Abnormal gene product. The c.339+2T>C variant results in an aberrantly spliced product containing a premature stop codon and no detectable DBH protein. Pathogenic variants in exons 2 and 6 prevent normal protein trafficking [Kim et al 2011].


Literature Cited

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  13. Garland EM, Gamboa A, Okamoto L, Raj SR, Black BK, Davis TL, Biaggioni I, Robertson D. Renal impairment of pure autonomic failure. Hypertension. 2009;54:1057–61. [PMC free article: PMC2796115] [PubMed: 19738158]
  14. Garland EM, Raj SR, Biaggioni I, Black BK, Robertson D. A hyperdopaminergic nephropathy in dopamine beta hydroxylase deficiency. Clin Auton Res. 2005a;15:321.
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Suggested Reading

  1. Corominas R, Ribases M, Camiña M, Cuenca-León E, Pardo J, Boronat S, Sobrido MJ, Cormand B, Macaya A. Two-stage case-control association study of dopamine-related genes and migraine. BMC Med Genet. 2009;10:95. [PMC free article: PMC2758864] [PubMed: 19772578]
  2. Fernandez F, Lea RA, Colson NJ, Bellis C, Quinlan S, Griffiths LR. Association between a 19 bp deletion polymorphism at the dopamine beta-hydroxylase (DBH) locus and migraine with aura. J Neurol Sci. 2006;251:118–23. [PubMed: 17095019]
  3. Robertson D, Biaggioni I, Burnstock G, Low PA, Paton JFR, eds. Primer on the Autonomic Nervous System. 3 ed. Oxford, UK: Academic Press; 2012.
  4. Senard JM, Rouet P. Dopamine beta-hydroxylase deficiency. Orphanet J Rare Dis. 2006;1:7. [PMC free article: PMC1459119] [PubMed: 16722595]
  5. Wei J, Ramchand CN, Hemmings GP. TaqI polymorphic sites at the human dopamine beta-hydroxylase gene possibly associated with biochemical alterations of the catecholamine pathway in schizophrenia. Psychiatr Genet. 1998;8:19–24. [PubMed: 9564683]

Chapter Notes

Revision History

  • 29 October 2015 (me) Comprehensive update posted live
  • 24 January 2013 (me) Comprehensive update posted live
  • 16 September 2010 (me) Comprehensive update posted live
  • 16 December 2005 (me) Comprehensive update posted to live Web site
  • 4 September 2003 (me) Review posted to live Web site
  • 27 June 2003 (dr) Original submission
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