DiagnosisClinical DiagnosisPhysical examination of individuals with dopamine beta-hydroxylase (DBH) deficiency reveals the following [Vincent & Robertson 2002, Timmers et al 2004]:Poor cardiovascular regulation:A low-to-normal supine blood pressure and low or normal supine heart rateSystolic blood pressure below 80 mm Hg in the upright positionAn inadequate compensatory rise in heart rate with standingInability to stand motionless for more than a minuteOther autonomic dysfunction:Ptosis in some individualsA marked decrease in intraocular pressure with standingSomewhat small pupils that respond to light and accommodation but not to hydroxyamphetamine. Parasympatholytics dilate the pupils appropriately.Intact sweatingSkeletal and muscle findings in some patients:Arched palateHyperextensible jointsSluggish deep-tendon reflexesMild facial-muscle weaknessHypotonic skeletal musclesPhysiologic tests of autonomic function. Physiologic tests of autonomic function 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.Muscle sympathetic nerve activity measured by microneurography is normal.Spectral analysis of beat-to-beat values of R–R interval and blood pressure indicates that individuals with DBH deficiency have greatly reduced supine resting blood pressure variability in the low-frequency component, a marker of sympathetic tone, but a relatively normal high-frequency component of heart rate variability, a marker of cardiac vagal tone [Okamoto et al 2012].Table 1. Results of Autonomic Function Testing in Patients with Dopamine Beta Hydroxylase Deficiency (DBHD)View in own windowDBHD ^{1Control 1Number:
DBHD/ControlP ValueAge (years)27±1434±100.091SA ratio1.3±0.231.4±0.217/860.338Valsalva phase IIDelta SBP (mm Hg)-40±27-7±226/550.001Delta HR (bpm)30±1130±166/530.971Valsalva phase IVDelta SBP (mm Hg)-22±1923±167/84<0.001Delta HR (bpm)7±8-8±117/82<0.001Valsalva ratio1.3±0.211.7±0.397/790.011HyperventilationDelta SBP (mm Hg)-13±13-7±128/860.148Delta HR (bpm)16±2011±117/860.308Cold pressorDelta SBP (mm Hg)5±1021±147/830.005Delta HR (bpm)16±1210±116/830.181HandgripDelta SBP (mm Hg)3±517±136/830.013Delta HR (bpm)15±1210±106/830.257EM Garland, unpublished data: Vanderbilt Autonomic Dysfunction CenterSA = sinus arrhythmiaSBP = systolic blood pressureHR = heart rate1. Mean ± SDPharmacologic tests of autonomic function. There is a several-fold hypersensitivity to α1-adrenoceptor agonists and β-adrenoceptor agonists:Propranolol, a β-adrenergic antagonist, does not lower heart rate.Intravenous atropine raises heart rate by 40-60 beats per minute.Pindolol, a β-adrenergic antagonist with some sympathomimetic activity, raises heart rate.Clonidine, a partial agonist of α2-adrenoceptors that acts centrally to reduce sympathetic outflow and lower blood pressure in normal individuals, can also exert peripheral pressor effects by stimulation of vascular α2-adrenoceptors. Individuals with DBH deficiency have no drop in seated mean arterial pressure following the administration of clonidine. On the contrary, significant increases in blood pressure are seen with higher doses of this agent.TestingDopamine beta-hydroxylase (EC 1.14.17.1) catalyzes the hydroxylation of dopamine (DA) to norepinephrine (NE). Although individuals with DBH deficiency lack plasma DBH activity and DBH immunoreactivity [Robertson et al 1986, Man in ‘t Veld et al 1987], the most helpful diagnostic test is measurement of the concentration of plasma norepinephrine (NE) and dopamine (DA). Plasma catecholamines. Biochemical features unique to DBH deficiency:Minimal or absent plasma NE and epinephrine AND a five- to tenfold elevation of plasma 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 100pg/mL (0.65 nmol/L). Note: One unusual patient who was not diagnosed until age 73 years was reported to have a plasma dopamine 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. Metabolites of NE including epinephrine, metanephrine, normetanephrine, vanillylmandelic acid (VMA), and dihydroxyphenylglycol (DHPG) are all very low or absent in plasma, urine, and CSF.Metabolites of DA including homovanillic acid (HVA) and 3-methoxytyramine are elevated [Robertson et al 1986, Man in ‘t Veld et al 1987].A more discriminating diagnostic measurement is the ratio of the DA metabolite dihydroxyphenylacetic acid (DOPAC) to dihydroxyphenylglycol (DHPG). In individuals with DBH deficiency, this ratio is at least 100:1 and may exceed 1000:1 (in healthy controls: <5:1). Note: (1) It is essential to assay both NE and DA with their metabolites 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 controls:Tyramine, for example, which normally is taken up by the NE transporter and stimulates NE release into the synapse, has no such effect in persons with DBH deficiency. NE remains undetectable after administration of high doses of tyramine, while DA increases [Robertson et al 1986]. This increase in plasma DA concentration probably reflects release of neuronal DA stores, but in some individuals, it may be the result of tyramine conversion to DA [Jacob et al 2003].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.Plasma DBH enzymatic assay. In addition to catalysis of DA, DBH catalyzes the hydroxylation of tyramine and other phenylethylamine derivatives. DBH is released into the synaptic cleft during vesicular exocytosis. A fraction of the DBH released into the synaptic cleft spills over into the blood, where it can be detected. Plasma levels of DBH enzyme activity vary over a wide range in different individuals, and most individuals with reduced plasma DBH enzyme activity do not have DBH deficiency. DBH enzyme activity is undetectable in the blood of individuals with DBH deficiency [Robertson et al 1986, Man in ‘t Veld et al 1987]. Assays for DBH enzymatic assay:A spectrophotometric procedure based on the enzymatic conversion of the substrate tyramine into the product octopamine in the presence of excess ascorbate, sodium fumarate, catalase, N-ethylmaleimide, and pargyline. The octopamine is then oxidized to p-hydroxybenzaldehyde. A two-step enzyme radioassay that incorporates conversion of phenylethylamine to phenylethanolamine by DBH, then metabolism of phenylethanolamine to N-methylphenylethanolamine by phenylethanolamine N-methyltransferase (PNMT) and radioactive S-adenosylmethionine. High-performance liquid chromatographic (HPLC) procedures. Plasma DBH immunoassay. This assay measures the total protein antigenically related to DBH, including inactive forms of the enzyme. Lack of DBH immunoreactivity in cerebrospinal fluid or plasma suggests that the cause of DBH deficiency is absent enzyme, rather than inactive enzyme.Immunocytochemical examination. DBH is located almost exclusively in the chromaffin granules of the adrenal medulla and in the large dense-core synaptic vesicles of both central and peripheral adrenergic and noradrenergic neurons. Immunocytochemical examination of these sympathetic fibers reveals undetectable DBH protein.Molecular Genetic TestingGene. DBH is the only gene in which mutations are known to cause DBH deficiency.Clinical testing Table 2. Summary of Molecular Genetic Testing Used in Dopamine Beta-Hydroxylase DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1Test AvailabilityDBHSequence analysisSequence variants 250%-100% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Cho et al [2003] Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandMeasurement of the plasma concentration of the catecholamines dopamine (DA) and norepinephrine (NE) and their metabolites, dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) is the most helpful and least expensive diagnostic test. This analysis is commonly performed with a high performance liquid chromatography (HPLC) procedure and electrochemical detection. This should be the first test undertaken in individuals who describe life-long orthostatic hypotension and profound symptoms that inhibit the ability to stand. Undetectable norepinephrine and elevated dopamine would strongly suggest a diagnosis of DBH deficiency. Autonomic function testing that assesses sympathetic and parasympathetic control of heart rate and blood pressure should confirm the noradrenergic sympathetic failure and intact parasympathetic function of patients with DBH deficiency. A standard battery of tests includes sinus arrhythmia (heart rate response to 5-sec inhalation and 5-sec exhalation for 90 sec), a cold pressor test (hand in ice water for 1 min), isometric handgrip (30% of maximum voluntary contraction for 3 min), hyperventilation (approximately 60 breaths/min for 30 sec), and a Valsalva maneuver (40 mm Hg pressure generated for 15 seconds). The blunted sympathetic vasopressor response with the handgrip and cold pressor tests and the abnormal response with the Valsalva maneuver are evident in Table 1.DBH enzymatic assay and immunoassay are not necessary to confirm the diagnosis of DBH deficiency. It is important to realize that many apparently healthy individuals have very low DBH enzyme activity.Molecular genetic testing of DBH cannot be recommended at this time for confirming the diagnosis, since DBH deficiency is such a rare disorder and its genetic basis has not been elucidated in all affected individuals. However, molecular genetic testing may be useful to further clarify genotype-phenotype correlations. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersSeveral normal allelic variants in DBH have been identified. Linkage and association studies with these variants have been conducted with mixed results in individuals with schizophrenia [Pal et al 2009], migraine [Fernandez et al 2009], attention deficit/hyperactivity disorder [Kopeckova et al 2006, Elia & Devoto 2007, Gizer et al 2009], Parkinson disease [Ross et al 2008], addictive behavior [Freire et al 2006, Köhnke et al 2006, Guindalini et al 2008], and depression [Togsverd et al 2008]. In addition, promoter variants associated with lower plasma DBH activity predict lower blood pressure [Chen et al 2010, Chen et al 2011].}

Natural HistoryDopamine 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].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 18 affected individuals (11 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 DeficiencyView in own windowFeature# of Individuals ^{1Severe orthostatic hypotension18/18 (100%)Anemia8/13 (61%)Ptosis of eyelids11/12 (92%)Abnormal sexual maturation0/11Hyperflexible or hypermobile joints6/9 (67%)ECG abnormalities 22/11 (18%)Epileptiform symptoms4/11 (36%)Nasal stuffiness9/9 (100%)Hypoglycemia3/10 (30%)Sluggish deep-tendon reflexes3/8 (38%)Increased plasma creatinine4/9 (44%)Polyuria/nocturia3/8 (38%)High palate9/9 (100%)Increased BUN5/8 (63%)Muscle hypotonia3/8 (38%)Postprandial hypotension3/7 (43%)Sleep irregularities5/6 (83%)Impaired ejaculation4/4 (100%)1. Number of individuals with the finding/total number evaluated for the finding2. ECG=electrocardiogramPresyncopal 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 five 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 aspects, 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 between 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 the gene 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. 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 CorrelationsBecause of the small number of individuals diagnosed with DBH deficiency, it is not possible to determine correlations between specific phenotypes and mutations in DBH.

Differential DiagnosisThe striking catecholamine abnormalities distinguish DBH deficiency from other disorders. Other catecholamine disorders, such as aromatic amino acid decarboxylase deficiency, 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 NE concentrations are greatly reduced, sometimes to 10% of normal; plasma 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 DHPG concentration is low; plasma DOPA 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 mutations account for more than 99% of mutant alleles in individuals of Ashkenazi Jewish descent.ATP7A-related copper transport disorders. Menkes disease and occipital horn syndrome (OHS) are disorders of copper transport caused by mutations in the copper-transporting ATPase gene, ATP7A. Inheritance is X-linked. 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 dihydroxyphenylglycol (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 occurs between ages seven months and 3.5 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. Molecular genetic testing of ATP7A detects mutations in more than 95% of affected individuals.Transthyretin amyloidosis is characterized by the neuropathic changes of peripheral 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. Molecular genetic testing of TTR detects more than 99% of disease-causing (amyloidogenic) mutations.Multiple system atrophy (MSA, Shy-Drager syndrome, SDS). As in DBH deficiency, signs include orthostatic hypotension, but extrapyramidal or cerebellar findings are also present. Age of onset in MSA is after age 30 years.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 historyMedical genetics consultationTreatment of ManifestationsFor 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 (DOPS or droxidopa). DOPS is converted directly to NE by L-aromatic amino acid decarboxylase, thereby bypassing DBH (Figure 1). Administration of 100 to 500 mg DOPS 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. DOPS 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].FigureFigure 1. Synthesis of norepinephrine from dopamine or L-DOPS 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 daily) has been of limited benefit in raising blood pressure.Some pressor response to phenylpropanolamine (25 mg) is observed, presumably owing to the denervation hypersensitivity of vascular α-adrenoceptors.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 ManifestationsDOPS can improve the orthostatic hypotension and symptoms, but these recur if treatment is stopped.Prevention of Secondary ComplicationsThe effect of DOPS on renal function is unknown. SurveillanceRenal 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 DOPS should be encouraged to report any adverse events to their physician.Agents/Circumstances to AvoidUntreated individuals with DBH deficiency should avoid hot environments, strenuous exercise, standing still, and dehydration.Evaluation of Relatives at RiskSibs should be tested only if symptomatic or if known to be a carrier of one of the causative mutations. While subtle impairment of autonomic function may be identified in carriers, sibs without orthostatic hypotension would be unlikely to have DBH deficiency. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDBH9q34​.2Dopamine beta-hydroxylaseDBH homepage - Mendelian genesDBHData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 223360DOPAMINE BETA-HYDROXYLASE DEFICIENCY, CONGENITAL 609312DOPAMINE BETA-HYDROXYLASE, PLASMA; DBHNormal allelic variants. DBH is approximately 23 kb and is composed of 12 exons. Linkage of DBH to the ABO blood group locus on chromosome 9 has been demonstrated. Normal allelic variants of DBH correlate with variation in the level of DBH activity in individuals who are neither affected nor carriers. A polymorphism in the promoter region contributes up to 52% of the variation (see Normal gene product).Pathologic allelic variants. The four putative disease mutations first identified by Kim et al [2002] in two patients with DBH deficiency have not been reported in other autonomic disorders [Cho et al 2003]. Affected individual #1 was a compound heterozygote for c.[348+2T>C];[342C>A]. Affected individual #2 had one allele with c.348+2T>C and a second allele with two missense variants c.[301G>A;1033G>A]. A third compound heterozygote was more recently identified: c.[348+2T>C];[c.1085C>A] [Kim et al 2011].The c.348+2T>C mutation and three additional mutations in exons 3, 4, and 11 have been identified in four families with DBH deficiency in the Netherlands [Deinum et al 2004]. The affected individuals were a c.348+2T>C homozygote, a c.806G>T homozygote, and a compound heterozygote for c.[348+2T>C];[617delA].Table 4. Selected DBH Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)LocationProtein Amino Acid Change
(Alias ¹)Reference SequencesNormal (19-bp insertion/deletion) ^{24.7 kb 5’ to the transcriptional start site--521(11_15) 35’UTR--X63418 (gene segment) c.486G>A
(444 g/a)Exon 2 splice donor site--NM_000787​.3
NP_000778​.3c.744+8C>T 4(IVS3+8C>T)Intron 3--c.1562+415G>A 4(IVS10+415G>A)Intron 10--c.-979C>T 5(-1021C>T)5' UTR--(MspI polymorphism) 5Intron 9Pathologicc.301G>A
(G259A)Exon 1p.Val101Met
(V87M)c.342C>A
(C300A)Exon 2p.Asp114Glu
(D100E)c.348+2T>C 6(IVS1+2T>C)Intron 1--c.617delA
(c.575delA)Exon 3p.Glu206Glyfs*82c.806G>T
(G764T)Exon 4p.Cys269Phe
(C255F)c.1033G>A
(G991A)Exon 6p.Asp345Asn
(D331N)c.1085C>A
(C1043A)Exon 6p.Ala362Glu
(A348E)c.1667A>G
(A1625G)Exon 11p.Tyr556Cys
(Y542C)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Cubells et al [2000]3. GT dinucleotide repeat sequence that varies between 11 and 15 repeats in a population [Porter et al 1992]4. Likely a normal variant on the same allele (in cis) as a pathologic mutation (see Pathologic allelic variants)5. Normal allelic variants that correlate with the level of DBH activity (see Normal gene product)6. An allele frequency of 0.001 has been reported for c. 348+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].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.-979C>T variant 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.486G>A) [Cubells et al 1998], and a GT microsatellite repeat 521(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 normal individuals have consistent levels of very low DBH activity [Zabetian et al 2001]. In European Americans, homozygosity at the T allele of c.-979C>T 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 the syndrome of complete DBH deficiency, millions of normal individuals also have low plasma DBH concentrations. Although the detailed phenotype of these normal individuals remains unexplored, they have been reported to have near-normal plasma concentrations of norepinephrine and epinephrine and do not have orthostatic symptoms. 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]. Abnormal gene product. The c.348+2T>C variant results in an aberrantly spliced product containing a premature stop codon and no detectable DBH protein. Mutations in exons 2 and 6 prevent normal protein trafficking [Kim et al 2011].}