Clinical Diagnosis

Physical 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 rate

  • Systolic blood pressure below 80 mm Hg in the upright position

  • A compensatory rise in heart rate with standing

  • Inability to stand motionless for more than a minute

• Other autonomic dysfunction:

  • Ptosis in some individuals

  • Somewhat small pupils that respond to light and accommodation but not to hydroxyamphetamine. Parasympatholytics dilate the pupils appropriately.

• Intact sweating

• Skeletal and muscle findings in some patients:

  • Hyperextensible joints

  • Sluggish deep-tendon reflexes

  • Mild facial-muscle weakness

  • Hypotonic skeletal muscles

  • Arched palate

Physiologic tests of autonomic function. Physiologic tests of autonomic function may provide diagnostic information of great specificity. Autonomic function testing 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.

Pharmacologic 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.

Testing

Dopamine 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 the plasma catecholamines norepinephrine (NE) and dopamine (DA).

Plasma catecholamines. Biochemical features unique to DBH deficiency:

• Minimal or undetectable 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 10.3 ng/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 b-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 low levels of 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 Testing

Gene. DBH is the only gene known to be associated with DBH deficiency.

Sequence analysis of the coding and flanking intronic regions of DBH detects missense, small deletion, and splicing mutations.

Table 2. Summary of Molecular Genetic Testing Used in Dopamine Beta-Hydroxylase Deficiency

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
DBH	Sequence analysis	Sequence variants 2	50%-100% 3	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Cho et al [2003]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Measurement 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 the DBH gene at this time cannot be recommended for confirming the diagnosis, since DBH deficiency is such a rare disorder and its genetic basis has not been elucidated in all affected individuals.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Several normal allelic variants in the DBH gene 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], depression [Togsverd et al 2008], and blood pressure [Chen et al 2010].

Natural History

Dopamine beta-hydroxylase (DBH) deficiency is characterized by normal parasympathetic and sympathetic cholinergic function but with a lack of sympathetic noradrenergic 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 profound 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.

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 five affected individuals in the United States [Garland et al 2005, 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/1.73m².

Despite the lack of norepinephrine, persons with DBH deficiency apparently have relatively normal mental status. Preliminary results from five individuals in an ongoing study in the Netherlands are consistent with no obvious cognitive impairment.

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].

Since 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 Correlations

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

Prevalence

The prevalence of DBH deficiency is unknown. Only 20 affected individuals, all of Western European descent, have been reported in the literature, suggesting that it is a rare disorder.

Evaluations Following Initial Diagnosis

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

• Standing time (length of time that the affected individual is able to stand)

• Medical history

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 (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.

Figure

Figure 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 Manifestations

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

Prevention of Secondary Complications

The effect of DOPS on renal function is unknown.

Surveillance

Renal function should be assessed every five years and more often if a loss of function is evident.

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

Agents/Circumstances to Avoid

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

Testing of Relatives at Risk

Siblings should be tested only if symptomatic.

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

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

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 is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with DBH deficiency are obligate heterozygotes (carriers) for a disease-causing mutation in the DBH gene.

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

Carrier Detection

Carrier testing using molecular genetic techniques is possible if the two disease-causing mutations in the family are known.

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 some of the 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Statements and Policies Regarding Genetic Testing

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page

Literature Cited

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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. Senard JM, Rouet P. Dopamine beta-hydroxylase deficiency. Orphanet J Rare Dis. 2006;1:7. [PMC free article: PMC1459119] [PubMed: 16722595]
4. 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]

Revision History

• 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