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; symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Life expectancy is unknown, but some affected individuals have lived beyond age 60 years.

Diagnosis/testing.

The diagnosis of DBH is established in a proband with profound neurogenic orthostatic hypotension, minimal or absent plasma concentrations of norepinephrine and epinephrine, and a five- to tenfold elevation of plasma dopamine; it is confirmed with identification of biallelic pathogenic variants in DBH by molecular genetic testing.

Management.

Treatment of manifestations: Administration of L-threo-3,4-dihydroxyphenylserine (droxidopa) restores norepinephrine and 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.

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. Yearly evaluation of efficacy of droxidopa against orthostatic hypotension as dosage adjustment may be required. Consultation with autonomic specialist prior to surgery or becoming pregnant.

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. Once the DBH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

No formal testing strategy has been presented for DBH deficiency; a clinical assessment including orthostatic vital signs and an ophthalmic exam should be the initial step and, if indicated, this should be followed by autonomic function testing and plasma catecholamine analysis.

DBH deficiency should be suspected in individuals with the following clinical, physiologic, and laboratory findings [Vincent & Robertson 2002, Timmers et al 2004]:

Establishing the Diagnosis

The diagnosis of DBH is established in a proband with profound neurogenic orthostatic hypotension, minimal or absent plasma concentrations of norepinephrine and epinephrine, and a five- to tenfold elevation of plasma dopamine; the diagnosis is confirmed with identification of biallelic pathogenic variants in DBH by molecular genetic testing (see Table 2).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of dopamine beta-hydroxylase deficiency is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of dopamine beta-hydroxylase deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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].

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

Features by age. The full clinical spectrum of DBH deficiency is not known because of the limited number of cases reported. Clinical features reported in 21 affected individuals (13 female, 8 male) are included in Table 3.

• Infancy:
  • 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.
• Childhood:
  • 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.
• Adolescence and early adulthood:
  • Symptoms generally worsen in late adolescence.
  • By early adulthood, affected individuals demonstrate profound orthostatic hypotension, fatigue, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Insulin resistance has been reported in an affected female age 15 years [Arnold et al 2017].
  • 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.

Renal function. Elevated blood urea nitrogen has been noted in six affected individuals in the USA [Garland et al 2005a, Garland et al 2009]. This may be evidence of a loss of renal function. A nephrologist who evaluated an individual age 16 years with a disproportionately high BUN (32 mg/dL) and slightly elevated creatinine (1.09 mg/dL) proposed that renal perfusion was reduced and that a BUN/Cr ratio <25 should be targeted. Although droxidopa acutely improved the ratio, the BUN/Cr ratio was further increased after a year of droxidopa treatment. The estimated GFR of an affected female age 57 years was reduced to 18 mL/min/1.73 m² [Emily Garland, personal observation]. Another patient with unexpectedly low eGFR and elevated creatinine was found, by electron microscopy, to have abnormal, fused mitochondria in the proximal, but not the distal, tubules. Associated problems with the glomerular-tubular balance can be at least partially reversed by treatment with droxidopa [Wassenberg et al 2017].

Cognitive function. 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].

Ptosis. Ptosis of the eyelids, defined as a reduction in the margin reflex distance, is common in individuals with DBH deficiency and can be noted at an early age. It was reported in the first descriptions of individuals with this disorder in the late 1980s and in more than 85% of all cases in the published literature. Levator function is intact. Some individuals undergo levator advancement surgery [Phillips et al 2013], which may mask this aspect of the phenotype.

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].

Hypoglycemia. Because so few individuals have been diagnosed with DBH deficiency, there has not been a clear explanation for the occurrence of hypoglycemic episodes in some of the individuals. It is not known if this is related to the absence of norepinephrine and epinephrine, or the elevated levels of dopamine. Investigators have speculated that it may result from loss of the counterregulatory actions of epinephrine that protect against hypoglycemia [Man in 't Veld et al 1987]. 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]. Her hyperinsulinemia persisted after a year of droxidopa treatment, despite improved orthostatic tolerance and restoration of plasma norepinephrine [Arnold et al 2017].

High palate. Physicians who inspect the palate often report that patients with DBH deficiency have a high, arched palate [Man in 't Veld et al 1988, Cheshire et al 2006; Emily Garland, unpublished findings]. This, however, is generally a subjective determination; it is not known how frequently it is either not assessed or reported incorrectly.

Life span. Four persons with DBH deficiency are known to have died. A woman age 57 years had chronic kidney disease and was undergoing treatment for breast cancer. Her listed cause of death at an assisted living facility was cardiac arrhythmia. Autopsy of a male age 28 years 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." Cardiac dysrhythmia, possibly related to fibrosis in the cardiac conduction system, may have contributed to the patient's sudden demise [Cheshire et al 2006]. One individual died at age 20 years, possibly by suicide. A person age 63 died of unknown causes. Other affected individuals are likely to be deceased, but there are no published reports of causes of death or of effects of the disorder on life span.

One individual was not diagnosed with DBH deficiency until age 73 years despite having long-lasting orthostatic hypotension [Despas et al 2010], suggesting that DBH deficiency may not necessarily shorten the life span.

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations.

Prevalence

The prevalence of DBH deficiency is unknown. Only 23 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 establish the extent of disease and needs in an individual diagnosed with dopamine beta-hydroxylase (DBH) deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Review of medical history to understand medical issues in context of the diagnosis of DBH deficiency. It can be helpful to recognize that some findings from a previous medical history or exam may be associated with the diagnosis of DBH deficiency and thus amenable to treatment with droxidopa.
• Assessment of standing time (length of time that the affected individual is able to stand)
• Assessment of renal function with, at a minimum, plasma and urinary electrolytes, creatinine, and BUN
• Ophthalmic examination with measurement of margin reflex distance to establish presence or absence of ptosis, followed by consideration of possible benefit of surgery
• Measurement of palate for an objective diagnosis of high-arched palate, which can cause feeding difficulties in infancy and breathing or sleeping difficulties. In the absence of these symptoms, no further evaluation or treatments are required.
• Consultation with a clinical geneticist and/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 norepinephrine (NE) by L-aromatic amino acid decarboxylase, thereby bypassing DBH (Figure 1).

Figure 1.

Synthesis of norepinephrine from dopamine or droxidopa

• Administration of 100-600 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 the dopamine precursor, L-3,4-dihydroxyphenylalanine (DOPA), to within the normal range and reduces dopamine (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 1,200 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.
• Midodrine 2.5-10 mg three times/day can be used to treat orthostatic hypotension.

By the time they are diagnosed, affected individuals have generally developed ways of coping with their presyncopal symptoms. Squatting or sitting/lying down can prevent falls.

Ptosis can be corrected by surgery.

Nasal stuffiness should be treated as needed.

Surveillance

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.

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

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

Affected persons or their physicians should consult with an autonomic specialist prior to undergoing surgical procedures or becoming pregnant. The type or dose of anesthesia may need to be modified, and droxidopa doses regulated.

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

The safety of using droxidopa during pregnancy has not been systematically evaluated, but its use appears justified considering that it is converted to norepinephrine, and that withholding treatment is likely to be riskier. At least three affected women have successfully given birth [Scurrah et al 2002; Author, personal observation] following uncomplicated deliveries while on droxidopa treatment.

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. See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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.
• 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. Each sib of the proband's parents is at a 50% risk of being a carrier of a DBH pathogenic variant.

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. Many healthy individuals without a pathogenic variant in DBH have extremely low plasma DBH activity, so DBH activity measurement does not provide information on carrier status. A systematic study of heterozygotes (carriers) has not been performed, but those parents of individuals with DBH deficiency (i.e., carriers) who have been studied have had 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the DBH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. 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 also requires molecular oxygen and ascorbic acid or some other electron source for enzyme activity. DBH catalyzes the conversion of dopamine to norepinephrine, a critical neurotransmitter in the central nervous system and in sympathetic noradrenergic pathways essential for cardiovascular regulation. Absence of functional DBH protein prevents synthesis of norepinephrine (noradrenaline).

Mechanism of disease causation. DBH deficiency occurs through a loss-of-function mechanism. Ten DBH pathogenic variants have been reported in individuals with DBH deficiency [Kim et al 2002, Deinum et al 2004, Kim et al 2011, Bartoletti-Stella et al 2015, Donadio et al 2016]. The majority are missense variants, with one splice variant, one frameshift, and one deletion.

DBH-specific laboratory considerations. Some apparently unaffected individuals consistently have very low DBH activity [Zabetian et al 2001]. Although a few individuals with low plasma DBH concentrations have clinical features of DBH deficiency, the vast majority with low plasma DBH concentrations are unaffected.

Several DBH variants that correlate with variation in the level of DBH activity have been identified in individuals neither affected by nor carriers of DBH deficiency. A variant in the promoter region, c.-979T>C, contributes up to 52% of the variation [Zabetian et al 2001].

Literature Cited

• Arnold AC, Garland EM, Celedonio JE, Raj SR, Abumrad NN, Biaggioni I, Robertson D, Luther JM, Shibao CA. Hyperinsulinemia and insulin resistance in dopamine β-hydroxylase deficiency. J Clin Endocrinol Metab. 2017;102:10–4. [PMC free article: PMC5413093] [PubMed: 27778639]
• Bartoletti-Stella A, Chiaro G, Calandra-Buonaura G, Contin M, Seaglione C, Barletta G, Cecere A, Garagnani P, Tieri P, Ferrarini A, Piras S, Franceschi C, Delledonne M, Cortelli P, Capellari S. A patient with PMP22-related hereditary neuropathy and DBH-gene-related dysautonomia. J Neurol. 2015;262:2373–81. [PubMed: 26410747]
• Biaggioni I, Robertson D. Endogenous restoration of noradrenaline by precursor therapy in dopamine-beta-hydroxylase deficiency. Lancet. 1987;2:1170–2. [PubMed: 2890806]
• Cheshire WP Jr, Dickson DW, Nahm KF, Kaufmann HC, Benarroch EE. Dopamine beta-hydroxylase deficiency involves the central autonomic network. Acta Neuropathol. 2006;112:227–9. [PubMed: 16830134]
• Deinum J, Steenbergen-Spanjers GC, Jansen M, Boomsma F, Lenders JW, van Ittersum FJ, Hück N, van den Heuvel LP, Wevers RA. DBH gene variants that cause low plasma dopamine beta hydroxylase with or without a severe orthostatic syndrome. J Med Genet. 2004;41:e38. [PMC free article: PMC1735728] [PubMed: 15060114]
• Despas F, Pathak A, Berry M, Cagnac R, Massabuau P, Liozon E, Galinier M, Senard JM. DBH deficiency in an elderly patient: efficacy and safety of chronic droxidopa. Clin Auton Res. 2010;20:205–7. [PubMed: 20063034]
• Donadio V, Liguori R, Incensi A, Chiaro G, Bartoletti-Stella A, Capellari S, Cortelli P. Skin biopsy and microneurography disclose selective noradrenergic dysfunction due to dopamine-β-hydroxylase deficiency. Auton Neurosci. 2016;197:56–9. [PubMed: 27237083]
• Elkayam L, Matalon A, Tseng CH, Axelrod F. Prevalence and severity of renal disease in familial dysautonomia. Am J Kidney Dis. 2006;48:780–6. [PubMed: 17059997]
• Erez A, Li J, Geraghty MT, Ben-Shachar S, Cooper ML, Mensing DE, Vonalt KD, Ou Z, Pursley AN, Chinault AC, Patel A, Cheung SW, Sahoo T. Mosaic deletion 11p13 in a child with dopamine beta-hydroxylase deficiency--case report and review of the literature. Am J Med Genet A. 2010;152A:732–6. [PubMed: 20186791]
• 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]
• Garland EM, Raj SR, Biaggioni I, Black BK, Robertson D. A hyperdopaminergic nephropathy in dopamine beta hydroxylase deficiency. Clin Auton Res. 2005a;15:321.
• Garland EM, Raj SR, Demartinis N, Robertson D. Case report: marathon runner with severe autonomic failure. Lancet. 2005b;366:S13. [PubMed: 16360730]
• Garland EM, Raj SR, Peltier AC, Robertson D, Biaggioni I. A cross-sectional study contrasting olfactory function in autonomic disorders. Neurology. 2011;76:456–60. [PMC free article: PMC3034411] [PubMed: 21282592]
• Goldstein DS, Holmes C, Axelrod FB. Plasma catechols in familial dysautonomia: a long-term follow-up study. Neurochem Res. 2008;33:1889–93. [PMC free article: PMC5241098] [PubMed: 18357519]
• Jepma M, Deinum J, Asplund CL, Rombouts SA, Tamsma JT, Tjeerdema N, Spapé MM, Garland EM, Robertson D, Lenders JW, Nieuwenhuis S. Neurocognitive function in dopamine-β-hydroxylase deficiency. Neuropsychopharmacology. 2011;36:1608–19. [PMC free article: PMC3138665] [PubMed: 21471955]
• Kim CH, Leung A, Huh YH, Yang E, Kim DJ, Leblanc P, Ryu H, Kim K, Kim DW, Garland EM, Raj SR, Biaggioni I, Robertson D, Kim KS. Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase. J Biol Chem. 2011;286:9196–204. [PMC free article: PMC3059068] [PubMed: 21209083]
• Kim CH, Zabetian CP, Cubells JF, Cho S, Biaggioni I, Cohen BM, Robertson D, Kim KS. Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet. 2002;108:140–7. [PubMed: 11857564]
• Man in 't Veld AJ, Boomsma F, Moleman P, Schalekamp MA. Congenital dopamine-beta-hydroxylase deficiency. A novel orthostatic syndrome. Lancet. 1987;1:183–8. [PubMed: 2880016]
• Man in 't Veld AJ, Boomsma F, van den Meiracker AH, Julien C, Lenders J, Schalekamp MA. d,l-threo-3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine beta-hydroxylase deficiency. J Hypertens Suppl. 1988;6:S547–9. [PubMed: 3149290]
• Phillips L, Robertson D, Melson MR, Garland EM, Joos KM. Pediatric ptosis as a sign of treatable autonomic dysfunction. Am J Ophthalmol. 2013;156:370–374.e2. [PMC free article: PMC3720787] [PubMed: 23622564]
• Robertson D, Goldberg MR, Onrot J, Hollister AS, Wiley R, Thompson JG Jr, Robertson RM. Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired beta-hydroxylation of dopamine. N Engl J Med. 1986;314:1494–7. [PubMed: 3010116]
• Scurrah NJ, Ross AW, Solly M. Peripartum management of a patient with dopamine beta-hydroxylase deficiency, a rare congenital cause of dysautonomia. Anaesth Intensive Care. 2002;30:484–6. [PubMed: 12180590]
• Shibao C, Garland EM, Luther JM, Celedonio JE, Raj SR, Biaggioni I, Robertson D. Hyperinsulinemia and insulin resistance in dopamine beta-hydroxylase deficiency. Clin Auton Res. 2014;24:223A. [PMC free article: PMC5413093] [PubMed: 27778639]
• Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54 Suppl 6:S49–55. [PubMed: 12891654]
• Timmers HJ, Deinum J, Wevers RA, Lenders JW. Congenital dopamine-beta-hydroxylase deficiency in humans. Ann N Y Acad Sci. 2004;1018:520–3. [PubMed: 15240410]
• van den Berg MP, Almomani R, Biaggioni I, van Faassen M, van der Harst P, Silljé HHW, Mateo Leach I, Hemmelder MH, Navis G, Luijckx GJ, de Brouwer APM, Venselaar H, Verbeek MM, van der Zwaag PA, Jongbloed JDH, van Tintelen JP, Wevers RA, Kema IP. Mutations in CYB561 causing a novel orthostatic hypotension syndrome. Circ Res. 2018;122:846–54. [PMC free article: PMC5924476] [PubMed: 29343526]
• van den Meiracker AH, Boomsma F, Man in 't Veld AJ. Dopamine-b-hydroxylase deficiency. In: Robertson D, Low PA, Polinsky RJ, eds. Primer on the Autonomic Nervous System. San Diego: Academic Press Inc; 1996:205-8.
• Vincent S, Robertson D. The broader view: catecholamine abnormalities. Clin Auton Res. 2002;12 Suppl 1:I44–9. [PubMed: 12102462]
• Wassenberg T, Willemsen M, Dijkman H, Deinum J, Monnens L. Congenital eyelid ptosis, decreased glomerular filtration, and orthostatic hypotension: questions. Pediatr Nephrol. 2017;32:1169–70. [PMC free article: PMC5440537] [PubMed: 27858193]
• Wei J, Ramchand CN, Hemmings GP. A study of the relationship between the DBH activity in serum and a MspI polymorphic site in intron 9 of the human DBH gene in schizophrenia. Schizophr Res. 1996;22:77–80. [PubMed: 8908693]
• Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, Kim KS, Kim CH, Malison RT, Gelernter J, Cubells JF. A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet. 2001;68:515–22. [PMC free article: PMC1235285] [PubMed: 11170900]

Author History

Italo Biaggioni, MD (2019-present)
Emily M Garland, PhD (2003-present)
David Robertson, MD; Vanderbilt University (2003-2019)

Revision History

• 25 April 2019 (ha) Comprehensive update posted live
• 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 live
• 4 September 2003 (me) Review posted live
• 27 June 2003 (dr) Original submission