Dopamine beta hydroxylase deficiency

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Dopamine beta hydroxylase deficiency
Other names: DβH deficiency
Dopamine beta hydroxylase is the enzyme responsible for converting dopamine (pictured) to norepinephrine.

Dopamine beta (β)-hydroxylase deficiency is a condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine. Dopamine is released, as a false neurotransmitter, in place of norepinephrine. Other names for norepinephrine include noradrenaline (NA) and noradrenalin. This condition is also sometimes referred to as "norepinephrine deficiency". Researchers of disorders such as schizophrenia are interested in studying this disorder, as patients with these specific diseases can have an increase in the amount of dopamine in their system and yet do not show other symptoms of DβH deficiency.

Dopamine beta-hydroxylase deficiency is a very rare form of dysautonomia. It belongs to the class of rare diseases, with "a prevalence of fewer than 20 affected individuals, all of Western European descent", as described in the scientific literature. It is an autosomal recessive disorder caused by a mutation in the DβH gene, which results in the production of a nonfunctional dopamine β-hydroxylase enzyme.[1] Without this enzyme, the patients with DβH deficiency develop many clinical manifestations which greatly affect their daily lives.

Signs and symptoms

Dopamine beta (β)-hydroxylase deficiency is a condition that affects the autonomic nervous system (ANS). The ANS works via two opposing branches, the sympathetic and parasympathetic, both of which antagonistically control involuntary processes that regulate bodily homeostasis. Problems related to DβH deficiency often first appear as complications shortly after birth. Postnatal episodes may include vomiting, dehydration, hypotension, muscle hypotonia, hypothermia, and hypoglycemia.[2]

Due to the deficiency of norepinephrine and epinephrine those affected by dopamine β-hydroxylase deficiency may present with droopy eyelids (ptosis), nasal congestion, and hypotension. The most common complaint of individuals with dopamine β-hydroxylase deficiency is orthostatic hypotension. The symptoms associated with orthostatic hypotension are dizziness, blurred vision, or fainting upon standing. Therefore, DβH deficiency patients may have an inability to stand for a prolonged period of time. This phenomenon is especially pronounced when going from supine to upright positions, such as getting out of bed in the morning. It is also worsened by extreme climates due to loss of fluid through excessive sweating. The inability to maintain normal blood pressure makes it difficult for people with DβH deficiency to exercise (exercise intolerance). Males with DβH deficiency may experience retrograde ejaculation, a discharge of semen backward into the bladder due to dysmotility of their smooth muscle, which as innervated by the ANS. A subset of DβH deficiency patients present with hypermobility.[1] Postural orthostatic tachycardia syndrome, another form of dysautonomia, also sees this comorbidity with hypermobility in the form of a rare connective tissue disorder called Ehlers Danlos syndrome.

Another commonly experienced symptom is hypoglycemia, which is thought to be caused by adrenomedullary failure. In looking at the cardiovascular system, a loss of noradrenergic control is seen as T-wave abnormalities on electrocardiogram. Prolactin is frequently suppressed by excessive dopamine found in the patient's central nervous system. Excess dopamine can also affect digestion, producing vomiting and inhibiting motor signaling to the GI tract.[3]


Scheme of catecholamine synthesis and breakdown in DBH‐deficiency

The etiology of Dopamine beta hydroxylase deficiency is due to mutations in the DBH gene (at 9q34). This results in very low levels of noradrenaline/adrenaline, and increased levels of dopamine in plasma.[4]


The diagnosis is done via genetic testing of the DBH gene.[4]

Differential diagnosis

The DDx is based on Orthostatic hypotension[4]



Untreated individuals with DβH deficiency should avoid hot environments, strenuous exercise, standing still for prolonged time and dehydration. Care should be taken when changing position from horizontal to upright.[3]


Since the conversion of dihydroxyphenylserine (Droxidopa; trade name: Northera; also known as L-DOPS, L-threo-dihydroxyphenylserine, L-threo-DOPS and SM-5688), to norepinephrine bypasses the dopamine beta-hydroxylation step of catecholamine synthesis, L-Threo-DOPS is the ideal therapeutic agent.[5][6][7][8] In humans with DβH deficiency, L-Threo-DOPS, a synthetic precursor of noradrenaline, administration has proven effective in dramatic increase of blood pressure and subsequent relief of postural symptoms.[9]

L-DOPS continues to be studied pharmacologically and pharmacokinetically and shows an ability to increase the levels of central nervous system norepinephrine by a significant amount. This is despite the fact that L-DOPS has a relative difficulty crossing the blood-brain barrier when compared to other medications such as L-DOPA. When used concurrently, there is evidence to show that there is increased efficacy as they are both intimately involved and connected to the pathway in becoming norepinephrine.

There is hope and evidence that L-DOPS can be used much more widely to help other conditions or symptoms such as pain, chronic stroke symptoms, and progressive supranuclear palsy, amongst others. Clinically, L-DOPS has been already shown to be helpful in treating a variety of other conditions related to hypotension including the following:

  • Diabetes induced orthostatic hypotension
  • Dialysis-induced hypotension
  • Orthostatic intolerance
  • Familial amyloidotic polyneuropathy
  • Spinal Cord Injury related hypotension[10]

Empirical evidence of mild effectiveness has been reported using mineralocorticoids or adrenergic receptor agonists as therapies.[2]

Other medications that can bring relief to symptoms include:[11]

Vitamin C (ascorbic acid) is also a required cofactor for the Dopamine beta hydroxylase enzyme. Recent research has shown that vitamin C rapidly catalyzes the conversion of dopamine to norepinephrine through stimulation of the dopamine beta hydroxylase enzyme.[11]


This is a form of dysautonomia but differentiated from familial dysautonomia by a lack of familial dysautonomic symptoms such as loss of sense of pain and smell. While L-threo-DOPS has been described as being "very effective for restoring noradrenergic tone and correcting postural hypotension, response to treatment is variable and the long-term and functional outcome is unknown."[12]

Researchers have put together retrospective data collections in order to better under the progression of this orphan disease. Most studies show a perinatal period marked by inadequacy of the ANS to control blood pressure, blood sugar, and body temperature. The experiences of orthostatic hypotension, exercise intolerance, and "traumatic morbidity related to falls and syncope" have been documented later in lives of people with this condition.[2] To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation, outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies, a patient registry was established by the non-commercial International Working Group on Neurotransmitter Related Disorders (iNTD).[13]

Current research

Recent studies have explored the connection between DβH deficiency, Droxidopa treatment, and the effect on orthostatic tolerance and glucose homeostasis. It was found that Droxidopa increased acute and late glucose-stimulated insulin secretion and improved patients' insulin sensitivity. However, the use of Droxidopa was found to only produce "modest changes in glucose homeostasis" overall. This shows that treatment modalities other than Droxidopa should be pursued as possible adjuncts for the hyperinsulinemia seen in DβH deficiency.[14]


  1. 1.0 1.1 Reference, Genetics Home. "dopamine beta-hydroxylase deficiency". Genetics Home Reference. Archived from the original on 2016-12-20. Retrieved 2016-12-15.
  2. 2.0 2.1 2.2 Senard, Jean-Michel; Rouet, Philippe (2006-01-01). "Dopamine beta-hydroxylase deficiency". Orphanet Journal of Rare Diseases. 1: 7. doi:10.1186/1750-1172-1-7. ISSN 1750-1172. PMC 1459119. PMID 16722595.
  3. 3.0 3.1 "Dopamine receptor antagonists - Pharmacorama". Archived from the original on 2016-12-13. Retrieved 2016-12-15.
  4. 4.0 4.1 4.2 RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Dopamine beta hydroxylase deficiency". Archived from the original on 27 November 2022. Retrieved 16 May 2023.
  5. Kaufmann, Horacio; Saadia, Daniela; Voustianiouk, Andrei; Goldstein, David S.; Holmes, Courtney; Yahr, Melvin D.; Nardin, Rachel; Freeman, Roy (2003-08-12). "Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension". Circulation. 108 (6): 724–728. doi:10.1161/01.CIR.0000083721.49847.D7. ISSN 0009-7322. PMID 12885750.
  6. Mathias, C. J.; Senard, J. M.; Braune, S.; Watson, L.; Aragishi, A.; Keeling, J. E.; Taylor, M. D. (2001-08-01). "L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure". Clinical Autonomic Research. 11 (4): 235–242. doi:10.1007/bf02298955. ISSN 0959-9851. PMID 11710796. S2CID 24567321.
  7. Isaacson, Stuart; Skettini, Julia (2014-04-03). "Neurogenic orthostatic hypotension in Parkinson's disease: evaluation, management, and emerging role of droxidopa". Vascular Health and Risk Management. 10: 169–76. doi:10.2147/vhrm.s53983. PMC 3979788. PMID 24729712.
  8. Biaggioni, Italo; Freeman, Roy; Mathias, Christopher J.; Low, Phillip; Hewitt, L. Arthur; Kaufmann, Horacio (2015-01-01). "Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to DroxidopaNovelty and Significance". Hypertension. 65 (1): 101–107. doi:10.1161/HYPERTENSIONAHA.114.04035. ISSN 0194-911X. PMC 4354798. PMID 25350981.
  9. Biaggioni, Italo; Robertson, David (1987). "Endogenous Restoration of Noradrenaline by Precursor Therapy in Dopamine-Beta-Hydroxylase Deficiency". The Lancet. 330 (8569): 1170–1172. doi:10.1016/s0140-6736(87)91317-1. PMID 2890806. S2CID 43845850.
  10. Goldstein, David S. (2006-09-01). "L-Dihydroxyphenylserine (L-DOPS): A Norepinephrine Prodrug". Cardiovascular Drug Reviews. 24 (3–4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. ISSN 1527-3466. PMID 17214596.
  11. 11.0 11.1 Robertson, David; Garland, Emily M. (1993-01-01). "Dopamine Beta-Hydroxylase Deficiency". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 20301647. Archived from the original on 2010-05-28. Retrieved 2022-06-29.
  12. Robertson, David; Goldberg, Michael R.; Onrot, Jack; Hollister, Alan S.; Wiley, Ron; Thompson, John G. Jr.; Robertson, Rose Marie (1986-06-05). "Isolated Failure of Autonomic Noradrenergic Neurotransmission". New England Journal of Medicine. 314 (23): 1494–1497. doi:10.1056/NEJM198606053142307. ISSN 0028-4793. PMID 3010116.
  13. "Patient Registry". Archived from the original on 2021-04-28.
  14. Arnold, Amy C.; Garland, Emily M.; Celedonio, Jorge E.; Raj, Satish R.; Abumrad, Naji N.; Biaggioni, Italo; Robertson, David; Luther, James M.; Shibao, Cyndya A. (2016-10-25). "Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency". The Journal of Clinical Endocrinology & Metabolism. 102 (1): jc.2016–3274. doi:10.1210/jc.2016-3274. ISSN 0021-972X. PMC 5413093. PMID 27778639.

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