| prognosis = Variable; manageable with treatment, but chronic symptoms often persist
| frequency =
| frequency = Extremely rare (less than 100 cases reported worldwide)
| deaths =
| deaths = Rare, usually related to severe hypotension or complications from autonomic dysfunction
}}
}}
'''Dopamine beta (β)-hydroxylase deficiency''' is a condition involving inadequate [[Dopamine beta hydroxylase|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 rare [[genetic disorder]] that affects the synthesis of [[catecholamines]], which are important neurotransmitters in the [[nervous system]]. This condition is characterized by a deficiency in the enzyme [[dopamine beta-hydroxylase]] (DBH), which is responsible for converting [[dopamine]] to [[norepinephrine]].
==Pathophysiology==
Dopamine beta-hydroxylase deficiency is a very rare form of [[dysautonomia]]. It belongs to the class of [[rare disease]]s, with "a prevalence of fewer than 20 affected individuals, all of Western European descent", as described in the scientific literature. It is an [[:Category:Autosomal recessive disorders|autosomal recessive disorder]] caused by a mutation in the DβH gene, which results in the production of a nonfunctional dopamine β-hydroxylase enzyme.<ref name=":0">{{Cite web|url=https://ghr.nlm.nih.gov/condition/dopamine-beta-hydroxylase-deficiency|title=dopamine beta-hydroxylase deficiency|last=Reference|first=Genetics Home|website=Genetics Home Reference|access-date=2016-12-15}}</ref> Without this enzyme, the patients with DβH deficiency suffer from many clinical manifestations which greatly affect their daily lives.
Dopamine beta-hydroxylase deficiency results from mutations in the [[DBH gene]], which encodes the enzyme responsible for the conversion of dopamine to norepinephrine. This enzyme is crucial for the production of norepinephrine, a neurotransmitter that plays a key role in the [[autonomic nervous system]] and the regulation of [[blood pressure]]. Without sufficient DBH activity, individuals have elevated levels of dopamine and reduced levels of norepinephrine and [[epinephrine]].
==Clinical Features==
== Signs and symptoms ==
The clinical presentation of dopamine beta-hydroxylase deficiency can vary, but common symptoms include:
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]].<ref name=":1">{{Cite journal|last=Senard|first=Jean-Michel|last2=Rouet|first2=Philippe|date=2006-01-01|title=Dopamine beta-hydroxylase deficiency|journal=Orphanet Journal of Rare Diseases|volume=1|pages=7|doi=10.1186/1750-1172-1-7|issn=1750-1172|pmc=1459119|pmid=16722595}}</ref>
* Severe [[orthostatic hypotension]], which is a significant drop in blood pressure upon standing, leading to dizziness or fainting.
* [[Ptosis]], or drooping of the eyelids.
Due to the deficiency of norepinephrine and epinephrine those affected by dopamine β-hydroxylase deficiency may present with droopy eyelids ([[Ptosis (eyelid)|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 (joints)|hypermobility]].<ref name=":0" /> [[Postural orthostatic tachycardia syndrome]], another form of dysautonomia, also sees this comorbidity with hypermobility in the form of a rare [[Connective tissue disease|connective tissue disorder]] called [[Ehlers–Danlos syndrome|Ehlers Danlos syndrome]].
* [[Nasal congestion]] due to the lack of sympathetic nervous system activity.
* [[Hypoglycemia]], or low blood sugar levels, particularly in infants.
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|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.<ref name=":2">{{Cite web|url=http://www.pharmacorama.com/en/Sections/Catecholamines_7_4.php|title=Dopamine receptor antagonists - Pharmacorama|website=www.pharmacorama.com|access-date=2016-12-15}}</ref>
* [[Exercise intolerance]] and fatigue.
==Diagnosis==
==Diagnosis==
{{Empty section|date=November 2017}}
Diagnosis of dopamine beta-hydroxylase deficiency is based on clinical symptoms, biochemical tests, and genetic testing. Key diagnostic indicators include:
* Elevated plasma dopamine levels.
== Treatment ==
* Low or undetectable plasma norepinephrine and epinephrine levels.
* Genetic testing to identify mutations in the DBH gene.
=== Lifestyle ===
==Treatment==
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.<ref name=":2" />
Treatment for dopamine beta-hydroxylase deficiency focuses on managing symptoms and may include:
* [[Droxidopa]], a synthetic amino acid that can be converted to norepinephrine, is often used to alleviate symptoms of orthostatic hypotension.
=== Medications ===
* [[Fludrocortisone]] may be prescribed to help increase blood volume and blood pressure.
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.<ref>{{Cite journal|last=Kaufmann|first=Horacio|last2=Saadia|first2=Daniela|last3=Voustianiouk|first3=Andrei|last4=Goldstein|first4=David S.|last5=Holmes|first5=Courtney|last6=Yahr|first6=Melvin D.|last7=Nardin|first7=Rachel|last8=Freeman|first8=Roy|date=2003-08-12|title=Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension|journal=Circulation|language=en|volume=108|issue=6|pages=724–728|doi=10.1161/01.CIR.0000083721.49847.D7|issn=0009-7322|pmid=12885750|doi-access=free}}</ref><ref>{{Cite journal|last=Mathias|first=C. J.|last2=Senard|first2=J. M.|last3=Braune|first3=S.|last4=Watson|first4=L.|last5=Aragishi|first5=A.|last6=Keeling|first6=J. E.|last7=Taylor|first7=M. D.|date=2001-08-01|title=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|journal=Clinical Autonomic Research|volume=11|issue=4|pages=235–242|issn=0959-9851|pmid=11710796|doi=10.1007/bf02298955}}</ref><ref>{{Cite journal|last=Isaacson|first=Stuart|last2=Skettini|first2=Julia|date=2014-04-03|title=Neurogenic orthostatic hypotension in Parkinson's disease: evaluation, management, and emerging role of droxidopa|journal=Vascular Health and Risk Management|language=English|volume=10|pages=169–76|doi=10.2147/vhrm.s53983|pmid=24729712|pmc=3979788}}</ref><ref>{{Cite journal|last=Biaggioni|first=Italo|last2=Freeman|first2=Roy|last3=Mathias|first3=Christopher J.|last4=Low|first4=Phillip|last5=Hewitt|first5=L. Arthur|last6=Kaufmann|first6=Horacio|date=2015-01-01|title=Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to DroxidopaNovelty and Significance|journal=Hypertension|language=en|volume=65|issue=1|pages=101–107|doi=10.1161/HYPERTENSIONAHA.114.04035|issn=0194-911X|pmc=4354798|pmid=25350981}}</ref> 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.<ref>{{Cite journal|last=Biaggioni|first=Italo|last2=Robertson|first2=David|title=ENDOGENOUS RESTORATION OF NORADRENALINE BY PRECURSOR THERAPY IN DOPAMINE-BETA-HYDROXYLASE DEFICIENCY|journal=The Lancet|volume=330|issue=8569|pages=1170–1172|doi=10.1016/s0140-6736(87)91317-1|year=1987}}</ref>
* Dietary modifications and increased salt intake to help manage blood pressure.
==Prognosis==
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|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.
The prognosis for individuals with dopamine beta-hydroxylase deficiency varies depending on the severity of symptoms and the effectiveness of treatment. With appropriate management, many individuals can lead relatively normal lives, although they may need ongoing treatment to manage symptoms.
==See also==
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:
* [[Catecholamine]]
* Diabetes induced orthostatic hypotension
* [[Norepinephrine]]
* Dialysis-induced hypotension
* [[Autonomic nervous system]]
* Orthostatic intolerance
* [[Orthostatic hypotension]]
* Familial amyloidotic polyneuropathy
* Spinal Cord Injury related hypotension<ref>{{Cite journal|last=Goldstein|first=David S.|date=2006-09-01|title=L-Dihydroxyphenylserine (L-DOPS): A Norepinephrine Prodrug|journal=Cardiovascular Drug Reviews|language=en|volume=24|issue=3–4|pages=189–203|doi=10.1111/j.1527-3466.2006.00189.x|pmid=17214596|issn=1527-3466}}</ref>
Empirical evidence of mild effectiveness has been reported using mineralocorticoids or adrenergic receptor agonists as therapies.<ref name=":1" />
Other medications that can bring relief to symptoms include:<ref name="Robertson">{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1474/|title=GeneReviews|last=Robertson|first=David|last2=Garland|first2=Emily M.|date=1993-01-01|publisher=University of Washington, Seattle|editor-last=Pagon|editor-first=Roberta A.|location=Seattle (WA)|pmid=20301647|editor-last2=Adam|editor-first2=Margaret P.|editor-last3=Ardinger|editor-first3=Holly H.|editor-last4=Wallace|editor-first4=Stephanie E.|editor-last5=Amemiya|editor-first5=Anne|editor-last6=Bean|editor-first6=Lora JH|editor-last7=Bird|editor-first7=Thomas D.|editor-last8=Fong|editor-first8=Chin-To|editor-last9=Mefford|editor-first9=Heather C.|chapter=Dopamine Beta-Hydroxylase Deficiency}}</ref>
* [[phenylpropanolamine]]- due to pressor response to vascular α-[[Adrenergic receptor|adrenoceptors]]
* [[indomethacin]]
Vitamin C ([[ascorbic acid]]) is also a required [[Cofactor (biochemistry)|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.<ref name="Robertson" />
== Prognosis ==
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."<ref>{{Cite journal|last=Robertson|first=David|last2=Goldberg|first2=Michael R.|last3=Onrot|first3=Jack|last4=Hollister|first4=Alan S.|last5=Wiley|first5=Ron|last6=Thompson|first6=John G. Jr.|last7=Robertson|first7=Rose Marie|date=1986-06-05|title=Isolated Failure of Autonomic Noradrenergic Neurotransmission|journal=New England Journal of Medicine|volume=314|issue=23|pages=1494–1497|doi=10.1056/NEJM198606053142307|issn=0028-4793|pmid=3010116}}</ref>
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.<ref name=":1" /> 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).<ref>{{Cite web|url=http://intd-online.org/|title=Patient Registry|last=|first=|date=|website=|access-date=}}</ref>
== 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.<ref>{{Cite journal|last=Arnold|first=Amy C.|last2=Garland|first2=Emily M.|last3=Celedonio|first3=Jorge E.|last4=Raj|first4=Satish R.|last5=Abumrad|first5=Naji N.|last6=Biaggioni|first6=Italo|last7=Robertson|first7=David|last8=Luther|first8=James M.|last9=Shibao|first9=Cyndya A.|date=2016-10-25|title=Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology & Metabolism|volume=102|issue=1|pages=jc.2016–3274|doi=10.1210/jc.2016-3274|pmid=27778639|pmc=5413093|issn=0021-972X}}</ref>
==References==
{{reflist}}
==Further reading==
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=dbh GeneReviews/NCBI/NIH/UW entry on Dopamine Beta-Hydroxylase Deficiency]
*{{cite journal |vauthors=Fu W, Shen J, Luo X, etal |title=Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations |journal=Biophysical Journal |volume=93 |issue=5 |pages=1431–41 |date=September 2007 |pmid=17468175 |pmc=1948031 |doi=10.1529/biophysj.106.088500|bibcode=2007BpJ....93.1431F }}
*{{cite journal |vauthors=Alaniz RC, Thomas SA, Perez-Melgosa M, etal |title=Dopamine beta-hydroxylase deficiency impairs cellular immunity |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=96 |issue=5 |pages=2274–8 |date=March 1999 |pmid=10051631 |pmc=26773 |doi=10.1073/pnas.96.5.2274|bibcode=1999PNAS...96.2274A }}
Dopamine beta-hydroxylase deficiency results from mutations in the DBH gene, which encodes the enzyme responsible for the conversion of dopamine to norepinephrine. This enzyme is crucial for the production of norepinephrine, a neurotransmitter that plays a key role in the autonomic nervous system and the regulation of blood pressure. Without sufficient DBH activity, individuals have elevated levels of dopamine and reduced levels of norepinephrine and epinephrine.
Diagnosis of dopamine beta-hydroxylase deficiency is based on clinical symptoms, biochemical tests, and genetic testing. Key diagnostic indicators include:
Elevated plasma dopamine levels.
Low or undetectable plasma norepinephrine and epinephrine levels.
Genetic testing to identify mutations in the DBH gene.
The prognosis for individuals with dopamine beta-hydroxylase deficiency varies depending on the severity of symptoms and the effectiveness of treatment. With appropriate management, many individuals can lead relatively normal lives, although they may need ongoing treatment to manage symptoms.
