View source for Medicine:Dopamine beta hydroxylase deficiency

{{Infobox medical condition (new)
| name            = Dopamine beta hydroxylase deficiency
| synonyms        = '''DβH deficiency'''
| image           = Dopamin - Dopamine.svg
| caption         = Dopamine beta hydroxylase is the enzyme responsible for converting [[Biology:Dopamine|dopamine]] (pictured) to [[Biology:Norepinephrine|norepinephrine]].
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'''Dopamine beta (β)-hydroxylase deficiency''' is a human medical condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum [[Biology:Dopamine|dopamine]] and the absence of [[Biology:Norepinephrine|norepinephrine]] (NE) and epinephrine. 

Dopamine is released, as a [[Biology:False neurotransmitter|false neurotransmitter]], in place of norepinephrine (aka noradrenaline and noradrenalin). This condition is sometimes referred to as "norepinephrine deficiency". Researchers of disorders such as [[Medicine:Schizophrenia|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.


== Signs and symptoms ==
Dopamine beta (β)-hydroxylase deficiency 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 body [[Homeostasis|homeostasis]]. Problems related to DβH deficiency often appear as complications shortly after birth. Postnatal symptoms may include vomiting, dehydration, [[Medicine:Hypotension|hypotension]], muscle [[Medicine:Hypotonia|hypotonia]], [[Physics:Hypothermia|hypothermia]], and [[Medicine:Hypoglycemia|hypoglycemia]].<ref name=":1">{{Cite journal|last1=Senard|first1=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 |doi-access=free }}</ref>

Due to the deficiency of norepinephrine and epinephrine, those affected may present with droopy eyelids (ptosis), nasal congestion, and hypotension. The most common complaint is [[Medicine:Orthostatic hypotension|orthostatic hypotension]]. The symptoms associated with orthostatic hypotension are dizziness, blurred vision, and fainting upon standing. Patients may have difficulty with prolonged standing. This phenomenon is especially pronounced when going from horizontal to upright, such as getting out of bed. It is worsened by hot climates due to loss of fluid through sweating. Difficulty maintaining normal [[Physics:Blood pressure|blood pressure]] makes it difficult to exercise ([[Medicine:Exercise intolerance|exercise intolerance]]). Males may experience retrograde ejaculation, a discharge of semen backward into the bladder due to dysmotility of their smooth muscle, which is innervated by the ANS. A subset of patients present with [[Medicine:Hypermobility (joints)|hypermobility]].<ref name=":0" /> [[Medicine:Postural orthostatic tachycardia syndrome|Postural orthostatic tachycardia syndrome]], another form of dysautonomia, also displays 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. Loss of noradrenergic control is seen as [[Medicine:T wave|T-wave]] abnormalities on electrocardiogram. [[Biology:Prolactin|Prolactin]] is frequently suppressed by excessive dopamine found in the 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>

==Diagnosis==

== Treatment ==

=== Lifestyle ===
Untreated individuals should avoid hot environments, strenuous exercise, prolonged standing and dehydration. Care should be taken when moving from horizontal to upright.<ref name=":2" />

=== Medications ===
L-threo-DOPS  is a synthetic precursor of noradrenaline. The conversion of dihydroxyphenylserine ([[Chemistry:Droxidopa|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 [[Biology:Catecholamine|catecholamine]] synthesis, L-Threo-DOPS is the preferred therapeutic agent.<ref>{{Cite journal|last1=Kaufmann|first1=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|last1=Mathias|first1=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|s2cid=24567321}}</ref><ref>{{Cite journal|last1=Isaacson|first1=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 |doi-access=free }}</ref><ref>{{Cite journal|last1=Biaggioni|first1=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, L-Threo-DOPS  administration has proven effective in managing blood pressure and postural symptoms.<ref>{{Cite journal|last1=Biaggioni|first1=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|pmid=2890806|s2cid=43845850}}</ref>

L-DOPS continues to be studied pharmacologically and pharmacokinetically and shows an ability to significantly increase the levels of central nervous system norepinephrine, even though L-DOPS has a relative difficulty crossing the [[Biology:Blood–brain barrier|blood-brain barrier]] when compared to medications such as [[Chemistry:L-DOPA|L-DOPA]]. Concurrent use increases efficacy, as they are both involved and connected to the norepinephrine synthesis pathway.

L-DOPS may eventually to help other conditions or symptoms such as pain, chronic stroke symptoms, and progressive supranuclear palsy. Clinically, L-DOPS has been reported to be helpful in treating other conditions related to hypotension such as:
* Diabetes induced orthostatic hypotension
* Dialysis-induced hypotension
* Orthostatic intolerance
* 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|doi-access=free}}</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|last1=Robertson|first1=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 J.H.|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>
* [[Chemistry:Phenylpropanolamine|phenylpropanolamine]]- due to pressor response to vascular α-[[Biology:Adrenergic receptor|adrenoceptors]]
* indomethacin
Vitamin C ([[Chemistry:Ascorbic acid|ascorbic acid]]) is a required [[Biology:Cofactor (biochemistry)|cofactor]] for the Dopamine beta hydroxylase enzyme. Vitamin C rapidly catalyzes the conversion of dopamine to norepinephrine through stimulation of dopamine beta hydroxylase.<ref name="Robertson" />

== Prognosis ==
This is a form of dysautonomia distinct from [[Medicine:Familial dysautonomia|familial dysautonomia]] because of its lack of familial dysautonomic symptoms such as loss of sense of pain and smell. 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|last1=Robertson|first1=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>

== Research ==
Researchers have gathered 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 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 [[Medicine:International Working Group on Neurotransmitter Related Disorders|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>

Studies have explored the connection between DβH deficiency, [[Chemistry:Droxidopa|Droxidopa]] treatment, and the effect on orthostatic tolerance and glucose [[Homeostasis|homeostasis]]. It was reported that Droxidopa increased acute and late glucose-stimulated insulin secretion and improved patients' insulin sensitivity. However, the use of Droxidopa was found to produce only "modest changes in glucose homeostasis". This shows that treatment modalities other than Droxidopa should be pursued as possible adjuncts for the hyperinsulinemia seen in DβH deficiency.<ref>{{Cite journal|last1=Arnold|first1=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 |doi-access=free }}

== External links ==
{{Medical resources
| DiseasesDB      = 33227
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| OMIM            = 223360
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| SNOMED CT       = 237923004
| Orphanet        = 230
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{{Amino acid metabolic pathology}}

{{DEFAULTSORT:Dopamine Beta Hydroxylase Deficiency}}
[[Category:Amino acid metabolism disorders]]
[[Category:Autosomal recessive disorders]]

{{Sourceattribution|Dopamine beta hydroxylase deficiency}}