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Dopamine Beta Hydroxylase (DBH) Enzyme Activity: The Missing Link in POTS, Dysautonomia, Autism, ADHD, Infertility, Impaired Immunity, and Many Other Diseases

Dopamine beta-hydroxylase (DBH) is a key enzyme in the conversion of dopamine to norepinephrine in the central nervous system and is the enzyme needed for the conversion of dopamine to norepinephrine in the sympathetic nervous system of the autonomic nervous system. Dopamine beta-hydroxylase can be readily measured in serum and correlates highly with the amount of the same enzyme in the cerebral spinal fluid. The DBH gene has been mapped to chromosome 9 at the q34 position. Seventy-one polymorphisms of the DBH gene have been identified in just 80 subjects: 68 single nucleotide polymorphisms (SNPs), two insertion/deletions, and one repeat. Because of the large number of SNPs, there are a very large number of possible combinations of variants for DBH (4,970 combinations).

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Abnormalities of DBH result in severe postural hypotension (POTS) and are also associated with the following symptoms and disorders:

  • Exercise Intolerance

  • Fainting Spells

  • Huntington’s Chorea

  • Hyperflexible Joints

  • Hypertension

  • Hypoglycemia

  • Impaired Ejaculation

  • Low Blood Pressure

  • Tourette’s Syndrome

  • Parkinson’s Disease

  • Psychosis

  • PTSD

  • Schizophrenia

  • Seizures

  • Spontaneous Abortion

  • Low Muscle Tone

  • ADD/ADHD

  • Alcoholism

  • Autism Spectrum Disorders

  • Alzheimer’s Disease

  • Bed Wetting (Enuresis)

  • Bipolar Depression

  • Cardiac Heart Failure

  • Depression

Women with DBH deficiency are much more likely to have children with autism. In animals, DBH deficiency is associated with severe immune deficiency, impaired response to immunization, and lack of maternal care. It might be expected that similar abnormalities occur in humans. Because of the very large number of possible combinations of variants for DBH and the fact that the amount of enzyme activity associated with each variant is unknown or reports on such SNPs are contradictory, assessment of DBH enzyme in serum or plasma is an excellent substitute for DNA testing.

DBH AND AUTISM

Abnormalities in the metabolism of dopamine in autism consistent with DBH deficiency have been reported in the research literature for more than 40 years (Lelord 1978). DBH deficiency greatly increases the concentration of dopamine and its metabolite homovanillic acid in the cerebrospinal fluid, blood, and urine because of the accumulation of dopamine when the DBH enzyme is less active.

Lelord, Callaway, Muh, Sauvage, and Arlot (1978) and Garreau et al. (1980) reported that urinary levels of the dopamine metabolite, homovanillic acid (HVA) were higher in autistic than in normal children, and that the clinical improvement of these young autistic patients under vitamin B6 was associated with a decrease of their urinary HVA excretion (Lelord, Muh, Barthelemy, Martineau, Garreau, & Callaway, 1981). Abnormalities also included elevated concentrations of HVA in cerebrospinal fluid (Cohen, Caparulo, Shaywitz, & Bower, 1977, Gillberg). In addition, the degree of elevation of HVA in urine was correlated with the increased severity of autistic symptoms (Garreau 1980).

The mean serum DBH was 30% lower in mothers of children with autism compared to mean values of those without a child with autism, indicating a likely genetic involvement of DBH as a cause of autism. In the same study, it was found that mothers of sons with autism had a higher incidence of a 19 base pair deletion polymorphism (DBH-) in the DBH gene. The epidemiological term “attributable risk” for this gene was 42%, interpreted as meaning that the risk of having a son with autism was 42% higher for the mothers with this genetic variant than without it. DBH genotypes also differed significantly among mothers and controls, with 37% of mothers with two affected sons having two DBH− alleles, compared to 19% of controls. The DBH− allele was associated with nearly a 50% lower mean serum DBH enzyme activity (nondeletion homozygotes: 41.02 ± 24.34 IU/liter; heterozygotes: 32.07 ± 18.10 IU/liter; and deletion homozygotes: 22.31 ± 13.48 IU/liter in a pooled sample of mothers and controls. These researchers suggest that lowered maternal serum DBH activity results in a suboptimal uterine environment (decreased norepinephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum disorder in some families.

Unfortunately, the children with autism of these mothers with low DBH were not tested for low DBH. However, a high incidence of hyperflexible joints and postural hypotension has been reported in autism, implicating a potential role of DBH deficiency as a cause of autism.

Dysautonomia and its Connection to DBH

Dysautonomia is an encompassing term used to describe several different medical conditions that cause a malfunction of the autonomic nervous system, the system that controls the automatic functions of the body that we do not consciously think about, such as heart rate, blood pressure, digestion, dilation and constriction of the pupils of the eye, kidney function, and temperature control. The autonomic nervous system consists of two main divisions: the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system is often considered the “fight or flight” system, while the parasympathetic nervous system is often considered the “rest and digest” or “feed and breed” system.

In many cases, both of these systems have “opposite” actions where one system activates a physiological response and the other inhibits it. At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine) while parasympathetic postganglionic neurons release acetylcholine as the main neurotransmitter. If DBH is deficient in the sympathetic nervous system, the substrate of the enzyme dopamine accumulates while the products of the enzyme, norepinephrine and epinephrine, decrease.

DBH and Infertility

Thomas and his colleagues (1995, 1997) found that in pregnant female mice that lacked DBH virtually all progeny died and that there were many deaths of progeny even in pregnant mice with only a single copy of the DBH gene. By providing additional norepinephrine from the Droxidopa drug to the pregnant mice with the genetic deficiency, the excess mortality of the offspring was prevented. Although not yet reported in humans, DBH deficiency may also be a cause of infertility in humans.

Help For a Patient with Severe Hypotension (Low Blood Pressure)

The following is a typical story of a patient dealing with severe hypotension written by the health writer Amanda Gardner on www.health.com:

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A patient, Megan, first experienced troubling symptoms as a child. Whenever she stood up for more than two minutes, she collapsed. She had similar problems whenever she stood up in church or school. She suffered from bed wetting when she was older and also had droopy eye lids, excessive bladder infections, and hypoglycemic (low blood sugar) episodes that left her shaky. As she became a teenager she suffered from severe exercise intolerance and was unable to walk a block or climb a flight of stairs without resting.

She consulted many physicians with no answers. Her standing blood pressure was extremely low (50/30). All of Megan’s symptoms were due to a deficiency of DBH. After finally finding a physician who diagnosed her with dopamine beta hydroxylase deficiency, she was put on the drug Northera® which was able to form norepinephrine by circumventing the impaired DBH pathway as illustrated (on the right). In 2010, after taking Northera®, Megan completed an Olympic-length triathlon: a 1,500-meter swim, 40-kilometer bike ride, and 10K run. “For me it was like checking this off the list,” Megan says. “I was so grateful for my new physicality.”

Droxidopa (Northera®) has been used as a replacement for norepinephrine and has been effective in treating other disorders besides POTS and hypotension, such as autism and Parkinson’s disease.

Postural Orthostatic Tachycardia Syndrome (POTS)

Dysautonomia is not rare. Over 70 million people worldwide live with various forms of dysautonomia. People of any age, gender or race can be impacted. POTS is estimated to impact a total of 1,000,000 to 3,000,000 Americans. The condition can cause lightheadness, fainting, tachycardia, chest pains, shortness of breath, GI upset, shaking, exercise intolerance, temperature sensitivity and more. While POTS predominantly impacts young women who look healthy on the outside, researchers compare the disability seen in POTS to the disability seen in conditions like COPD and congestive heart failure.

Normal Values for DBH   A normal range study at The Great Plains Laboratory of both adult males and females found no difference between adult males and females, so data were combined into a single normal range shown below.

Normal Values for DBH

A normal range study at The Great Plains Laboratory of both adult males and females found no difference between adult males and females, so data were combined into a single normal range shown below.

Effect of Age and Sex on DBH Results

Previous studies have found no significant differences between male and female results. We do not have normal ranges for children but previous studies have found significantly lower values of DBH for children. We will test children since a complete absence of DBH would be significant even in the absence of children’s reference ranges but all children’s results will have the message:

“Reference ranges have been established for adults but not yet for children under 13 years old. All children’s values should be interpreted with great caution.”

Possible Interferences

The following substances may interfere in the test and cause lower results:

  • Clostridia metabolites

  • Phenols

  • Fusaric acid from Fusarium mold species

  • Antabuse®

  • Nutrasweet® (aspartame)

 

Sample Collection

This test requires a serum sample. The sample is stable for one week at room temperature and three weeks at -20 degrees C. Dried blood spot (DBS) samples are not currently acceptable.

Discounts

Discounts for the DBH test are available when ordered on the same sample as the IgG Food Allergy Test (serum only). This discount is not available for the dried blood spot (DBS) IgG Food Allergy Test.


References

  1. Rare Disorder Causes Severe Head Rushes. By Amanda Gardner https://www.health.com/hypertension/dopamine-beta-hydroxylase-deficiency Accessed January 16, 2019.

  2. Fred H. Previc. Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. Medical Hypotheses (2007) 68, 46–60

  3. Lelord G, Callaway E, Muh JP, Arlot JC, Sauvage D, Garreau B,Domenech J. Modifications in urinary homovanillic acid after ingestion of vitamin B6; functional study in autistic children. Rev Neurol (Paris. 1978 Dec;134(12):797-801.

  4. Cohen, D. J., Caparulo, B. K., Shaywitz, B. A., & Bower, M. B., Jr. (1977). Dopamine and serotonin metabolism in neuropsychiatrically disturbed children: CSF homovanillic acid and 5-hydroxyindoleacetic acid. Archives of General Psychiatry, 34, 545-550.

  5. Gillberg, C, and Svennerholm, L. CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. British Journal of Psychiatry, 151:89-94, 1987.

  6. Gillberg C, Svennerholm L, Hamilton-Hellberg C. Childhood psychosis and monoamine metabolites in spinal fluid J Autism Dev Disord. 1983 13(4):383-96.

  7. Garnier C, Barthelemy C, Garreau B, Jouve J, Muh JP, Lelord G. Monoamine and monoamine enzyme abnormalities in childhood autism. Encephale. 1983; 9(3):201-62.

  8. Garreau B, Barthelemy C, Domenech J, Sauvage D, Muh JP, Lelord G, Callaway E. Disturbances in dopamine metabolism in autistic children: results of clinical tests and urinary dosages of homovanilic acid (HVA)]. Acta Psychiatr Belg. 1980 May-Jun;80(3):249-65.

  9. Garreau B, Barthélémy C, Jouve J, Bruneau N, Muh JP, Lelord G. Urinary homovanillic acid levels of autistic children. Dev Med Child Neurol. 1988 Feb;30(1):93-8.

  10. David Robertson, Virginia Haile, Sharon E. Perry,Rose Marie Robertson, John A. Phillips III, and Italo Biaggioni. Dopamine /beta-Hydroxylase Deficiency A Genetic Disorder of Cardiovascular Regulation Hypertension 1991;18: 1-8.

  11. Yuqing Chen, Gen Wen, Fangwen Rao, Kuixing Zhang, Lei Wang, Juan L. Rodriguez-Flores, Amber P. Sanchez, Manjula Mahata, Laurent Taupenot, Ping Sun, Sushil K. Mahata, Bamidele Tayo, Nicholas J. Schork, Michael G. Ziegler, Bruce A. Hamilton, and Daniel T. O’Connor Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure. J Hypertens. 2010 January ; 28(1): 76–86. doi:10.1097/HJH.0b013e328332bc87.

  12. Munoz, P., Huenchuguala, S., Paris, I., and Segura-Aguilar, J. 2012. Dopamine oxidation and autophagy. Parkinson’s Dis 2012: Article ID 920953. doi:10.1155/2012/920953.

  13. Ikuko Miyazaki and Masato Asanuma Dopaminergic Neuron-Specific Oxidative Stress Caused by Dopamine Itself. Acta Medica Okayama 62(3):141-150 (2008).

  14. Abhijeet Kapoor, Manish Shandilya, Suman Kundu Structural Insight of Dopamine b-Hydroxylase, a Drug Target for Complex Traits, and Functional Significance of Exonic Single Nucleotide Polymorphisms PLoS ONE October 2011 Volume 6 Issue 10 e26509.

  15. Maja Mustapic, Adam X. Maihofer, Manjula Mahata, Yuqing Chen, Dewleen G. Baker, Daniel T. O’Connor, and Caroline. M. Nievergelt. The catecholamine biosynthetic enzyme dopamine b-hydroxylase (DBH): first genome-wide search positions trait-determining variants acting additively in the proximal promoter. Human Molecular Genetics, 2014, Vol. 23, No. 23 6375–6384.

  16. Robinson PD Schutz CK Macciardi F White BN Holden JJ Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders. Am J Med Genet. 2001 Apr 15;100(1):30-6.

  17. Thomas, S. A., Matsumoto, A. M., Palmiter, R. D. Noradrenaline is essential for mouse fetal development. Nature 374: 643-646, 1995.

  18. Thomas, S. A., Palmiter, R. D. Impaired maternal behavior in mice lacking norepinephrine and epinephrine. Cell 91: 583-592, 1997.

  19. Goodman B, Autonomic Dysfunction in Autism Spectrum Disorders (ASD) Neurol April 05, 2016; 86 (16 Supplement) April 20, 2016.

  20. Carolina Baeza-Velasco Ca, Claude Hamonetb, Amaria Baghdadlic & Régine Brissotd Autism Spectrum Disorders and Ehlers-Danlos Syndrome Hypermobility-Type : Similarities in clinical presentation C. Med. Psicosom, Vol 118 – 2016.