Dopamine β-hydroxylase deficiency

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The dopamine β-hydroxylase deficiency (DBH) deficiency, also known as norepinephrine deficiency called, is a very rare autosomal - recessive inherited metabolic disease . The affected patients due to a defect in are DBH - gene , the hormones adrenaline and noradrenaline in the blood plasma does not exist, whereas the dopamine -mirror is significantly increased.

The enzyme dopamine-β-hydroxylase catalyzes the hydroxylation of dopamine to noradrenaline, which is methylated to adrenaline with the help of the enzyme phenylethanolamine-N-methyltransferase .

Prevalence and symptoms

Autosomal recessive inheritance

The exact prevalence of dopamine β-hydroxylase deficiency is not known, but is apparently less than 1: 1 million. The disease is extremely rare and very few patients have been described to date. The prevalence of the disease is likely to be significantly higher as the disease can lead to miscarriages . In the mouse animal model , the dopamine β-hydroxylase deficiency is often fatal even prenatally.

Cardiovascular disorders and severe orthostatic hypotension are the main symptoms of dopamine β-hydroxylase deficiency and occur immediately after birth . Low blood pressure , hypotonia , hypothermia and hypoglycemia are occurring in the neonatal period complications . As the blood pressure cannot adapt to changing physical stress, the affected children cannot tolerate active movement or physical exertion. This condition only worsens with age. Severe orthostatic hypotension and ptosis, among other things, can therefore be observed in early adulthood . It is not possible for those affected to stand for a longer period of time. Circulatory collapses that lead to fall injuries are common.

Genetics and Pathogenesis

Dopamine+ Ascorbate + O 2 → Norepinephrine+ dehydroascorbate + H 2 O

The DBH gene coding for the enzyme dopamine β-hydroxylase is located in humans on chromosome 9 gene locus q34. The DBH gene is approximately 23 kb long and consists of 12 exons . Mutations in the DBH gene can cause the gene product - dopamine β-hydroxylase - to be restricted in its function or even completely defective. The enzyme catalyzes the oxidation of dopamine to norepinephrine. If the activity is restricted by mutations in the DBH gene, then little or no noradrenaline is produced and no adrenaline is subsequently produced from dopamine. On the other hand, the starting substance dopamine accumulates in the plasma.

The mutations in the DBH gene are inherited in an autosomal recessive manner. So far, missense mutations on exons 1, 2 or 6 have mainly been found.

diagnosis

Dopamine β-hydroxylase is undetectable in about 4% of the population with normal catecholamine concentrations, so that the determination of the enzyme alone is not a reliable diagnosis. The increased plasma level of dopamine and the absence of measurable amounts of norepinephrine and adrenaline in the blood of the patient enables a safe laboratory diagnosis of dopamine-β-hydroxylase deficiency. The metabolic products of norepinephrine are also missing in the urine .

therapy

Droxidopa, a precursor to norepinephrine

Dopamine-β-hydroxylase deficiency can be treated by administering droxidopa ( L- threo-3,4-dihyroxyphenylserine). Droxidopa is a precursor molecule ( prodrug ) to norepinephrine.

In the mouse animal model with the Dhb gene switched off ( knockout mouse ), the administration of droxidopa causes the plasma concentration of norepinephrine to assume normal values ​​and the behavioral disorders of the mice disappear. In sick people, the same substance causes a drastic increase in blood pressure and an alleviation of postural symptoms.

The active ingredient is usually taken orally two or three times a day and corrects the imbalance.

forecast

So far, very little data are available on the prognosis of the disease. The administration of droxidopa is a very effective form of therapy to significantly alleviate the most important symptoms of dopamine β-hydroxylase deficiency.

Initial description

The dopamine β-hydroxylase deficiency was first described in 1986 by a research group led by the doctor David Robertson at Vanderbilt University in Nashville .

further reading

  • JF Cubells and CP Zabetian: Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology. In: Psychopharmacology (Berl) 174, 2004, pp. 463-476. PMID 15088079 (Review)
  • HJ Timmers et al: Congenital dopamine-beta-hydroxylase deficiency in humans. In: Ann NY Acad Sci 1018, 2004, pp. 520-523. PMID 15240410 (Review)
  • D. Robertson et al: Dopamine-b-hydroxylase deficiency and cardiovascular control. In: Hypertension Pathophysiology, Diagnosis and Management. Raven Press Ltd, New York, 1990, pp. 749-759.

Web links

Individual evidence

  1. ↑ a b c d e f g h J. M. Senard and P. Rouet: Dopamine beta-hydroxylase deficiency. In: Orphanet J Rare Dis 1, 2006, 7 PMID 16722595 (Review, Open Access under CC-by-2.0 )
  2. ^ SA Thomas: Noradrenaline is essential for mouse foetal development. In: Nature 374, 1995, pp. 643-646. PMID 7715704
  3. ↑ SP Craig et al.: Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34. In: Cytogenet Cell Genet 48, 1988, pp. 48-50. PMID 3180847
  4. ↑ K. Kobayashi, Y. Kurosawa, K. Fujita, T. Nagatsu: Human dopamine beta-hydroxylase gene: two mRNA types having different 3'-terminal regions are produced through alternative polyadenylation. In: Nucleic acids research. Volume 17, Number 3, February 1989, pp. 1089-1102, PMID 2922261 , PMC 331724 (free full text).
  5. ↑ CH Kim et al .: Mutations in the dopamine β-hydroxylase gene are associated with human norepinephrine deficiency. In: Am J Med Genet 108, 2002, pp. 140-147. PMID 11857564
  6. ↑ RM Weinshilboum, HG Schorott, FA Raymond, WH Weidman, LR Elveback: Inheritance of very low serum dopamine-beta-hydroxylase activity. In: American Journal of Human Genetics . Volume 27, Number 5, September 1975, pp. 573-585, PMID 1163533 , PMC 1762832 (free full text).
  7. ^ D. Robertson et al.: Dopamine β-hydroxylase deficiency. A genetic disorder of cardiovascular regulation. In: Hypertension 18, 1991, pp. 1-8. PMID 1677640
  8. ↑ S. Braune and CH Lücking: Orthostatic hypotension: pathophysiology, differential diagnosis and therapy. In: Dtsch Arztebl 94, 1997, pp. A-3413 / B-2877 / C-2673
  9. ^ DS Goldstein: L-dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug. In: Cardiovasc Drug Rev 24, 2006, pp. 189-203. PMID 17214596 (Review)
  10. ^ CJ Mathias: L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience. In: Clin Auton Res 18, 2008, pp. 25-29. PMID 18368304 (Review)
  11. ↑ SA Thomas et al .: Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine β-hydroxylase. In: J Neurochem 70, 1998, pp. 2468-2476. PMID 9603211
  12. ↑ I. Biaggioni and D. Robertson: Endogenous restoration of noradrenaline by precursor therapy in dopamine-beta-hydroxylase deficiency. In: The Lancet 330, 1987, pp. 1170-1172. PMID 2890806
  13. ↑ D. Robertson et al .: Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired β-hydroxylation of dopamine. In: NEJM 314, 1986, pp. 1494-1497. PMID 3010116