DBH – Orthostatic Hypotension Type 1

Dopamine β-hydroxylase (DBH) is the enzyme that converts dopamine to norepinephrine in sympathetic neurons. Biallelic DBH loss-of-function abolishes norepinephrine and epinephrine synthesis, leading to severe orthostatic hypotension, ptosis, and autonomic failure. This condition is classified as Orthostatic Hypotension 1, an autosomal recessive disorder.

Genetic evidence comprises three unrelated probands with DBH deficiency: two congenital cases with compound heterozygous splice and missense alleles ([PMID:12438171], [PMID:11857564]) and one late-onset case diagnosed at age 73, demonstrating absent sympathetic activity and clinical response to droxidopa ([PMID:20063034]). Segregation in each family is consistent with autosomal recessive inheritance and undetectable plasma DBH activity.

The variant spectrum includes splice-donor (c.339+2T>C), frameshift (c.468dup (p.Lys157fsTer)), and missense alleles (c.342C>A (p.Asp114Glu); c.1033G>A (p.Asp345Asn)), all leading to deficient DBH protein. The recurrent intron 1 splice variant c.339+2T>C occurs in multiple individuals and abolishes normal mRNA processing.

Functional studies in cellular systems show that the IVS1+2T>C mutation abolishes DBH protein production and that missense variants trap DBH in the endoplasmic reticulum, inducing ER stress. Pharmacological chaperones such as glycerol rescue trafficking defects and restore enzyme secretion, confirming loss-of-function as the pathogenic mechanism ([PMID:21209083]).

Therapeutically, chronic administration of L-threo-3,4-dihydroxyphenylserine (droxidopa) bypasses DBH to replenish norepinephrine, safely correcting orthostatic hypotension in both congenital and elderly patients ([PMID:20063034]).

Collectively, genetic and experimental concordance supports a Strong DBH–Orthostatic Hypotension 1 association. Key take-home: identification of biallelic DBH variants enables definitive diagnosis and guides droxidopa therapy.

References

• Clinical autonomic research • 2010 • DBH deficiency in an elderly patient: efficacy and safety of chronic droxidopa. PMID:20063034
• Annals of the New York Academy of Sciences • 2002 • Genetic basis of clinical catecholamine disorders. PMID:12438171
• American journal of medical genetics • 2002 • Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. PMID:11857564
• The Journal of Biological Chemistry • 2011 • Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase. PMID:21209083

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