Given the fundamental role of NE in CNS and peripheral nervous system functions, the report of adult patients with undetectable NE is both surprising and interesting. NE deficiency (or DBH deficiency) is a rare congenital disorder, first described in 1986 ( 4, 5). As a result of such synaptic release, both NE and DBH are readily detectable in plasma and cerebrospinal fluid ( 3). During neurotransmission, the soluble form of DBH is released into the synaptic cleft together with NE by exocytosis ( 2). Among catecholamine-synthesizing enzymes, DBH is unique in that it is localized within large dense core vesicles (LDCV), where it exists in both soluble and membrane-bound forms ( 1). DBH is a hallmark protein of noradrenergic cells and is specifically expressed in noradrenergic neurons and chromaffin cells of the adrenal medulla. Like dopamine (DA) and epinephrine, NE is a catecholamine neurotransmitter and is synthesized by oxidative hydroxylation of DA catalyzed by dopamine β-hydroxylase (DBH). Norepinephrine (NE) 3 is a key neurotransmitter that is synthesized in both the CNS and the peripheral nervous system and regulates many essential functions, including attention, memory, emotion, and autonomic and cardiovascular function. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s). Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Here, we show that the IVS1+2T→C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER).

Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1+2T→C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Human norepinephrine (NE) deficiency (or dopamine β-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable.

Epinephrine deficiency diseases