Abstract P2063: Isolated Noradrenergic Failure Due Tocongenital Cyb561 Deficiency

Abstract

CYB561 generates ascorbic acid, a cofactor for the function of dopamine-beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine. We report a novel genetic defect in the CYB561 gene and provide the clinical characteristics of CYB561 deficiency. We evaluated 4 patients referred for life-long disabling orthostatic hypotension and performed whole genome sequencing of the CYB561 gene. Patients had disabling orthostatic hypotension (OH) since infancy and impaired blood pressure response to the Valsalva maneuver (VM) with exaggerated phase 2 hypotension and absence of phase 2 late recovery and phase 4 blood pressure overshoot consistent with sympathetic failure. Heart rate ratio to sinus arrhythmia and the VM, however, were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine and improved orthostatic hypotension. Patients 1 and 2 were sisters and were homozygous for a nonsense mutation in Exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a mutation in Exon 2, c157C>T, p.His.53Tyr, and the other had an Exon 2 deletion. In conclusion, CYB561 deficiency is characterized by isolated sympathetic noradrenergic failure with disabling orthostatic hypotension since infancy, but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. The genetic defect differed between patients; we report a novel case of CYB561 deficiency due to compound heterozygosity, with a gene deletion in one allele, and a missense mutation in the other. These patients highlight the critical role of CYB561 in sympathetic function and cardiovascular regulation.