Norepinephrine deficiency with normal blood pressure control in congenital insensitivity to pain with anhidrosis.

OBJECTIVE: Congenital insensitivity to pain with anhidrosis (CIPA) is caused by mutations in the NKTR1 gene. This affects the development of nerve growth factor (NGF)-dependent neurons including sympathetic cholinergic neurons in the skin, causing anhidrosis. Cardiovascular and blood pressure regulation appears normal, but the integrity of sympathetic adrenergic neurons has not been tested.

METHODS: We examined the effect of posture on blood pressure, heart rate, plasma concentration of catecholamines, vasopressin, endothelin, and renin activity in 14 patients with CIPA, 10 patients with chronically deficient sympathetic activity (pure autonomic failure), and 15 normal age-matched controls.

RESULTS: In all 14 patients with CIPA, plasma norepinephrine levels were very low or undetectable and failed to increase when the patient was upright, yet upright blood pressure was well maintained. Plasma epinephrine levels were normal and increased when the patient was upright. Plasma renin activity also increased appropriately when the patient was upright and after furosemide-induced volume depletion. Nitric oxide-mediated endothelial function was intact. Patients with pure autonomic failure also had very low levels of plasma norepinephrine both supine and upright, but in contrast to patients with CIPA failed to maintain blood pressure upright.

INTERPRETATION: The results indicate that postganglionic sympathetic neurons are severely depleted in CIPA, but chromaffin cells of the adrenal medulla are spared. This confirms the differential effect of NGF signaling for sympathetic neural and chromaffin cell development. The finding that patients with CIPA maintain blood pressure well on standing challenges current concepts of the role of norepinephrine in the regulation of arterial pressure.