In marked contrast, both in patients with FD and patients with PAF, head-down tilt induced an increase in systolic blood pressure of more than 10 mm Hg, compared to the blood pressure level when supine, demonstrating, like during upright tilt, inappropriate baroreflex function. == Changes in FVR. in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF. == Conclusion: == Hydroxyurea The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients. == GLOSSARY == = familial dysautonomia; = forearm vascular resistance; = pure autonomic failure. == == Familial dysautonomia (FD) is usually a hereditary disease caused by a mutation affecting the protein IKAP.1,2Patients with FD have a complex neurologic phenotype, first described by Riley et al.3Their original report featured 5 children who responded to mild anxiety with hypertension, tachycardia, red blotching of the skin, and diaphoresis. Interestingly, the patients also had postural hypotension and did not complain of pain when their feet were immersed in ice-cold water. Neuropathology studies in samples from patients with FD showed reduced number of primary sensory neurons in dorsal root ganglia4and fiber loss in spinothalamic and spinocerebellar tracts as well as in posterior columns of the spinal cord.5These findings provided an explanation for the impaired pain and temperature perception as well as the characteristic decreased/absent myotatic reflexes and gait ataxia. The autonomic phenotype of these patients, particularly their blood pressure abnormalities, have, however, remained unexplained. Subjects have supine hypertension and severe orthostatic hypotension, which could be perhaps due to a presumed decrease in the number of sympathetic neurons. 68Yet patients with FD also have recurrent episodes of hypertension with tachycardia, which are frequently associated with skin flushing and diaphoresis and suggest that sympathetic neurons can be activated and are functional. We noted that these episodes resemble those described in the very rare patients in whom afferents fibers from baroreceptor in the carotid sinus and aortic arch traveling in the vagus and glossopharyngeal nerves have been damaged by tumors, surgery, or radiotherapy.9,10Thus, we postulated that this blood pressure abnormalities of patients with FD might be due to a selective impairment of the afferent neurons of the baroreflex. To test this hypothesis, we analyzed the autonomic and neuroendocrine responses brought on by stimuli that either engage or Hydroxyurea bypass afferent baroreflex pathways and compared them to those of normal subjects and to those of Hydroxyurea patients with selective efferent autonomic dysfunction due to pure autonomic failure (PAF).11,12 == METHODS == == Patients. == Fifty patients with FD (age 22 2 years, 23 men), confirmed by genetic testing,1310 patients with PAF (age 64 4 years, 5 men),11and 12 normal controls (age 26 2 years, 5 men) participated in the study. Although matched for age, patients with FD were shorter (height: FD 146 2 vs controls 166 1 cm,p< 0.001) and lighter (weight: FD 40 2 vs controls 58 10 kg,p< 0.001) than normal controls, a well-described abnormality in these patients. The diagnosis of PAF was based on the presence of severe orthostatic hypotension, low plasma norepinephrine concentration, no antibody titers to nicotinic ganglionic cholinergic receptors, absent blood pressure overshoot during LAMA5 phase IV of a Valsalva maneuver, no somatic neurologic deficits, and a disease duration of 5 years or more.14Because FD is a congenital disorder and PAF is a neurodegenerative disorder, patients with FD were younger than patients with PAF. All procedures were approved by the Institutional Review Board of New York University and informed consent was obtained from all subjects. == Laboratory protocol. == An IV catheter was inserted into the left cubital vein and the subject was transferred to a tilt table. After a period of at least 20 minutes of supine rest when the patient appeared relaxed, blood pressure, heart rate, forearm blood flow velocity, and end-tidal co2levels were recorded during spontaneous breathing for 5 minutes. Blood samples were drawn for the measurement.