Faculty Bibliography

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::

OBJECTIVE: Panayiotopoulos syndrome is a benign idiopathic childhood epilepsy characterized by altered autonomic activity at seizure onset. METHODS: Three siblings with Panayiotopoulos syndrome underwent 24-hour EEG recording and head-up tilt testing with continuous blood pressure and RR interval monitoring. Plasma catecholamines and vasopressin were measured while supine, upright, and during a typical seizure. RESULTS: Patient 1, a 12-year-old girl, had a history of involuntary lacrimation, abdominal pain, and recurrent episodes of loss of muscle tone and unresponsiveness followed by somnolence. Her EEG revealed bilateral frontotemporal spikes. Patient 2, a 10-year-old boy, had episodic headaches with pinpoint pupils, skin flushing of the face, trunk, and extremities, purple discoloration of hands and feet, diaphoresis, nausea, and vomiting. Tilt testing triggered a typical seizure after 9minutes; there was a small increase in blood pressure (+5/4mm Hg, systolic/diastolic) and pronounced increases in heart rate (+59bpm) and norepinephrine (+242pg/mL), epinephrine (+175pg/mL), and vasopressin (+22.1pg/mL) plasma concentrations. Serum glucose was elevated (206mg/dL). His EEG revealed right temporal and parietal spikes. Patient 3, an 8-year-old boy, had a history of restless legs at night, enuresis, night terrors, visual hallucinations, cyclic abdominal pain, and nausea. His EEG showed bitemporal spikes. CONCLUSION: Hypertension, tachycardia, and the release of vasopressin suggest activation of the central autonomic network during seizures in familial Panayiotopoulos syndrome. These autonomic and neuroendocrine features may be useful in the diagnosis and may have therapeutic implications

Background: Patients with familial dysautonomia (FD) fail to increase respiratory drive in response to low oxygen and high CO₂ levels. Many hypoventilate and have frequent apneic events during sleep, a time associated with an increased incidence of sudden death. To assess the need for non-invasive ventilation, patients with FD routinely undergo sleep studies with end-tidal CO₂ monitoring. Because most have severe lung disease, it is not known, however, whether end-tidal CO₂ levels accurately reflect arterial blood CO₂ levels. Methods: We studied 88 patients with FD (mean age 25 +/- 1, 45; females:43 males). We measured the partial pressure of CO₂ in blood obtained from the radial artery at the wrist (ABL80 FLEX, Radiometer, Denmark). End-tidal CO₂ was continuously sampled from a nasal canula (infrared analysis 5200 Ohmeda, USA). The average CO₂ value obtained over 10 full tidal breaths was used. All measurements were obtained during relaxed spontaneous breathing in the supine position. The relationship between end-tidal and arterial CO₂ measurements was examined using Pearson correlations. Results: All patients had a history of at least one aspiration pneumonia. The average partial pressure of oxygen in arterial blood was 87 +/- 2 mmHg. Thirty-one patients (36%) had arterial oxygen levels B80 mmHg. The average partial pressure of CO₂ was 43 +/- 0.4 mmHg (range 34-57 mmHg). Thirty-four patients (39%) had hypercapnia with CO₂ in arterial blood >=45 mmHg. Measurements of end-tidal CO₂ correlated tightly with CO₂ measured in arterial blood (y = 0.88x + 2.23, R² = 0.50, p<0.001). Conclusions: Our results show that in patients with FD, despite severe lung disease, the partial pressure of CO₂ measured in expired air (i.e. end tidal CO₂) accurately reflects the partial pressure ofCO₂ in arterial blood. Monitoring end tidal CO₂ is critically important to determine the potential role of apnea/hypoventilation in sudden death during sleep

Background: Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a recessive disease caused by mutations affecting the tyrosine kinase receptor. The disorder affects the development of sensory and sudomotor sympathetic nerve fibers resulting in complete insensitivity to pain and anhidrosis. However, little is known about the cardiovascular autonomic phenotype of the disorder. Methods: We measured blood pressure, heart rate and catecholamines, vasopressin, endothelin and renin activity in plasma while supine and after 10 min of passive upright tilt in 10 patients with typical clinical features of HSAN-IV and diagnostic confirmation with genetic testing (mean age 9 +/- 2 years old, 4 females). Results: In the supine position, blood pressures (104 +/- 5/ 58 +/- 4 mmHg) and heart rates (87 +/- 9 beats/min) were normal. During upright tilt, mean arterial blood pressure changed little (-5 +/- 5 mmHg, p = 0.17) and heart rate increased appropriately (+23 +/- 5 beat/min, p<0.001). In all patients, plasma norepinephrine levels were low or undetectable while in the supine position (31 +/- 3 pg/ml) and failed to increase with upright tilt (4 +/- 5 pg/ml). Plasma renin activity levels increased slightly from 2.0 +/- 0.6 to 3.6 +/- 1.1 pg/ml with head-up tilt (+68 +/- 33 D%, p<0.03). Plasma vasopressin increased little and endothelin levels were essentially unchanged during upright tilt. Conclusions: Patients with HSAN-IV have very low levels of norepinephrine while supine and upright, but do not have orthostatic hypotension. Other vasoactive peptides involved in orthostatic blood pressure maintenance are not increased. These results challenge our current concepts of the role of norepinephrine in the regulation of blood pressure. The mechanism by which patients with HSAN-IV maintain their blood pressure is unknown

Background: Visceral sensations are relayed to the brain through a network of afferent nerves. Awareness of these sensations differs among individuals, likely due to different thresholds and CNS processing characteristics. Differences in the conscious awareness of bodily sensations may explain specific cardiovascular phenotypes. Thus, our goal was to evaluate the role, if any, of conscious awareness of body sensations and their relationship with hemodynamic responses to tilt in patients with orthostatic intolerance. Methods: Thirty-two otherwise healthy patients who complained of orthostatic intolerance participated in the study. We assessed perception of body sensations on a self-reported body vigilance scale. We measured blood pressure, heart rate and plasma catecholamine responses to passive upright tilt. Thirteen patients experienced typical vasovagal syncope (i.e., a fall in blood pressure and heart rate) 4; patients had an increase in heart rate >30 beat/min without a fall in blood pressure and were diagnosed as postural tachycardia syndrome; and 15 patients had normal cardiovascular responses to tilt and were classified as having unexplained orthostatic intolerance. Results: Self-reported feelings of shortness of breath (p<0.05), tingling (p<0.01), numbness (p<0.003) and chest discomfort (p<0.01) were correlated positively with supine plasma epinephrine levels and the increase in plasma epinephrine levels with tilt (p<0.02). Higher body vigilance was significantly related with the increase in heart rate during tilt, both at 3 min (p<0.02) and the maximum heart rate recorded (p<0.002). Patients with unexplained orthostatic intolerance scored higher for the time spent 'scanning their body for sensations' compared with patients who had vasovagal syncope during tilt (52 +/- 9 vs. 23 +/- 6%, p<0.02). Conclusion: Increased somatic vigilance is associated with a greater release of epinephrine on standing and faster heart rates. Increased somatic vigilance is associated with the postural tachycardia syndrome and may be the cause of hitherto unexplained orthostatic intolerance

Background: Patients with familial dysautonomia have a selective defect in the afferent neurons of the baroreflex. Failure to sense blood pressure result in the unregulated release of plasma catecholamines and volatile blood pressure. One of the most disabling features of familial dysautonomia are the recurrent attacks of nausea, retching and vomiting triggered by emotional or physiological stressors and associated with hypertension, tachycardia and psychomotor agitation. A pronounced surge in circulating norepinephrine during these crises readily explains the hypertension, but the cause of the nausea and vomiting remains unknown. Methods: Seven patients with familial dysautonomia (mean age 17 +/- 3 years, 4 females) confirmed by genetic testing were studied. We monitored blood pressure and heart rate and measured plasma catecholamines when they were feeling well and during typical vomiting crises triggered by emotionally charged situations. Results: When the patients were feeling well, average supine blood pressure was 124 +/- 7/64 +/- 5 mmHg with a heart rate of 81 +/- 3 beats/min. All patients experienced typical crises when they complained of severe nausea and were retching loudly. Vomiting was prevented by the fundoplication surgery. During crises, all patients were hypertensive (180 +/- 9/116 +/- 4 mmHg) and tachycardic (124 +/- 4 beats/min) but denied feeling palpitations. While supine, plasma norepinephrine levels increased from 130 +/- 42 to 772 +/- 151 pg/ml (p<0.002), plasma epinephrine levels increased from 20 +/- 5 to 63 pg/ml, and plasma dopamine levels increased markedly from 22 +/- 2 to 96 +/- 20 pg/ml. Conclusions: Our finding of high levels of circulating dopamine during crises in patients with familial dysautonomia suggest that the severe nausea and vomiting is due to activation of dopamine receptors in the chemoreceptor trigger zone

Familial dysautonomia is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced or absent pain and temperature sensibilities, postural hypotension, absent baroreflex function and labile blood pressure that increases markedly during emotional excitement (Norcliffe-Kaufmann et al. 2010). Given the absent baroreflex function we tested the hypothesis that cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 10 patients with FD. Spontaneous bursts of MSNA were absent, but we found evidence of tonically firing sympathetic neurones that increased during emotional arousal. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia

The glutamate neurotransmitter system has the potential to transform our knowledge of the pathophysiology of schizophrenia and help us identify potential treatment targets. In this section of the supplement, the dopamine system is first reviewed as it relates to schizophrenia and its treatment with the currently available antipsychotics, followed by a discussion of glutamate receptors and how they, too, can impact on positive, negative, and cognitive symptoms. Symptoms of schizophrenia can be theoretically explained by a hyper-dopaminergic state existing in the mesolimbic pathway and a hypodopaminergic state in the mesocortical pathways; the former results in positive symptoms and the latter leads to negative, cognitive, and affective symptoms. Current FDA-approved pharmacologic options for the treatment of schizophrenia involve dopamine blockade at the dopamine D2 receptor. Although commercially available antipsychotic agents have at least some degree of antagonism at the dopamine D2 receptor, there are some investigational agents that produce an antipsychotic effect in the absence of direct dopamine D2 receptor antagonism. The glutamate-dopamine model of schizophrenia offers new therapeutic targets, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists.