Faculty Bibliography

Familial dysautonomia (Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) is a rare autosomal recessive disease characterized by impaired development of primary sensory and autonomic neurons resulting in a severe neurological phenotype, which includes arterial baroreflex and chemoreflex failure with high frequency of sleep-disordered breathing and sudden death during sleep. Although a rare disease, familial dysautonomia represents a unique template to study the interactions between sleep-disordered breathing and abnormal chemo- and baroreflex function. In patients with familial dysautonomia, ventilatory responses to hypercapnia are reduced, and to hypoxia are almost absent. In response to hypoxia, these patients develop paradoxical hypoventilation, hypotension, bradycardia, and potentially, death. Impaired ventilatory control due to chemoreflex failure acquires special relevance during sleep when conscious control of respiration withdraws. Overall, almost all adult (85%) and pediatric (95%) patients have some degree of sleep-disordered breathing. Obstructive apnea events are more frequent in adults, whereas central apnea events are more severe and frequent in children. The annual incidence rate of sudden death during sleep in patients with familial dysautonomia is 3.4 per 1000 person-year, compared to 0.5-1 per 1000 person-year of sudden unexpected death in epilepsy. This review summarizes recent developments in the understanding of sleep-disordered breathing in patients with familial dysautonomia, the risk factors for sudden death during sleep, and the specific interventions that could prevent it.

OBJECTIVES/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS:Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C- reactive protein, yearly frequency of hyper-adrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS:Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body Mass Index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower Inspiratory Capacity (IC) (42.7% predicted vs 62.8% predicted; p=0.04). CONCLUSIONS:Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

Hypokalemia of renal origin can arise from genetic abnormalities in a variety of transporters or channel proteins that mediate tubular handling of potassium. Recently, mutations in claudin 10 have been documented in patients with hypokalemia in association with a range of other electrolyte abnormalities and skin and sweat gland manifestations. We report a 12-year-old Hispanic boy who presented with anhydrosis, aptyalism, alacrima, hypokalemia, and hypocalciuria, in whom we detected a homozygous mutation in the claudin 10 gene. During the 4-year follow-up period, he developed hypermagnesemia and a decline in estimated glomerular filtration rate to 59mL/min/1.73m². His unaffected parents and siblings were heterozygous for the mutation. We summarize the clinical phenotype encountered in patients with claudin 10 mutations. It is characterized by significant heterogeneity in electrolyte and extrarenal abnormalities and is associated with a risk for progressive loss of kidney function in up to 33% of cases. Awareness of this association between claudin 10 mutations and electrolyte abnormalities, namely hypokalemia and hypermagnesemia, sheds new light on the physiology of potassium and magnesium handling along the nephron and increases the likelihood of identifying the underlying tubular mechanism in patients with newly diagnosed hypokalemia with or without concomitant hypermagnesemia.

Objective: To assess efficacy and durability (using Orthostatic Hypotension Symptom Assessment [OHSA] and OH Daily Activities Scale [OHDAS]), and safety of ampreloxetine, once-daily to treat neurogenic orthostatic hypotension (nOH) in subjects with synucleinopathies.
Background(s): Failure of the autonomic nervous system results in nOH with inadequate increase in synaptic norepinephrine (NE) and maintenance of upright blood pressure (BP) following postural change. Ampreloxetine is a novel norepinephrine reuptake inhibitor being investigated for treatment of symptomatic nOH.
Method(s): In a 24-week open-label phase 2 multicenter study of subjects with nOH, following a single-dose escalation phase, responders were treated with oral ampreloxetine (3-20 mg) once-daily for up to 20 weeks with 4-week follow-up after treatment withdrawal (Week 24). Primary efficacy endpoint OHSA#1 (dizziness, lightheadedness, feeling faint) was assessed at end of Week 4; end of open-label treatment (Week 20); and after treatment withdrawal (Week 24).
Result(s): Twenty-one subjects enrolled in the open-label phase (mean age, 64 years; 57% multiple-system atrophy). Sixteen (76%), 11 (52%), and 10 (48%) subjects completed assessments at Weeks 4, 20, and 24, respectively. Mean (SD) improvement from baseline in OHSA#1 was 2.4 (4.5) and 1.9 (3.1) for all subjects, and 3.8 (3.1) and 3.1 (3.0) for symptomatic subjects (OHSA#1 C4 at baseline) at Weeks 4 and 20, respectively, scores were back to baseline levels at Week 24. Similar trends in improvement were observed in OHSA and OHDAS composite scores. Most common adverse events (AEs) were urinary tract infection (24%), hypertension (19%), and headache (14%). Two subjects (10%) discontinued treatment due to AEs and 5 (24%) reported serious AEs, none considered related to study medication.
Conclusion(s): In subjects with nOH, ampreloxetine demonstrated clinically meaningful improvement in OHSA#1 at Week 4, which was sustained over 20 weeks, and reverted to baseline after treatment withdrawal. Similar trends were observed in OHSA and OHDAS composite scores. Ampreloxetine was well-tolerated

Objective: To assess the acute effects of ampreloxetine in subjects with symptomatic neurogenic orthostatic hypotension (nOH).
Background(s): Failure of the autonomic nervous system results in nOH with inadequate increase in synaptic norepinephrine (NE) and maintenance of blood pressure (BP) following postural change to the upright position. Ampreloxetine is a novel NE reuptake inhibitor for the treatment of symptomatic nOH.
Method(s): A multicenter, 2-part study of the acute effects of ampreloxetine versus placebo was conducted. Part A was an ascending single-dose, 5-day study with placebo on Day 1, followed by escalating doses of ampreloxetine (2.5, 5, 10, 20 mg), based on safety, tolerability, and pressor effect (change from baseline in seated systolic BP [SBP], duration of standing, OH symptoms). Part B was a one-day, double-blind, parallel-design study in which subjects were randomized to receive one dose of placebo or ampreloxetine (dose determined by Part A response; maximum, 15 mg).
Result(s): Of 34 enrolled subjects (mean age, 66 years), 29 (85%) completed all dosing levels of Part A. Four hours after ampreloxetine 10 mg, mean (SD) increase from baseline in standing duration and seated SBP were 1.6 (3.6) minutes and 4.9 (20.1) mmHg more than 4 hours after placebo. The commonest adverse events (AEs) were headache and urinary tract infection; one subject discontinued treatment due to AE; no serious AEs were reported. In Part B, 5 subjects were randomized to ampreloxetine and 5 to placebo. Mean (95% CI) difference in seated SBP between subjects receiving ampreloxetine and subjects receiving placebo was 29.9 (7.6, 52.3) mmHg.
Conclusion(s): In subjects with nOH, single doses of ampreloxetine resulted in acute increase from baseline in seated SBP and standing duration 4 hours post-dose. Ampreloxetine was generally well-tolerated. These results support further assessment to evaluate longer-term effects of ampreloxetine on symptoms of nOH