Faculty Bibliography

Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.

BACKGROUND: Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing which can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions particularly in the elderly (233 per 100,000 patients over 75 years of age in the US). OH can be due to volume depletion, blood loss, large varicose veins, medications, or due to defective activation of sympathetic nerves and reduced norepinephrine release upon standing (i.e., neurogenic OH). METHODS AND FINDINGS: Literature review. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and is commonly associated with supine hypertension. Several pharmacological and non-pharmacological therapeutic options are available. CONCLUSIONS: Here we review the epidemiology, diagnosis, and management of neurogenic OH, and provide an algorithm for its treatment emphasizing the importance of removing aggravating factors, implementing non-pharmacologic measures, and selecting appropriate pharmacological treatments.

Objective: The purpose of this study was to determine the predictors of the improvement in orthostatic symptoms with atomoxetine. Background: We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improves upright blood pressure and pre-syncopal symptoms as measured by the orthostatic hypotension symptom assessment (OHSA) in patients with neurogenic orthostatic hypotension (nOH). Design/Methods: Our sample size consisted of 101 autonomic failure patients with nOH who participated in clinical trials (NCT00223691, NCT1316666) conducted in two national referral centers for autonomic disorders (Vanderbilt Autonomic Dysfunction Center and NYU Langone Medical Center Dysautonomia Center). The analyses was performed in patients with symptomatic nOH defined as item-1 OHSA (lightheadedness) equal or more than four points. Seated blood pressure was measured in three occasions before and 60 minutes after receiving 18 mg of atomoxetine. Standing blood pressure at 1, 3, 5 and 10 minutes and OHSA questionnaire was collected before and after the atomoxetine dose. Multiple linear regression was used to test for overall linear relations between the dependent variable (OHSA score after atomoxetine) and independent variables (baseline OHSA score, age, diagnosis, baseline supine norepinephrine levels) and to assess the significance of these relations after adjustments for each covariate. Results: 47 patients (47%) met criteria for symptomatic nOH. The average age at the time of evaluation was 67+/-9 years, 47 % were males. 55% were diagnosed as pure autonomic failure, 30% as multiple system atrophy, 11% as Parkinson disease and 4% were patients with nOH of unknown etiology. Adjusted R2 for this model was 0.3, only supine norepinephrine levels (P=0.047) accurately predicted orthostatic symptoms following atomoxetine after adjusting for baseline OHSA, age and specific diagnosis. Conclusions: Supine baseline norepinephrine levels predict the improvement in symptoms produced by atomoxetine in patients with symptomatic nOH