Faculty Bibliography

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter and multinational NIH-sponsored Natural History Study of the Synucleinopathies.
Method(s): Patients with a clinical diagnosis of probable or possible MSA were prospectively enrolled at 11 participating centers. Demographic data, clinical variables, and autonomic testing results were included.
Result(s): 293 patients with MSA (125 women) have been enrolled. MSA-C was predominant (154 patients, 52.6%). Mean age at symptom onset was 57.6+/-8.4 (mean+/-SD) and at enrollment was 62.0+/-7.8 years old. UMSARS-1 was 21.1+/-7.6 and UMSARS-2 was 21.2+/-9.1. MoCA score was 26.3+/-4.4 indicating normal cognition. In the supine position, blood pressure (systolic BP/diastolic BP) was 143.0+/-25.2/84.0+/-14.5 mmHg, and heart rate was 75.0+/-11.5 bpm. After 3-min head-up tilt, BP fell to 113.1+/-25.5/69.6+/-15.9 mmHg and HR increased to 82.9+/-12.7 bpm. Supine plasma norepinephrine levels were 365.4+/-408.5 pg/ml and increased only to 449.8+/-277.2 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. The University of Pennsylvania Smell Identification Test (UPSIT) score was 28.5+/-8.1 indicating preserved olfaction. Probable rapid eye movement (REM) sleep behavior disorder was reported by 85%.
Conclusion(s): This is the largest cross-sectional sample of patients with MSA recruited consecutively reported so far. Our results confirm that: i) symptom onset in MSA is remarkable consistent at 57 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) probable REM behavior disorder is very frequent. The prospective follow-up of these patients will provide additional information on the natural history of the disease

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

Background: Disease progression of multiple system atrophy (MSA) as measured by the Unified Multiple System Atrophy Rating Scale (UMSARS) varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2, respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): 293 patients (62.0+/-7.8 years old) with MSA were enrolled. Disease duration was 4.5+/-3.6 years. 98 patients completed 1-year evaluations and 48 completed the 2-year evaluation. The 12-month progression rates were 5.5+/-5.3 for the UMSARS-I, 6.6+/-5.2 for the UMSARS-II, and 11.9+/-9.8 for the total score. The 24-month progression rates were 10.8+/-7.1 for the UMSARS-I, 12.5+/-7.9 for the UMSARS-II, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p=0.0461) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

Objective: To describe an unusual case of a young girl of Jewish Ashkenazi descent with two rare genetic disorders: familial dysautonomia and congenital adrenal hyperplasia.
Method(s): Case report.
Result(s): Female patient presenting with hypotonia, failure to thrive, recurrent vomiting and frequent lower respiratory tract infections during the first year of life. Her physical exam disclosed genital ambiguity and, because an older sister had a diagnosis of congenital adrenal hyperplasia, the diagnosis was suspected in this case, and confirmed by low levels of cortisol and aldosterone. Targeted genetic testing showed homozygosis for a pathogenic variant in the CYP21A2 gene (c.293-13C[G, aka I2G, well-described in Jewish Ashkenazi patients) and heterozygosis for 7 other variants in the same gene. She was started on fludrocortisone for mineralocorticoid replacement therapy. Additional signs and symptoms were identified including frequent aspiration pneumonias prompting a gastrostomy tube placement at 6 months of age, emotionally-induced episodes of face, hand and feet blotching, frequent falls, impaired sensitivity to pain, and lack of tears. Additional genetic testing at age 2 disclosed homozygous copies of the founder mutation variant of familial dysautonomia (variant IVS20?6 T[C) in the IKBKAP gene.
Conclusion(s): The presence of one rare genetic disorder does not preclude the presence of another rare genetic disorder. Signs and symptoms not consistent with one diagnosed genetic disorder should prompt suspicion of additional causes

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