Faculty Bibliography

Objective: We present the protocol, recruitment numbers, and preliminary adverse event profile of patients enrolled in a single-center phase-2 futility trial using sirolimus for multiple system atrophy (MSA) (ClinicalTrials.gov: NCT03589976).
Background(s): In patients with MSA, autophagy is impaired and misfolded aSyn accumulates in neurons and glia, causing neurodegeneration. Sirolimus, a medication that has been approved by the U.S. Food and Drug Administration for chronic treatment in humans for a variety of disorders for almost 20 years, is a potent activator of autophagy. We hypothesize that treatment with sirolimus might activate autophagy of aSyn resulting in reduced neurodegeneration and slower progression of the neurological deficits in patients with MSA.
Method(s): Single-center, randomized, placebo-controlled, phase-2 futility clinical trial to determine if sirolimus is of sufficient promise to slow the disease progression of patients with MSA, prior to embarking on a large-scale and costly phase-3 study to assess its efficacy. Non-futility will offer strong support for a phase-3 trial to detect clinical efficacy. We will enroll 56 patients with a 3:1 (sirolimus:placebo) randomization. We expect to complete enrollment in 2 years.
Result(s): The first patient was screened and enrolled in September 2018. By May 2019, 35 patients had been screened and 31 had been enrolled and randomized. By October 2019 we expect to have enrolled 43 patients (76% of our final target enrollment). Common adverse events included oral ulcers, abdominal discomfort and diarrhea/loose stools. Recruitment and adverse events will be updated by the time of this abstract presentation.
Conclusion(s): This is the first time sirolimus or analogs are being used clinically with the aim of slowing disease progression in patients with neurodegenerative disorders. Our observations may offer strong support for a phase-3 trial to confirm the efficacy of sirolimus in MSA

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

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 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

Patients with Hereditary Sensory & Autonomic Neuropathy type III exhibit marked ataxia, including gait disturbances. We recently showed that functional muscle spindle afferents in the leg, recorded via intraneural microelectrodes inserted into the peroneal nerve, are absent in HSAN III, although large-diameter cutaneous afferents are intact. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. We tested the hypothesis that manual motor performance is also compromised in HSAN III, attributed to the predicted absence of muscle spindles in the intrinsic muscles of the hand. Manual performance in the Purdue pegboard task was assessed in 12 individuals with HSAN III and 11 age-matched healthy controls. The mean (SD) pegboard score (number of pins inserted in 30 s) was 8.11.9 and 8.61.8 for the left and right hand respectively, significantly lower than the scores for the controls (15.01.3 and 16.01.1; p<0.0001). Performance was not improved after applying kinesiology tape over the joints of the hand. In five patients we inserted a tungsten microelectrode into the ulnar nerve at the wrist. No spontaneous or stretch-evoked muscle afferent activity could be identified in any of the 11 fascicles supplying intrinsic muscles of the hand, whereas rich tactile afferent activity could be recorded from four cutaneous fascicles. We conclude that functional muscle spindles are absent in the hand, and most likely absent in the long finger flexors and extensors, and that this largely accounts for the poor manual motor performance in HSAN III.