Faculty Bibliography

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 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

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.

INTRODUCTION/BACKGROUND:This study aimed to assess the outcomes of mirabegron for the treatment of overactive bladder (OAB) symptoms in patients with Parkinson disease (PD). METHODS:A retrospective study was conducted including patients with PD who received mirabegron 50 mg once daily for OAB symptoms between 2012 and 2017. The primary endpoint was clinical success defined as any improvement in overactive bladder symptoms self-assessed by the patients 6 weeks after mirabegron initiation. Secondary endpoints included number of pads per day, number of nocturia episodes and adverse events. RESULTS:Fifty patients (mean 74 years old) were included. Before being treated with mirabegron, 56% had failed prior anticholinergic therapy. After 6 weeks of mirabegron 50 mg, five patients (11.4%) had a complete resolution of their OAB symptoms; 25 patients (50%) reported improvement, 23 (46%) reported no change and 2(4%) reported worsening of their OAB symptoms. The number of pads per day decreased from 1.5 to 0.9 (p = 0.01) and so did the number of nocturia episodes (from 3 to 2.6/night; p = 0.02). Only 2 adverse events were reported during mirabegron treatment (4%): one dizziness and one diaphoresis, that disappeared after mirabegron discontinuation. After a median follow-up of 19 months, 23 patients (46%) persisted on mirabegron. Persistence rates were 51.5%, 44.6% and 36.4% at 1, 2 and 3 years respectively. CONCLUSION/CONCLUSIONS:Mirabegron has an excellent safety profile and appears to be an effective treatment for overactive bladder symptoms in patients with PD. Further prospective randomized trials are needed to properly assess mirabegron in PD patients.