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.

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.

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

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