Issue Navigator

Volume 12 No. 12
Earn CME
Accepted Papers


Sleep Apnea in Familial Dysautonomia: A Reflection of Apnea Pathogenesis

Jeremy E. Orr, MD1; Naomi Deacon, PhD1; John Ravits, MD2
1Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego, CA; 2Department of Neurology, University of California, San Diego, CA

The pathogenesis of sleep-disordered breathing is complex, with interactions between upper airway anatomy, muscle responsiveness, threshold to arousal and ventilatory control stability determining whether individuals have stable breathing during sleep—or manifest obstructive apneas, central apnea, or mixed events.1,2 Examination of these underlying causes of sleep apnea to both explain pathophysiological mechanisms and develop targeted treatments has been shown useful in a variety of groups; in patients with obesity, highly effective upper airway muscles can rescue individuals from a collapsible airway, and in patients with heart failure, unstable control of breathing causes a very high prevalence of central sleep apnea.35 Recently there has been substantial interest in examining neurological conditions not traditionally associated with sleep apnea, based on contributions of these key determinants and the growing recognition of the complexity of neurobiological regulation of sleep, and appreciation of the detrimental effects of untreated sleep apnea.6

Familial dysautonomia (FD), sometimes called Riley-Day syndrome and hereditary sensory and autonomic neuropathy type III (HSAN-III), is a rare recessive neurogenetic disorder causing severe deficits in sensory and autonomic neurons, leading to several abnormalities that might be expected to pre-dispose these patients to sleep disordered breathing. Prior case series suggest a high prevalence of sleep apnea, although the nature of these events (obstructive versus central) are unclear. In this issue of the Journal of Clinical Sleep Medicine, a study by Hilz et al.7 assessed the prevalence and characteristics of sleep-disordered breathing in patients with FD and compared them to a control group. The authors chose to specifically focus on asymptomatic individuals in whom sleep apnea might not otherwise be suspected. Since there appears to be a high rate of death during sleep in FD patients, the question of whether there is a high prevalence of unsuspected and untreated sleep apnea in this group is an obvious concern. Indeed, they found sleep-disordered breathing in 5 of 11 patients, which was primarily mild and obstructive, but associated with mild hypercapnia and worsening during REM.

As suggested above, these findings are not unexpected, but nonetheless are of interest. Although specific mechanisms were not evaluated in this study, the findings and knowledge of the disease suggest several possible reasons for the high prevalence. Craniofacial and thoracic abnormalities may increase airway collapsibility.8 Normally, the negative pressure reflex would activate pharyngeal dilators, but it is possible that afferent neuropathy in FD would render this ineffective, which would be a highly unique pathophysiology. Indeed, the increased ratio of events during REM compared to NREM suggests a collapsible airway with only partially effective pharyngeal dilators.9 Baseline oxygenation was slightly low in the FD group, which may contribute to desaturation independently of variation in ventilation by nature of greater proximity to the steep portion of the oxyhemoglobin dissociation curve. Elevated carbon dioxide levels might reflect low chemosensitivity and poor respiratory mechanics, which would preclude an adequate response to reductions in ventilation from airway narrowing. Finally, we are just beginning to unravel the complex neuroanatomical regulation of breathing during sleep and many aspects remain to be elucidated.

Whether detection and subsequent treatment of sleep apnea in asymptomatic FD patients improves outcomes is an important question raised by this study. Since a randomized trial is unlikely to be feasible, we look forward to interventional studies that focus on other important outcomes, including changes in quality of life and cardiovascular profiles in this unique group of patients.


The authors have indicated no financial conflicts of interest.


Orr JE, Deacon N, Ravits J. Sleep apnea in familial dysautonomia: a reflection of apnea pathogenesis. J Clin Sleep Med 2016;12(12):1583–1584.



Eckert DJ, Malhotra A, Jordan AS. Mechanisms of apnea. Prog Cardiovasc Dis. 2009;51:313–23. [PubMed Central][PubMed]


Wellman A, Edwards BA, Sands SA, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol. 2013;114:911–22. [PubMed Central][PubMed]


Sands SA, Eckert DJ, Jordan AS, et al. Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea. Am J Respir Crit Care Med. 2014;190:930–7. [PubMed Central][PubMed]


Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999;341:949–54. [PubMed]


Sands SA, Edwards BA, Kee K, et al. Control theory prediction of resolved Cheyne-Stokes respiration in heart failure. Eur Respir J. 2016;48:1351–9. [PubMed]


Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47–112. [PubMed Central][PubMed]


Hilz MJ, Moeller S, Buechner S, et al. Obstructive sleep-disordered breathing is more common than central in mild familial dysautonomia. J Clin Sleep Med. 2016;12:1607–14.


Miles PG, Vig PS, Weyant RJ, Forrest TD, Rockette HE Jr. Craniofacial structure and obstructive sleep apnea syndrome--a qualitative analysis and meta-analysis of the literature. Am J Orthod Dentofacial Orthop. 1996;109:163–72. [PubMed]


Mokhlesi B, Punjabi NM. “REM-related” obstructive sleep apnea: an epiphenomenon or a clinically important entity? Sleep. 2012;35:5–7. [PubMed Central][PubMed]