Publications

2018
Alkozei A, Killgore WD, Smith R, Dailey NS, Bajaj S, Raikes AC, Haack M. Chronic sleep restriction differentially affects implicit biases toward food among men and women: preliminary evidence. J Sleep Res. 2018;27 (4) :e12629.Abstract
Chronic sleep restriction and obesity are two major public health concerns. This study investigated how chronic sleep restriction changes implicit attitudes towards low- and high-calorie foods. In a randomized, counterbalanced cross-over design, 17 participants (eight females, nine males) underwent two laboratory testing sessions where they were either sleep-restricted for 3 weeks (i.e. underwent three weekly cycles of 5 nights of 4 h of sleep followed by 2 nights of 8 h of sleep opportunity) or received 3 weeks of control sleep (i.e. 8 h of sleep opportunity per night for 3 weeks). There was evidence for a significant sleep condition x sex interaction (F  = 4.60, P = 0.04). After chronic sleep restriction, men showed a trend towards a significant decrease in their implicit attitudes favouring low-calorie foods (P = 0.08), whereas women did not show a significant change (P = 0.16). Men may be at increased risk of weight gain when sleep-deprived due to a reduced bias towards low-calorie foods.
Baker K, Gordon SL, Melland H, Bumbak F, Scott DJ, Jiang TJ, Owen D, Turner BJ, Boyd SG, Rossi M, et al. SYT1-associated neurodevelopmental disorder: a case series. Brain. 2018;141 (9) :2576-2591.Abstract
Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.
Simpson NS, Scott-Sutherland J, Gautam S, Sethna N, Haack M. Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization. Pain. 2018;159 :33-40. Publisher's VersionAbstract
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
simpson_pain_2018.pdf
2017
Morgenthaler TI, Dort L, Mullington J. Transparency and Partnership. J Clin Sleep Med. 2017;13 (5) :763.
Alkozei A, Killgore WD, Smith R, Dailey NS, Bajaj S, Haack M. Chronic Sleep Restriction Increases Negative Implicit Attitudes Toward Arab Muslims. Sci Rep. 2017;7 (1) :4285.Abstract
Chronic sleep restriction is a common experience; and while it has negative physiological effects, little is known about how it affects human behavior. To date, no study has investigated whether chronic sleep restriction can influence implicit attitudes (e.g., towards a race). Here, in a randomized, counterbalanced crossover design, we subjected participants to 3 weeks of chronic sleep restriction in the lab (i.e., 3 weekly cycles of 5 nights of 4 hours of sleep per night followed by 2 nights of 8 hours of sleep) and found evidence for an increased negative implicit bias towards Arab Muslims. No indicators of an implicit bias were found in these same individuals when they were rested (during a counterbalanced 3-week period of 8 hours time in bed per night). These findings suggest that chronic sleep restriction may "unmask" implicit racial or ethnic biases that are otherwise inhibited when in a rested state. Because chronic sleep restriction is prevalent among many occupations that routinely interact with ethnic minorities in potentially high-conflict situations (e.g., police officers), it is critical to consider the role that restricted sleep may play in exacerbating negative implicit attitudes and their potential for provoking unintentional and potentially harmful behavioral consequences.
Yang H, Haack M, Gautam S, Meier-Ewert HK, Mullington JM. Repetitive exposure to shortened sleep leads to blunted sleep-associated blood pressure dipping. J Hypertens. 2017;35 (6) :1187-1194.Abstract
BACKGROUND: Blood pressure (BP) dips at night during sleep in healthy individuals but in disturbed sleep, dipping is blunted. However, the impact of chronic insufficient sleep duration, with limited intermittent recovery sleep, on BP dipping is not known. The objective of this study was to examine, in a controlled experimental model, the influence of chronic sleep restriction on BP patterns at night and during the day. METHOD: In a highly controlled 22-day in-hospital protocol, 45 healthy participants (age 32 ± 2 years; BMI 24 ± 1 kg/m; 22 men and 23 women) were randomly assigned to one of two conditions: repeated sleep restriction (4 h of sleep/night from 0300 to 0700 h for three nights followed by recovery sleep of 8 h, repeated four times in succession) or a sleep control group (8 h/night from 2300 to 0700 h). RESULTS: Beat-to-beat BP and polysomnography were recorded and revealed that sleep-associated DBP dipping was significantly blunted during all four blocks of sleep restriction (P = 0.002). Further, DBP was significantly increased for the whole day during the first, second, and fourth block of sleep restriction (all P < 0.01), and SBP was significantly increased for the whole day during the first block of sleep restriction. CONCLUSION: Repeated exposure to significantly shortened sleep blunts sleep-associated BP dipping, despite intermittent catch-up sleep. Individuals frequently experiencing insufficient sleep may be at increased risk for hypertension due to repetitive blunting of sleep-associated BP dipping, and resultant elevations in average circadian BP.
Alkozei A, Killgore WD, Smith R, Dailey NS, Bajaj S, Haack M. Chronic Sleep Restriction Increases Negative Implicit Attitudes Toward Arab Muslims. Scientific Reports. 2017;7 :4285.Abstract
Chronic sleep restriction is a common experience; and while it has negative physiological effects, little is known about how it affects human behavior. To date, no study has investigated whether chronic sleep restriction can influence implicit attitudes (e.g., towards a race). Here, in a randomized, counterbalanced crossover design, we subjected participants to 3 weeks of chronic sleep restriction in the lab (i.e., 3 weekly cycles of 5 nights of 4 hours of sleep per night followed by 2 nights of 8 hours of sleep) and found evidence for an increased negative implicit bias towards Arab Muslims. No indicators of an implicit bias were found in these same individuals when they were rested (during a counterbalanced 3-week period of 8 hours time in bed per night). These findings suggest that chronic sleep restriction may "unmask" implicit racial or ethnic biases that are otherwise inhibited when in a rested state. Because chronic sleep restriction is prevalent among many occupations that routinely interact with ethnic minorities in potentially high-conflict situations (e.g., police officers), it is critical to consider the role that restricted sleep may play in exacerbating negative implicit attitudes and their potential for provoking unintentional and potentially harmful behavioral consequences.
alkozei_2017_scientific_reports_iat.pdf
Yang H, Haack M, Gautam S, Meier-Ewert HK, Mullington J. Repetitive exposure to shortened sleep leads to blunted sleep-associated blood pressure dipping. Journal of Hypertension. 2017.Abstract

Background: Blood pressure (BP) dips at night during sleep in healthy individuals but in disturbed sleep, dipping is blunted. However, the impact of chronic insufficient sleep duration, with limited intermittent recovery sleep, on BP dipping is not known. The objective of this study was to examine, in a controlled experimental model, the influence of chronic sleep restriction on BP patterns at night and during the day.
Method: In a highly controlled 22-day in-hospital protocol, 45 healthy participants (age 322 years; BMI 241kg/m2; 22 men and 23 women) were randomly assigned to one of two conditions: repeated sleep restriction (4 h of sleep/night from 0300 to 0700 h for three nights followed by recovery sleep of 8 h, repeated four times in succession) or a sleep control group (8 h/night from 2300 to 0700 h).
Results: Beat-to-beat BP and polysomnography were recorded and revealed that sleep-associated DBP dipping was significantly blunted during all four blocks of sleep restriction (P¼0.002). Further, DBP was significantly increased for the whole day during the first, second, and fourth block of sleep restriction (all P<0.01), and SBP was significantly increased for the whole day during the first block of sleep restriction.
Conclusion: Repeated exposure to significantly shortened sleep blunts sleep-associated BP dipping, despite intermittent catch-up sleep. Individuals frequently experiencing insufficient sleep may be at increased risk for hypertension due to repetitive blunting of sleep-associated BP dipping, and resultant elevations in average circadian BP.
Keywords: autonomic nervous system, blood pressure, circadian, blood pressure dipping, diurnal, heart rate, sleep deprivation, sodium excretion
Abbreviations: BL, baseline; BP, blood pressure; CRC, clinical research center; CVD, cardiovascular disease; HR, heart rate; N1, N2, N3, stages 1–3 in nonrapid eye movement sleep; Rec, recovery; REM, rapid eye movement; SE, sleep efficiency; TST, total sleep time

yang_et_al_journal_of_hypertension_2017.pdf
2016
Morgenthaler TI, Hashmi S, Croft JB, Dort L, Heald JL, Mullington J. High School Start Times and the Impact on High School Students: What We Know, and What We Hope to Learn. J Clin Sleep Med. 2016;12 (12) :1681-1689.Abstract
STUDY OBJECTIVES: Several organizations have provided recommendations to ensure high school starts no sooner than 08:30. However, although there are plausible biological reasons to support such recommendations, published recommendations have been based largely on expert opinion and a few observational studies. We sought to perform a critical review of published evidence regarding the effect of high school start times on sleep and other relevant outcomes. METHODS: We performed a broad literature search to identify 287 candidate publications for inclusion in our review, which focused on studies offering direct comparison of sleep time, academic or physical performance, behavioral health measures, or motor vehicular accidents in high school students. Where possible, outcomes were combined for meta-analysis. RESULTS: After application of study criteria, only 18 studies were suitable for review. Eight studies were amenable to meta-analysis for some outcomes. We found that later school start times, particularly when compared with start times more than 60 min earlier, are associated with longer weekday sleep durations, lower weekday-weekend sleep duration differences, reduced vehicular accident rates, and reduced subjective daytime sleepiness. Improvement in academic performance and behavioral issues is less established. CONCLUSIONS: The literature regarding effect of school start time delays on important aspects of high school life suggests some salutary effects, but often the evidence is indirect, imprecise, or derived from cohorts of convenience, making the overall quality of evidence weak or very weak. This review highlights a need for higher-quality data upon which to base important and complex public health decisions.
Simpson NS, Diolombi M, Scott-Sutherland J, Yang H, Bhatt V, Gautam S, Mullington J, Haack M. Repeating patterns of sleep restriction and recovery: Do we get used to it?. Brain Behav Immun. 2016;58 :142-151.Abstract
Despite its prevalence in modern society, little is known about the long-term impact of restricting sleep during the week and 'catching up' on weekends. This common sleep pattern was experimentally modeled with three weeks of 5 nights of sleep restricted to 4h followed by two nights of 8-h recovery sleep. In an intra-individual design, 14 healthy adults completed both the sleep restriction and an 8-h control condition, and the subjective impact and the effects on physiological markers of stress (cortisol, the inflammatory marker IL-6, glucocorticoid receptor sensitivity) were assessed. Sleep restriction was not perceived to be subjectively stressful and some degree of resilience or resistance to the effects of sleep restriction was observed in subjective domains. In contrast, physiological stress response systems remain activated with repeated exposures to sleep restriction and limited recovery opportunity. Morning IL-6 expression in monocytes was significantly increased during week 2 and 3 of sleep restriction, and remained increased after recovery sleep in week 2 (p<0.05) and week 3 (p<0.09). Serum cortisol showed a significantly dysregulated 24h-rhythm during weeks 1, 2, and 3 of sleep restriction, with elevated morning cortisol, and decreased cortisol in the second half of the night. Glucocorticoid sensitivity of monocytes was increased, rather than decreased, during the sleep restriction and sleep recovery portion of each week. These results suggest a disrupted interplay between the hypothalamic-pituitary-adrenal and inflammatory systems in the context of repeated exposure to sleep restriction and recovery. The observed dissociation between subjective and physiological responses may help explain why many individuals continue with the behavior pattern of restricting and recovering sleep over long time periods, despite a cumulative deleterious physiological effect.
Simpson NS, Diolombi M, Scott-Sutherland J, Yang H, Bhatt V, Gautam S, Mullington JM, Haack M. Repeating patterns of sleep restriction and recovery: Do we get used to it?. Brain, Behavior, and Immunity. 2016;58 :142-151.Abstract

Despite its prevalence in modern society, little is known about the long-term impact of restricting sleep during the week and ‘catching up’ on weekends. This common sleep pattern was experimentally modeled with three weeks of 5 nights of sleep restricted to 4 h followed by two nights of 8-h recovery sleep. In an
intra-individual design, 14 healthy adults completed both the sleep restriction and an 8-h control condition, and the subjective impact and the effects on physiological markers of stress (cortisol, the inflammatory marker IL-6, glucocorticoid receptor sensitivity) were assessed. Sleep restriction was not perceived to be subjectively stressful and some degree of resilience or resistance to the effects of sleep restriction was observed in subjective domains. In contrast, physiological stress response systems remain activated with repeated exposures to sleep restriction and limited recovery opportunity. Morning IL-6 expression in monocytes was significantly increased during week 2 and 3 of sleep restriction, and remained
increased after recovery sleep in week 2 (p < 0.05) and week 3 (p < 0.09). Serum cortisol showed a significantly dysregulated 24 h-rhythm during weeks 1, 2, and 3 of sleep restriction, with elevated morning cortisol, and decreased cortisol in the second half of the night. Glucocorticoid sensitivity of monocytes
was increased, rather than decreased, during the sleep restriction and sleep recovery portion of each week. These results suggest a disrupted interplay between the hypothalamic-pituitary-adrenal and inflammatory systems in the context of repeated exposure to sleep restriction and recovery. The observed
dissociation between subjective and physiological responses may help explain why many individuals continue with the behavior pattern of restricting and recovering sleep over long time periods, despite a cumulative deleterious physiological effect.

simpson_2016_bbi.pdf
Mullington JM, Abbott SM, Carroll JE, Davis CJ, Dijk D-J, Dinges DF, Gehrman PR, Ginsburg GS, Gozal D, Haack M, et al. Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health. Sleep. 2016;39 (4) :727-36.
2015
Morgenthaler TI, Croft JB, Dort LC, Loeding LD, Mullington JM, Thomas SM. Development of the National Healthy Sleep Awareness Project Sleep Health Surveillance Questions. J Clin Sleep Med. 2015;11 (9) :1057-62.Abstract
OBJECTIVES: For the first time ever, as emphasized by inclusion in the Healthy People 2020 goals, sleep health is an emphasis of national health aims. The National Healthy Sleep Awareness Project (NHSAP) was tasked to propose questions for inclusion in the next Behavioral Risk Factor Surveillance System (BRFSS), a survey that includes a number of questions that target behaviors thought to impact health, as a means to measure community sleep health. The total number of questions could not exceed five, and had to include an assessment of the risk for obstructive sleep apnea (OSA). METHODS: An appointed workgroup met via teleconference and face-to-face venues to develop an inventory of published survey questions being used to identify sleep health, to develop a framework on which to analyze the strengths and weaknesses of current survey questions concerning sleep, and to develop recommendations for sleep health and disease surveillance questions going forward. RESULTS: The recommendation was to focus on certain existing BRFSS questions pertaining to sleep duration, quality, satisfaction, daytime alertness, and to add to these other BRFSS existing questions to make a modified STOP-BANG questionnaire (minus the N for neck circumference) to assess for risk of OSA. CONCLUSIONS: Sleep health is an important dimension of health that has previously received less attention in national health surveys. We believe that 5 questions recommended for the upcoming BRFSS question banks will assist as important measures of sleep health, and may help to evaluate the effectiveness of interventions to improve sleep health in our nation.
Mullington J, Pack AI, Ginsburg GS. In Pursuit of Sleep-Circadian Biomarkers. Sleep. 2015;38 (11) :1665-6.
Floam S, Simpson N, Nemeth E, Scott-Sutherland J, Gautam S, Haack M. Sleep characteristics as predictor variables of stress systems markers in insomnia disorder. J Sleep Res. 2015;24 (3) :296-304.Abstract
This study investigates the extent to which sleep characteristics serve as predictor variables for inflammatory, hypothalamic-pituitary-adrenal and autonomic systems markers. Twenty-nine participants with a diagnosis of insomnia disorder based on the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (age 25.3 ± 1.6 years, insomnia duration 6.6 ± 0.8 years) and 19 healthy control sleepers (age 25.4 ± 1.4 years) underwent a 2-week at-home evaluation keeping a sleep diary and wearing an actigraph, followed by a visit to the Research Center to measure blood pressure, and collect blood and urine samples. The actigraphy- and diary-based variables of sleep duration, sleep-onset latency, wake after sleep onset and sleep fragmentation/number of night-time awakenings were averaged and entered as dependent variables in regression analyses. Composite scores were calculated for the autonomic (blood pressure, norepinephrine), inflammatory (monocyte counts, interleukin-6, C-reactive protein) and hypothalamic-pituitary-adrenal systems (cortisol), and used as predictor variables in regression models. Compared with controls, individuals with insomnia had a shorter sleep duration (P < 0.05), and a higher hypothalamic-pituitary-adrenal and inflammatory composite score (P < 0.05). The higher inflammatory score was mainly due to higher circulating monocytes (P < 0.05), rather than differences in interleukin-6 or C-reactive protein. In persistent insomnia disorder, cortisol is upregulated and associated with actigraphy- and diary-based wake after sleep onset, suggesting that wake after sleep onset may serve as a marker to identify individuals at increased risks for disorders associated with a hyperactive hypothalamic-pituitary-adrenal system. The absence of autonomic and pro-inflammatory changes (interleukin-6, C-reactive protein), despite a substantial decrease in actigraphic sleep duration, may relate to a higher resilience to the adverse biological consequences of insomnia in this young age group.
floam_jsr_2015.pdf
2014
Haack KKV, Marcus NJ, Del Rio R, Zucker IH, Schultz HD. Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure. Hypertension. 2014;63 (5) :1041-9.Abstract
Cheyne-Stokes respiration and cardiac arrhythmias are associated with increased morbidity and mortality in patients with chronic heart failure (CHF). Enhanced carotid body chemoreflex (CBC) sensitivity is associated with these abnormalities in CHF. Reduced carotid body (CB) nitric oxide and nitric oxide synthase (NOS) levels play an important role in the enhanced CBC. In other disease models, Simvastatin (statin) treatment increases endothelial NOS, in part, by increasing Krüppel-like Factor 2 expression. We hypothesized that statin treatment would ameliorate enhanced CBC sensitivity as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index, in a rodent model of CHF. Resting breathing pattern, cardiac rhythm, and the ventilatory and CB chemoreceptor afferent responses to hypoxia were assessed in rats with CHF induced by coronary ligation. CHF was associated with enhanced ventilatory and CB afferent responses to hypoxia as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index. Statin treatment prevented the increases in CBC sensitivity and the concomitant increases in respiratory variability, apnea/hypopnea index, and arrhythmia index. Krüppel-like Factor 2 and endothelial NOS protein were decreased in the CB and nucleus tractus solitarii of CHF animals, and statin treatment increased the expression of these proteins. Our findings demonstrate that the increased CBC sensitivity, respiratory instability, and cardiac arrhythmias observed in CHF are ameliorated by statin treatment and suggest that statins may be an effective treatment for Cheyne-Stokes respiration and arrhythmias in patient populations with high chemoreflex sensitivity.
Zee PC, Badr SM, Kushida C, Mullington JM, Pack AI, Parthasarathy S, Redline S, Szymusiak RS, Walsh JK, Watson NF. Strategic opportunities in sleep and circadian research: report of the Joint Task Force of the Sleep Research Society and American Academy of Sleep Medicine. Sleep. 2014;37 (2) :219-27.
2013
Chesson AL, Chervin RD, Benca RM, Greenough GP, O'Hearn DJ, Auckley DH, Littner M, Mullington JM, Malhotra A, Berry RB, et al. Organization and structure for sleep medicine programs at academic institutions: Part 2--goals and strategies to optimize patient care, education, and discovery. Sleep. 2013;36 (6) :803-11.
Hayflick SJ, Kruer MC, Gregory A, Haack TB, Kurian MA, Houlden HH, Anderson J, Boddaert N, Sanford L, Harik SI, et al. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain. 2013;136 (Pt 6) :1708-17.Abstract
Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
Chervin RD, Chesson AL, Benca RM, Greenough GP, O'Hearn DJ, Auckley DH, Littner M, Mullington JM, Malhotra A, Berry RB, et al. Organization and structure for sleep medicine programs at academic institutions: Part 1--current challenges. Sleep. 2013;36 (6) :795-801.

Pages