National Sleep Disorders Research Plan
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Section 6 Content:
Neuropsychiatric Disorders in Childhood and Sleep
Sleep and Early Brain Development and Plasticity
Adolescent Sleep


Sleep in Medical Disorders

Genetic Diseases and Syndromes Affecting Sleep And Breathing


A large number of unique genetic disorders have primary or secondary sleep abnormalities. Understanding the pathophysiology of the autonomic nervous system (ANS) dysregulation that occurs in many of these pediatric disorders could improve our understanding of the maturation of the ANS and the abnormalities that occur in common sleep disorders such as Sleep-Disordered Breathing (SDB). Investigating anatomical mechanisms for the upper airway obstruction found in children with craniofacial malformation could shed light on mechanisms for upper airway obstruction in SDB. Understanding how other disorders produce primary insomnia or daytime hypersomnolence may also shed light on novel sleep regulatory mechanisms.

Studies have demonstrated SDB and symptoms compatible with ANS dysregulation in children with Idiopathic Congenital Central Hypoventilation Syndrome (CCHS), Rett Syndrome (Xq28, MECP2), and Familial Dysautonomia (9q31, IKBKAP). Very few sleep studies have been performed, however, in children with craniofacial malformations, chromosomal/genetic abnormalities, and in children with neuromuscular diseases.

Genetic and familial craniofacial syndromes are often subdivided into those with micrognathia, midfacial hypoplasia, and protuberant tongue disorders. The micrognathia syndromes include Treacher Collins Syndrome, an autosomal dominant syndrome (5q32-33.1, TCOF1), and Pierre Robin Sequence. Infants with these syndromes can experience profound SDB requiring aggressive intervention to prevent physiologic compromise. The midfacial hypoplasia syndromes include Apert Syndrome (10q26, FGFR2), Crouzon Syndrome (10q26, FGFR2), and Pfeiffer Syndrome (8p11.2-p11.1 or 10q26, FGFR1 or 2). These are all autosomal dominant, and typically represent a fresh mutation. Children with midfacial hypoplasia often have increasingly severe SDB with advancing age due to maldevelopment and surgical intervention. Another example of midfacial hypoplasia is achondroplasia, an autosomal dominant skeletal dysplasia (4p16.3, FGFR3) in which respiratory compromise is due to an abnormal rib cage, small foramen magnum, and SDB. Disorders with a protuberant tongue include the mucopolysaccharidoses, (ex. Hunter Syndrome and Hurler Syndrome) and Down Syndrome (Trisomy 21), all with identified genetic mutations and often with severe SDB requiring early intervention.

Disorders of the neuromuscular system impose a substantial burden at the multi-system level. Many of these children exhibit dysfunction of the respiratory and upper airway musculature that contributes to the development of SDB. For example, 15-20% of children with Duchenne Muscular Dystrophy will develop sleep disturbances, and this prevalence is even greater among patients with spinal muscular atrophy and myelomeningocele. There are currently no well defined clinical or biological criteria that allow for prediction of which affected children will have a sleep disturbance, and hence there is widespread under-recognition of these problems. The morbidity and impact on quality of life due to sleep disturbances in this population are currently unknown.

SDB is frequently observed in the above-described syndromes as a result of anatomic malformation, neuromuscular weakness, or morbid obesity. In addition, however, central factors also appear to be involved in addition or independently of symptoms related to SDB. This may be the case for Prader Willi Syndrome (15q12, SNRPN) and Angelman Syndrome (15q11-q13, UBE3A), in which daytime sleepiness and low hypocretin levels have been reported independently of SDB, suggesting hypothalamic dysregulation of sleep regulation. These disorders also frequently produce complex behavioral and medical problems that have secondary effects on sleep, particularly disturbed nocturnal sleep and sleep apnea. It is thus often difficult to identify disease-specific sleep phenotypes.

Other unique genetic syndromes without overt SDB may also have associated primary central nervous system (CNS) sleep disorders. Fragile X Syndrome (Xq28, FRAXF; Xq28, L1CAM) children experience sleep disturbances and low melatonin levels while subjects with Norrie disease (genetic alterations in a region encompassing the Monoamine oxidase genes at Xp11.4, NDP; Xp11.2, BMP15) or Niemann Pick Type C (18q-q12, NCPC1; 18q12.1-q12.2, DSG2) may experience cataplexy and sleep disturbances. Subjects with myotonic dystrophy (DM1, 19q13) often have abnormal breathing during sleep and possibly centrally mediated hypersomnolence. Smith-Magenis syndrome (SMS), including multiple congenital anomalies and mental retardation (17p11.2, SMCR; 17q, PSORS2), is also associated with severe sleep disturbances.

Progress In The Last 5 Years

- The phenomenon of generalized ANS dysfunction has become clearer among children with CCHS and Rett syndrome. Patients with Rett syndrome exhibit unique respiratory disturbances that are state-dependent.

- Patients with Prader Willi syndrome present with universal reductions in their hypoxic ventilatory responses and with frequent alterations in their breathing patterns during sleep. Animal models for some of these genetic conditions have become available, thereby opening important opportunities for the study of respiratory control and sleep interactions.

- The study of control of breathing patterns in wakefulness and sleep in inbred mice strains has allowed for identification of putative chromosomal locations for several of the respiratory control components.

- Despite extensive progress in understanding the molecular and genetic mechanisms underlying many of the neuromuscular diseases, the progress achieved in understanding and defining when patients with these disorders will manifest sleep disturbances has been extremely limited.

Research Recommendations

- Improve phenotypic and genotypic characterization of SDB with ANS dysfunction and craniofacial maldevelopment through extended population studies in children, incorporating gene databases and including multi-organ and multi-functional categorization of disease-related morbidity and response to therapy.

- Increase our understanding of primary sleep disturbances in genetic disorders of children, with the goal of discovering new sleep-regulating mechanisms.

- In naturally occurring diseases of ANS dysfunction, conduct studies to better understand the ontogeny of the ANS from infancy through adulthood.

- In naturally occurring diseases with anatomical malformations of the face and upper airway, conduct studies to better understand SDB and its pathophysiology and consequences with advancing age.

- Determine how and if SDB in these unique diseases during childhood is linked to other diseases in adulthood.

- Develop novel interventional approaches to treat SDB in these special children, in collaboration with craniofacial and dental colleagues.

- Develop animal models to test hypotheses generated from delineation of phenotype-genotype correlations.

- Establish the clinical correlates of sleep disruption and SDB in children with neuromuscular disease.

- Determine the implications of sleep disturbances on end-organ morbidity and mortality as well as on health related cost and quality of life in children with neuromuscular disease.

Sudden Infant Death Syndrome (SIDS)

SIDS is the sudden and unexpected death of an infant under one year of age that remains unexplained after an autopsy, examination of the death scene, and thorough review of the medical and family history. With the introduction of the Back to Sleep programs over the past decade, a remarkable decline in the incidence of SIDS has occurred worldwide. In the U.S. alone, the aggressive educational campaign targeting infant sleep position and other modifiable factors known to be related to SIDS has resulted in a decrease from 7,000 babies dying each year to fewer than 3,000. The National Institute of Child Health and Human Development (NICHD) has completed a 5-year SIDS plan divided into four sections: Etiology and Pathogenesis, Prognostics and Diagnostics, Prevention, and Health Disparities. The NICHD document contains a statement in each section of the problem, background, and specific recommendations to address gaps in knowledge, for intervention activities, and for infrastructure needs. (The complete NICHD document is available on-line at For a comprehensive review of SIDS and research recommendations, readers are directed to the NICHD document.

National Institutes of Health (NIH) Department of Health and Human Services (click here) First Gov Website (Click here)
National Heart Lung and Blood Institute (Click Here) National Center on Sleep Disorders Research (Click Here)