Do metabolic deficits contribute to sleep disruption in monogenic intellectual disability syndromes?

Abstract

Intellectual disability is defined as limitations in cognitive and adaptive behavior that often arise during development. Disordered sleep is common in intellectual disability and, given the importance of sleep for cognitive function, it may contribute to other behavioral phenotypes. Animal models of intellectual disability, in particular of monogenic intellectual disability syndromes (MIDS), recapitulate many disease phenotypes and have been invaluable for linking some of these phenotypes to specific molecular pathways. An emerging feature of MIDS, in both animal models and humans, is the prevalence of metabolic abnormalities, which could be relevant for behavior. Focusing on specific MIDS that have been molecularly characterized, we review sleep, circadian, and metabolic phenotypes in animal models and humans and propose that altered metabolic state contributes to the abnormal sleep/circadian phenotypes in MIDS.

Keywords: Angelman syndrome; circadian rhythms; fragile X syndrome; neurodevelopmental disorders; neurofibromatosis 1; tuberous sclerosis complex.

Figure 1.. A possible role for metabolic impairments in the origin of sleep deficits in monogenic intellectual disability syndromes (MIDS).

This diagram depicts three hypotheses for the origin of sleep deficits in MIDS. The first is that the genetic mutation itself directly leads to changes in sleep–wake cycles. The second is that some of the behavioral problems in MIDS, such as impaired attention and hyperactivity, impact sleep. The third possibility is that the mutations lead to metabolic deficits that in turn disrupt sleep–wake cycles. Based on the evidence presented in this article, we favor the third hypothesis. Figure created with BioRender.com. Abbreviation: ADHD, attention deficit hyperactivity disorder.