Abstract
Kleine–Levin Syndrome is a rare neurological disorder with onset typically during adolescence that is characterized by recurrent episodes of hypersomnia, behavioral changes, and cognitive abnormalities, in the absence of structural changes in neuroimaging. As for many functional brain disorders, the exact disease mechanism in Kleine-Levin Syndrome is presently unknown, preventing the development of specific treatment approaches or protective measures. Here we review the pathophysiology and genetics of this functional brain disorder and then present a specific working hypothesis. A neurodevelopmental mechanism has been suspected based on associations with obstetric complications. Recent studies have focused on genetic factors whereby the first genome-wide association study (GWAS) in Kleine–Levin Syndrome has defined a linkage at the TRANK1 locus. A Gene x Environment interaction model involving obstetric complications was proposed based on concepts developed for other functional brain disorders. To stimulate future research, we here performed annotations of the genes under consideration for Kleine–Levin Syndrome in relation to factors expected to be associated with obstetric complications. Annotations used data-mining of gene/protein lists related to for hypoxia, ischemia, and vascular factors and targeted literature searches. Tentative links for TRANK1, four additional genes in the TRANK1 locus, and LMOD3-LMO2 are described. Protein interaction data for TRANK1 indicate links to CBX2, CBX4, and KDM3A, that in turn can be tied to hypoxia. Taken together, the neurological sleep disorder, Kleine-Levin Syndrome, shows genetic and mechanistic overlap with well analyzed brain disorders such as schizophrenia, autism spectrum disorder and ADHD in which polygenic predisposition interacts with external events during brain development, including obstetric complications.
Graphical Abstract
Gene x Environment interaction (G x E) model for the sleep disorder, Kleine-Levin Syndrome (KLS). This hypothesis-generating study proposes that perturbations during neurodevelopment affect the formation of neural circuits for sleep regulation in KLS. Thereby, genetic factors linked to KLS interact (“x”) with obstetric complications as environmental factors. A subset of genes may mediate between the risk for KLS and hypoxia, ischemia, or vascular changes during obstetric complications.
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Acknowledgements
Michael Hamper dedicates his work on KLS to the Kleine-Levin Syndrome community for their continued support. Rainald Schmidt-Kastner acknowledges support from Dept. Clinical Neuroscience, College of Medicine, FAU.
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The senior author is supported by departmental funding by Dept. Clinical Neuroscience, College of Medicine, FAU.
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Both authors contributed equally to the manuscript’s conception and writing. MH: provided expertise on Kleine–Levin Syndrome. RS-K: provided expertise on hypoxia–ischemia gene interactions and performed the gene annotations. Both authors read and approved the final manuscript.
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Hamper, M., Schmidt-Kastner, R. Sleep Disorder Kleine–Levin Syndrome (KLS) Joins the List of Polygenic Brain Disorders Associated with Obstetric Complications. Cell Mol Neurobiol 43, 3393–3403 (2023). https://doi.org/10.1007/s10571-023-01391-z
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DOI: https://doi.org/10.1007/s10571-023-01391-z