Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Abstract

Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region of TRANK1 gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reduced TRANK1 rs71947865 association. While theTRANK1 rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p<2.0×10−22 at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.Significance StatementGenetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.

Journal of Multiscale Neuroscience

“…Finally, the mechanism of KLS is complex, possibly linked to genetic variants in the TRANK1 gene loci [22], and more studies are needed to explore its mechanism in the future.…”

Functional brain imaging using 18F-fluorodeoxyglucose positron emission tomography/computerized tomography in 138 patients with Kleine–Levin syndrome: an early marker?

“…A recent genetic study (performed in most KLS cases in the world, including the patients here) suggests that the risk of developing KLS results from an interaction between a genetic (carrying a TRANK-1 gene mutation) predisposition and birth problems. 30 As the hippocampus plays a major role in episodic memory, one may be anxious about observing some hypometabolism in this area, especially in teenagers and young adults following academic studies. Indeed, approximately one-third of 120 patients with KLS have residual, mild cognitive problems during asymptomatic periods, including reduced logical reasoning, short-term verbal memory, processing speed, attention and retrieval strategies in verbal memory.…”

The orexin story, sleep and sleep disturbances

“…CSF ORX‐A level fluctuations appeared within values considered above the diagnostic cut‐off for NT1 in most patients (Podestá et al, 2006; Usuda et al, 2018), but in some cases also a reduction up to below 110 pg ml –1 was reported (Lopez et al, 2015; Wang et al, 2016). It is therefore unclear the relation between hypersomnia episodes and CSF ORX levels, whereas a recent study disclosed that polymorphisms of the TRANK1 gene (already associated with bipolar disorder and schizophrenia) constitute a genetic predisposition to the disorder (Ambati et al, 2021).…”