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 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, 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, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Treatment of Kleine-Levin Syndrome With Intranasal Photobiomodulation and Methylene Blue

“…Gene-wide association studies have shown a link to variants in the TRANK1 gene loci, which is a major gene in bipolar disorder. It has been hypothesized that variants in the TRANK1 region may increase the risk of developing KLS, with a correlation between TRANK1 polymorphisms and difficult births, in patients who have KLS [ 3 ]. A second hypothesis is that there are autoimmune mechanisms that lead to the development of KLS, or at least, contribute to the symptoms.…”

“…Lithium has shown great promise in patients treated with the medication. It has been found that Lithium may increase the duration of the inter-episodic period over time [ 3 , 14 ]. Anticonvulsants, particularly valproate, have been attempted with the suspicion of thalamic dysfunction and may be used as an alternative to lithium [ 15 ].…”

The Genetics of Sleep Disorders in Children: A Narrative Review

“…Pathway analysis also revealed the involvement of circadian regulation genes. This study also showed that variants in the TRANK1 gene region may predispose to KLS in participants with a difficult birth, suggesting that the TRANK1 gene region modulates newborns' response to brain injury, resulting in mental and neurological health consequences [113].…”

Impaired blood‐brain barrier in the microbiota‐gut‐brain axis: Potential role of bipolar susceptibility gene TRANK1

“… 11 In addition, TRANK1 rs71947856 variant was associated with circadian regulation and reported birth difficulties in patients with Kleine‐Levin syndrome, which is a rare disease characterized by severe episodic hypersomnia, with cognitive impairment and apathy or disinhibition. 15 However, the specific function of the TRANK1 gene in BD has not been clarified so far.…”

“…An integrated analysis of mRNA co‐expression network revealed that genes highly correlated with TRANK1 were significantly involved in the biological processes related to synaptic plasticity, dendritic spine, axon guidance and circadian rhythm 11 . In addition, TRANK1 rs71947856 variant was associated with circadian regulation and reported birth difficulties in patients with Kleine‐Levin syndrome, which is a rare disease characterized by severe episodic hypersomnia, with cognitive impairment and apathy or disinhibition 15 . However, the specific function of the TRANK1 gene in BD has not been clarified so far.…”