Subjective sleep assessment in individuals with SYNGAP1-associated syndrome.

STUDY OBJECTIVES: Sleep disturbances are common in neurodevelopmental disorders (NDDs), affecting patients and caregivers' quality of life. SYNGAP1-associated syndrome, a rare NDD, is marked by intellectual disability, developmental delay, epilepsy, and sleep issues. However, research on sleep quality in these individuals is limited. This study aimed to evaluate genetic variants, epilepsy, and sleep patterns in SYNGAP1-associated syndrome patients and their caregivers. METHODS: An online survey was applied to 11 caregivers of individuals diagnosed with SYNGAP1-associated syndrome. Specific clinical inquiries were included, addressing childbirth, previous surgeries, and medication use. Inquiries about epilepsy included type of epilepsy, type and frequency of seizures, anti-seizure medications, and complementary non-pharmacological treatments. Children's Sleep Habits Questionnaire (CSHQ) was applied to assess the patients' sleep profile. Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of caregivers. RESULTS: Genetic analysis showed heterozygous mutations in SYNGAP1, often leading to loss of function. Epilepsy was present in 82% of participants, with 77.8% having drug-resistant seizures. Using the Children's Sleep Habits Questionnaire (CSHQ), 81.8% of patients exhibited poor sleep habits, including bedtime resistance, anxiety, night awakenings, parasomnias, and daytime sleepiness. Caregivers also reported poor sleep quality according to the Pittsburgh Sleep Quality Index (PSQI). CONCLUSIONS: This study highlights the high prevalence of epilepsy and sleep problems in SYNGAP1-associated syndrome, impacting both patients and caregivers. Further research is crucial to understand the syndrome's effects on sleep disturbances, emphasizing the need for targeted interventions to improve sleep quality in individuals with rare genetic syndromes and their caregivers.

Kinesin binding as a shared pathway underlying the genetic basis of male infertility and insomnia.

OBJECTIVE: To study whether male infertility and insomnia share genetic risk variants, and to identify any molecular, cellular and biological interactions between these traits. DESIGN: The in silico study was performed. Two lists of genetics variants were manually curated through a literature review, 1 of those associated with male infertility and the other with insomnia. Genes were assigned to these variants to compose male infertility (454 genes) and insomnia (921 genes)-associated gene lists. SUBJECTS: Not applicable. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Enrichment of biological pathways and protein-protein interaction (PPI) analysis. RESULTS: Twenty-eight genes were common to both lists, representing a greater overlap than would be expected by chance. In the 28 genes contained in the intersection list, there was a significant enrichment of pathways related to kinesin binding. A PPI analysis using the intersection list as input retrieved 25 nodes and indicated that 2 of them were kinesin-related proteins (PLEKHM2 and KCL1). CONCLUSIONS: The shared male infertility and insomnia genes, and the biological pathways highlighted in this study, suggest that further functional investigations into the interplay between fertility and sleep are warranted.

Leptin moderates the relationship between sleep quality and memory function: A population-based study.

Sleep is crucial for memory, as it promotes its encoding, consolidation, storage, and retrieval. Sleep periods following learning enhance memory consolidation. Leptin, a hormone that regulates appetite and energy balance, also influences memory and neuroplasticity. It plays a neurotrophic role in the hippocampus, enhancing synaptic function and promoting memory processes. Given these associations between sleep, memory, and leptin, this study aimed to evaluate the interplay between sleep quality, memory complaints and leptin levels. Using data from the São Paulo Epidemiologic Sleep Study (EPISONO) 2007 edition, we analyzed data from 881 participants who underwent evaluations for subjective sleep quality (Pittsburgh Sleep Quality Index), memory function (Prospective and Retrospective Memory Questionnaire), body mass index and plasmatic leptin levels. After confirming that subjects with poor sleep quality had more memory complaints in our cohort, we observed that leptin levels were increased in individuals with more memory complaints, but there was no association between leptin levels and sleep quality. Mediation analysis reinforced the direct effect of sleep quality on memory function, but leptin had no indirect effect as mediator over the sleep-memory association. Moderation analysis revealed that leptin acted as a moderator in the relationship between sleep quality and memory, with increased leptin levels enhancing the effect of sleep quality over memory function. These findings underscore the intricate interplay between sleep, memory, and metabolic factors like leptin, shedding light on potential mechanisms through which sleep influences memory and cognitive functions. Further research is needed to elucidate the exact mechanisms underlying these relationships and their implications for overall health and well-being.

Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder.

Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the POGZ regulatory targets, aiming to uncover the molecular pathways that, when disrupted by POGZ loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between POGZ targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.

Lipid metabolism and neuromuscular junction as common pathways underlying the genetic basis of erectile dysfunction and obstructive sleep apnea.

Erectile dysfunction (ED) incidence is higher in patients with obstructive sleep apnea (OSA). Studies have suggested that ED and OSA may activate similar pathways; however, few have investigated the links between their underlying genotypic profiles. Therefore, we conducted an in-silico analysis to test whether ED and OSA share genetic variants of risk and to identify any molecular, cellular and biological interactions between them. Two gene lists were manually curated through a literature review based on a PUBMED search, which resulted in one gene list associated with ED (total of 205 genes) and the other with OSA (total of 2622 genes). Between those gene sets, 35 were common for both lists (Fisher exact test, p-value = 0.027). The Protein-protein interaction (PPI) analysis using the intersect list as input showed that 3 of them had direct interactions (LPL, DGKB and PLCB1). In addition, the biological function of the genes contained in the intersect list suggested that pathways related to lipid metabolism and the neuromuscular junction were commonly found in the genetic basis of ED and OSA. From the shared genes between both conditions, the biological pathways highlighted in this study may serve as preliminary findings for future functional investigations on OSA and ED association.

The relationship between neurodevelopmental transcriptional programs and insomnia: From Rubinstein-Taybi syndrome into energy metabolism.

Neurodevelopmental disorders (NDD) are characterized by cognitive, emotional, and/or motor skills impairment since childhood, and sleep disturbances are a common comorbidity. Rubinstein-Taybi syndrome (RSTS), a rare genetic syndrome associated with NDD, is caused by CREBBP haploinsufficiency. This gene encodes an acetyltransferase with crucial role on the establishment of transcriptional programs during neurodevelopment. Although insomnia has been reported in RSTS patients, the convergent mechanisms between this sleep disturbance and CREBBP loss-of-function are not fully understood. We tested weather the genetic architecture underlying CREBBP regulatory targets and insomnia-associated genes is significantly shared. We then identified the biological pathways enriched among these shared genes. The intersection between CREBBP regulatory targets and genes associated with insomnia included 7 overlapping genes, indicating significantly more overlap than expected by chance. An over-representation analysis on these intersect genes identified pathways related to mitochondrial activity. This finding indicates that the transcriptional programs established by CREBBP might impact insomnia-related biological pathways through the modulation of energy metabolism. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between insomnia and CREBBP regulatory targets.

Endocrine and Epigenetic Regulation as Common Pathways Underlying the Genetic Basis of Sleep Traits and Longevity.

The amount of sleep needed over one's lifespan is age dependent and not sleeping enough or sleeping in excess is associated with increased morbidity and mortality. Yet, the convergent molecular mechanisms that link longevity and sleep are largely unknown. We performed a gene enrichment study that (1) identified genes associated with both longevity and sleep traits and (2) determined molecular pathways enriched among these shared genes. We manually curated two sets of genes, one associated with longevity and aging and the other with sleep traits (e.g., insomnia, narcolepsy, sleep duration, chronotype, among others), with both gene lists heavily driven by hits from recent large-scale Genome-Wide Association Studies. There were 47 overlapping genes between the gene list associated with sleep traits (1064 genes total) and the genes associated with longevity (367 genes total), indicating significantly more overlap than expected by chance. An overrepresentation analysis identified enriched pathways that suggest endocrine and epigenetic regulation as potential shared mechanisms between sleep traits and longevity. Concordantly, functional network analysis retrieved two clusters, being one associated with proteins of nuclear functions and the other, with extracellular proteins. This overlapping gene set, and the highlighted biological pathways may serve as preliminary findings for new functional investigations of sleep and longevity shared genetic mechanisms.

Genetic basis of sleep phenotypes and rare neurodevelopmental syndromes reveal shared molecular pathways.

Sleep-related phenotypes have been frequently reported in early on-set epileptic encephalopathies and in developmental delay syndromes, in particular in syndromes related to autism spectrum disorder. Yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown. We first performed a gene enrichment study that identified shared risk genes among rare epileptic encephalopathies/neurodevelopmental disorders, rare developmental delay genetic syndromes and sleep disturbances. We then determined cellular and molecular pathways enriched among genes shared between sleep phenotypes and those two early onset mental illnesses, aiming to identify genetic disparities and commonalities among these phenotypic groups. The sleep gene set was observed as significantly overlapped with the two gene lists associated to rare genetic syndromes (i.e., epileptic encephalopathies/neurodevelopmental disorders and developmental delay gene sets), suggesting shared genetic contribution. Similarities across significantly enriched pathways between the two intersect lists comprehended mostly synapse-related pathways, such as retrograde endocannabinoid signaling, serotonergic, and GABAergic synapse. Network analysis indicates epileptic encephalopathies/neurodevelopmental disorders versus sleep-specific clusters and developmental delay versus sleep-specific clusters related to synaptic and transcriptional regulation, respectively. Longstanding functional patterns previously described in epileptic encephalopathies and neurodevelopmental disorders genetic architecture were recaptured after dissecting the overlap between the genes associated to those developmental phenotypes and sleep disturbances, suggesting that during neurodevelopment different molecular and functional mechanisms are related to alterations on circadian rhythm. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between sleep disturbances and rare developmental syndromes.

Effect of chronic sleep deprivation on acrosomal integrity and functional parameters of murine sperm.

OBJECTIVE: To evaluate the effect of chronic sleep deprivation on sperm function quality in mice. DESIGN: Experimental study. SETTING: Not applicable. ANIMALS: Spermatozoa from twenty-four 10-week-old C57BL/6J male mice. INTERVENTION(S): The sleep deprivation group underwent gentle handling for 6 hours for 5 consecutive days. The mice in the sleep recovery group were allowed to sleep during the 24-hour period after the sleep deprivation protocol. MAIN OUTCOME MEASURE(S): After euthanasia, the spermatozoa were collected for analysis. Sperm motility was evaluated using computer-assisted sperm analyzer. Intracellular superoxide anion (O2-) activity, acrosome integrity, mitochondrial activity, and DNA fragmentation assays were conducted afterward. RESULT(S): Sleep deprivation and sleep recovery groups presented a lower percentage of spermatozoa with an intact acrosome, compared with the respective control groups. Regarding DNA fragmentation, a decreased proportion of spermatozoa with Comet I class intact DNA was observed in the sleep recovery group, compared with the recovery control group. Beat cross frequency was increased in the sleep recovery group. CONCLUSION(S): Sleep deprivation can reduce sperm quality, impairing acrosome integrity. Sleep recovery decreased DNA integrity and increased beat cross frequency.

Influence of physical activity on male fertility.

Infertility is a worldwide issue impacting 15% of couples' population. Male-related infertility results in almost 50% of these cases. Considering lifestyle factors associated with infertility, here in this literature review article, we aimed to discuss training/sport effects on male-related infertility. Regarding this issue, human and animal model studies related to the subject were gathered and analysed. Exercise is well known as a general improving factor, however, excessive exercise can result in male infertility due to reduced hypothalamus-pituitary-gonadal axis (HPT) function, increased oxidative stress and chronic inflammation. Consequently, these underlying impacts result in a low testosterone production, and reduced semen quality, and can lead to infertility. In contrast, it has been revealed that exercise can improve male fertility status in lifestyle-induced infertility condition such as obesity and diabetes. Indeed, exercise, by increasing testicular antioxidant defence, reducing pro-inflammatory cytokines level and enhancing the steroidogenesis process, leads to improved spermatogenesis and semen quality in lifestyle-induced infertility. In fact, it seems that individual health status as well as exercise volume, intensity and duration are effective-involved co-factors that influence the impact that exercise will promote on male fertility. Regarding these findings, it is important to study exercise different impacts in further clinical trials in order to generate preservative guidelines for exercise and also considering exercise as a treatment option in lifestyle-induced disease management.

Carnosine treatment during human semen processing by discontinuous density gradient.

The aim of this article was to evaluate the effects of different concentrations of carnosine added during human semen processing. Semen samples from 34 patients were submitted to processing by discontinuous density gradient centrifugation without (control) or with different concentrations of carnosine supplementation as follows: (a) 20 mM of carnosine supplementation on the layers of Percoll; and (b) 50 mM carnosine supplementation. Sperm samples were then washed with human tubal fluid medium and evaluated according to sperm kinetics and functional assessment. For statistical analysis, data were evaluated by a general linear model or a Friedman test, whenever appropriate. The 50 mM carnosine supplementation led to improved sperm mitochondrial activity when compared to untreated samples. Motility variables, such as percentage of motile and progressively motile spermatozoa, average path velocity, straight line velocity, curvilinear velocity and linearity, showed an improvement after semen processing irrespective of carnosine supplementation. Both concentrations of carnosine increased the beat-cross frequency (BCF) when compared to samples before processing. We conclude that carnosine supplementation in semen samples benefits sperm mitochondrial activity and BCF.