The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype–phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder caused by pathogenic loss of function variants in the tumour suppressor genes TSC1 and TSC2. The resultant hamartomas confer significant medical risks by disruption of local tissues. Risk of mortality in TSC is known to be elevated, but only recently have multiple studies assessed specific causes of mortality in TSC. A critical literature review of all available studies examining mortality in TSC was conducted using the terms "TSC", "Tuberous Sclerosis Complex", "mortality", "death", and "life expectancy", in PubMed and Google Scholar, until December 15, 2024. We identified 13 studies that reported a total of 411 deaths from 6735 TSC individuals. Data were typically incomplete and causes of death in many cases were obtained from death certificates. Crude mortality per 100 individuals ranged from 1.4 to 13.8 over average intervals of 11-45 years. Standardized Mortality Ratios or hazard ratios (versus control group) ranged from 3.0 to 4.9 (mean 4.3). Mean life expectancy was 66.2 years compared to an average of 81.8 in the general population. In the seven studies that reported specific causes of mortality in the general TSC population, 6/7 studies (85 %) had renal or central nervous system disease as the most common cause of mortality. Lymphangioleiomyomatosis was also found to confer significant risk of mortality in adult women and cardiac rhabdomyomas were the dominant cause of neonatal mortality. TSC-associated neuropsychiatric disorders-related mortality and morbidity may be underestimated. Mortality in TSC is elevated compared to the general population, with central nervous system and renal disease most frequently culpable. Further cohort studies will be required to establish and characterize the risk of mortality in TSC in the age of disease-modifying therapies.

Background: Tuberous sclerosis complex (TSC) is a multisystemic disorder caused by inactivating variants in the mTOR pathway inhibitors genes TSC1 and TSC2. Individuals with TSC are predisposed to benign tumors in multiple organs as well as TSC-associated neuropsychiatric disorders (TAND) and epilepsy. Pathogenic variants in TSC2 are typically associated with a more severe phenotype compared to TSC1; the TSC2 R905Q variant has been shown to be an exception, where patients have been reported to present with unusually mild TSC features that may be undetected. Methods: We studied the TSC phenotype of a 13-year-old individual and three family members with a TSC2 c.2714G>A (R905Q) pathogenic variant. Results: Patient 1 presented with severe medically refractory epilepsy without tubers or subependymal nodules, and only mild dermatologic features of TSC missed on virtual examinations. Her mother and maternal aunt (Patients 2 and 3 - diagnosed after age 50 years) presented with a mild phenotype, with dermatologic features and TAND. Her maternal uncle (Patient 4 - diagnosed at age 47 years) displayed the most severe phenotype, presenting with intellectual disability, medically refractory epilepsy, obsessive-compulsive disorder, post-traumatic stress disorder, and psychosis. Conclusions: This study expands the possible phenotypic spectrum of TSC2 R905Q variant, demonstrating an association with severe epilepsy without associated neuroradiological stigmata. This presentation highlights the possibility of occult focal cortical dysplasia in TSC and emphasizes the importance of genetic testing in individuals with severe epilepsy. Moreover, a late adult diagnosis was subsequently made in other family members allowing for appropriate TSC surveillance to occur. Crown Copyright (c) 2024 Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Background: Effects of SSRI for symptoms of ASD and comorbid conditions are uncertain. We conducted a systematic review and meta-analyses to determine the efficacy and safety of SSRIs in children with ASD on 8 clinically relevant outcomes. Methods: We searched 7 databases to retrieve RCT of SSRIs versus placebo in children with ASD. Two authors independently extracted data, assessed risk of bias and rated the certainty of evidence using the GRADE method. Results: Seven RCTs with a total of 606 participants were included. The evidence is very uncertain on the effect of SSRIs on restricted repetitive behaviors and anxiety symptoms in children with ASD. There is low certainty of the evidence suggesting that SSRIs result in little to no effect on obsessive-compulsive symptoms and disruptive behaviors, and there is moderate certainty of the evidence that SSRIs likely result in little to no difference in global functioning and a slight increase in adverse events. No studies evaluated depressive symptoms. Conclusions: The number of studies on this population remains limited. The current body of evidence shows no benefit of the use of SSRIs in children with ASD. Risk/benefit assessment should be carefully considered on an individual basis until further evidence is made available. Protocol registration number: PROSPERO-CRD42020169836 Lay Efficacy of SSRIs in children with ASD Do SSRIs Help Children with Autism? The scope of this systematic review of the literature was to identify if medications called SSRIs (Selective Serotonin Reuptake Inhibitors) are helpful and safe for children with Autism Spectrum Disorder (ASD). These medicines are sometimes used to treat anxiety, obsessive-compulsive behaviors, or other symptoms. What Did the Study Look At? The researchers carefully examined seven studies that included 606 children with ASD. They compared the effects of SSRIs to a placebo (a pill with no active medicine). What Did They Find? The researchers found that there is not enough data to confidently judge the effect of SSRI on restricted-repetitive behaviors and anxiety symptoms in children with ASD. Data available shows that SSRIs likely don’t improve obsessive-compulsive symptoms or disruptive behaviors in children with ASD. SSRIs probably don’t make a noticeable difference in overall daily functioning in children with ASD. Children taking SSRIs might experience a small increase in side effects like upset stomach or sleep problems. No studies looked at how SSRIs affect depression in children with ASD. What Does This Mean for Families? Right now, there isn’t strong evidence to support using SSRIs for children with ASD. Every child is unique, so if you’re considering this medication, it’s essential to weigh the possible risks and benefits with your doctor. More research is needed to provide better guidance for families and physicians.

Background Effects of Selective Serotonin Reuptake Inhibitors (SSRI) for symptoms of autism spectrum disorder (ASD) or comorbid conditions are uncertain. We conducted a systematic review and meta-analyses to determine the efficacy and safety of SSRIs in children with ASD on restricted repetitive behaviors, obsessive-compulsive, anxiety and depressive symptoms, disruptive behaviors, global functioning, and quality of life. Methods We searched MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, WHO ICTRP, Clinical.Trials.gov. to retrieve RCT of SSRIs versus placebo in children with ASD that evaluated the outcomes of interest with a validated measurement instrument. Two authors independently extracted data, assessed risk of bias and rated the certainty of evidence. Results Seven RCTs with a total of 606 participants were included. The evidence is very uncertain on the effect of SSRIs on restricted-repetitive behaviors and anxiety symptoms in children with ASD, there is low certainty of the evidence suggesting that SSRIs result in little to no effect on obsessive-compulsive symptoms and disruptive behaviors and there is moderate certainty of the evidence that SSRIs likely result in little to no difference in global functioning and a slight increase in adverse events. No studies evaluated depressive symptoms. Conclusions The number of studies on this population remains limited, and there is a lack of commonly accepted outcome measures able to identify relevant changes for patients and families. Protocol registration number:PROSPERO-CRD42020169836

There is increasing interest in parent-child technoference: the interference with personal interactions caused by technology devices. This study examined the reliability and construct validity of the Technology Device Interference Scale (TDIS) to measure technoference in a sample of Canadian parents and children. Parents (n=883) and children (n=376) were recruited from clinical and community settings and completed the TDIS for their own and family member technoference over three timepoints (T1=2023, T2=2024, T3=2025). TDIS internal consistency, test-retest reliability, and construct validity were assessed using Cronbach’s alpha, intraclass correlation coefficient, and confirmatory factor analysis, respectively. The TDIS showed good internal consistency and adequate to good construct validity when used by children to report on their own technoference (all α >.70; CFI>.95, TLI>.95, RMSEA<.07) or their parents’ technoference (all α >.70; CFI>.95, TLI>.90, RMSEA≤.11). The TDIS had low to acceptable internal consistency and poor model fit for parent report of their own technoference ( α range: .63 - .66; CFI<.95, TLI≤.80, RMSEA≥.14) or their child’s technoference ( α range: .56 - .63; CFI<.95, TLI≤.85, RMSEA≥.11); factor loadings for the items “phone” and “tablet” were low (phone<.50, tablet<.50). Test–retest reliability was moderate for all reports. The TDIS demonstrated good reliability and construct validity of child-reported technoference. Parent-reported technoference demonstrated lower reliability and construct validity, with “phone” and “tablet” weakly associated with the other technological devices. Future studies should distinguish between handheld vs. non-handheld devices when investigating parent-reported technoference.