The research landscape of tuberous sclerosis complex–associated neuropsychiatric disorders (TAND)—a comprehensive scoping review

Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. Methods The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. Results Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). Conclusions Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified

Post-traumatic stress in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden

Post-traumatic stress in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden

Post-traumatic stress in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden

Understanding Relationships Between Autism, Intelligence, and Epilepsy: A Cross-Disorder Approach

Aim As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy. Method The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype. Results A total of 180 SRS questionnaires were filled out in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21y, range 4–63y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9y range 4–22y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism. Interpretation Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific for these conditions

Personalized medicine for rare neurogenetic disorders: can we make it happen?

Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients

Optometry in adults with microdeletion 22q11.2:The eye as a window to the brain

Purpose: The 22q11.2 deletion syndrome (22q11.2DS) has an estimated prevalence of 1:2148 live births and is associated with an increased risk of schizophrenia, cognitive decline and early-onset Parkinson's disease. Because retinal and cerebral tissue share embryological, physiological and anatomical characteristics, retinal blood vessel morphology and retinal nerve fiber layer (RNFL) thickness have been proposed as non-invasive biomarkers for psychiatric and neurodegenerative disorders. In this exploratory study, we examined these potential biomarkers in adults with 22q11.2DS relative to controls, and in relation to age. Methods: Central retinal artery and vein equivalent, fractal dimension, and vascular tortuosity, obtained through fundoscopy, and peripapillary RNFL and macular thickness, obtained through optical coherence tomography, were compared between adults with 22q11.2DS and sex- and age-matched controls. Results: Mean retinal vascular fractal dimension and tortuosity values were significantly higher in the group of adults with 22q11.2DS than in controls (p &lt; 0.001; p &lt; 0.001). RNFL was thicker in the nasal segment (p = 0.002) in 22q11.2DS, and a trend for thinner RNFL in the nasal and temporal inferior segments (p = 0.05 and p = 0.06, respectively) was found. There were significant negative correlations with age for fractal dimension (p &lt; 0.001) and RNFL thickness in the global (p = 0.007), temporal inferior (p = 0.005) and temporal superior (p = 0.04) segments in adults with 22q11.2DS, but not in controls. Conclusions: Our results indicate higher retinal vascular fractal dimension and tortuosity, and a decrease in fractal dimension and RNFL thickness in relation to age in adults with 22q11.2DS. Our findings support future studies that focus on retinal fractal dimension and RNFL thickness as potential biomarkers for age-related manifestations in 22q11.2 including psychotic and (early) neurodegenerative disorders