BACKGROUND:Tuberous sclerosis complex (TSC) is associated with intellectual disability (ID), autism spectrum disorder (ASD), and TSC-associated neuropsychiatric disorders. Early prospective studies have characterized neurodevelopmental outcomes in infants and toddlers with TSC. Leveraging longitudinal data from the TSC Autism Center of Excellence Research Network and the Rare Diseases Clinical Research Network, we examined longer-term developmental trajectories and ASD diagnostic stability in a cohort of children with TSC. METHODS:Participants were originally enrolled in TSC Autism Center of Excellence Research Network and followed through 36 months and then subsequently enrolled in Rare Diseases Clinical Research Network for continued follow-up. Longitudinal neurodevelopmental assessments were performed. Analyses focused on participants' most recent assessment to accommodate study overlap and missing data. Outcomes were compared by ASD status, sex, and adaptive functioning. RESULTS:Thirty-two participants with TSC (50% female; mean age 4.5 years) were included. Cognitive and adaptive functioning scores were generally in the delayed range and remained relatively stable over time. At the most recent visit, 48% met criteria for ASD, with ASD diagnosis remaining stable in most participants. Lower adaptive functioning was significantly associated with ASD diagnosis (P = 0.016) and greater social and behavioral impairment. Females demonstrated significantly higher levels of social impairment on the Social Responsiveness Scale, Second Edition compared to males, even after adjusting for ASD diagnosis. CONCLUSIONS:Early cognitive and adaptive assessments in children with TSC inform later neurodevelopmental outcomes. While ASD diagnosis is largely stable over time, subtle social impairments may be under-recognized. Routine, longitudinal screening for TSC-associated neuropsychiatric disorders symptoms is essential to support timely identification and intervention in TSC.

Transient beta events (TBE) during electroencephalography (EEG) reflect thalamocortical activity, bridging genotype to phenotype and impacting sensory responsivity. Compared to typically developing controls, we found elevated TBE rate in some children with idiopathic Autism Spectrum Disorder (ASD) and a majority of children with Phelan-McDermid Syndrome, Rett Syndrome, and SYNGAP1-related disorder. TBE rate thus offers promise as a stratification biomarker with divergent and convergent properties across ASD and neurogenetic conditions, respectively.

BACKGROUND:The PREVeNT trial enrolled 72 infants with tuberous sclerosis complex using the presence of interictal epileptiform discharges (IEDs) on a one-h electroencephalography (EEG) to randomize into a trial of placebo versus early vigabatrin. Here, we ask if early vigabatrin impacts IED presence over the first 3 years of life. METHODS:Participants underwent an EEG every 6 weeks/first year of life, every 3 months/second year of life and once at age 36 months. EEGs were reviewed by two treatment blinded electrophysiologists; if they disagreed, a third reader adjudicated. RESULTS:Seven hundred ninety-three EEGs were recorded, with IEDs present in 33.5% and at a higher percentage in the placebo arm of the study (n = 27 participants, 45.9% of 296 EEGs) than in the early vigabatrin group (n = 29, 34.3% of 332 EEGs) P = 0.0496. Infantile spasm-free participants in the vigabatrin group drove this reduction: placebo n = 14/26 without spasms, 41.7% of EEGs had IEDs versus vigabatrin n = 23/29 without spasms, and 27.7% of EEGSs had IEDs, P = 0.0185. In contrast the placebo group with spasms n = 12/26 had 51.9% IED positive EEGs versus early vigabatrin n = 6/29 with spasms had 60.3% IED positive, P = 0.5182. Overall, participants with spasms n = 18 had a higher rate of EEGs with IEDs versus those without n = 37, 54.8% vs 33.0%, P = 0.0005. CONCLUSIONS:Early treatment with vigabatrin decreased by ∼20% the proportion of EEGs with IEDs over 3 years. Vigabatrin group participants who did not develop epileptic spasms drove this reduction. Participants who developed spasms in either group had IEDs in over half of their EEGs.

Background Tuberous Sclerosis Complex (TSC) is associated with high prevalence of epilepsy, intellectual and developmental disability, and autism spectrum disorder (ASD). PREVeNT, a Phase IIb, multicenter, double-blind placebo-controlled trial, evaluated the efficacy of vigabatrin in preventing intellectual and developmental disability and ASD in infants with TSC. Phenotypic, developmental, and ASD-specific outcomes at 36 months are presented. Methods Eighty-four infants with TSC were enrolled in PREVeNT across 13 TSC clinics in the United States. Participants underwent neurodevelopmental assessments at ages 6 months through 36 months. Clinical best estimate diagnosis of ASD or non-ASD along with a rating of clinical certainty was determined at 36 months. Results Sixty-five participants completed assessments through 36 months of age. Mean cognitive scores on the Bayley-III were in the low average range at 12 months. Cognitive scores declined slightly in all groups over time. Adaptive scores were in the low average range for the seizure groups. For all neurocognitive measures, those in the watchful waiting group exhibited higher scores compared to the other cohorts. Language scores became more commensurate with cognitive scores by 36 months. The Clinical Certainty Rating was available for 58 patients, with 31% rated as having ASD; this did not differ by treatment assignment. Conclusions No significant differences in developmental or autism-specific outcomes were seen between treatment groups, and no participants without epilepsy were diagnosed with ASD. This may be due to early detection of seizures, closer developmental monitoring and follow-up in the trial, and impacts of the pandemic on study participation.

The Developmental Synaptopathies Consortium is a multisite natural history network studying rare, neurogenetic syndromes associated with synaptic dysfunction and developmental delays. One aim of the Consortium is clinical trial readiness, including identifying clinical concepts and validating their measurement. We evaluated the scope and limitations of conventional cognitive and behavioral measurement strategies in 2-21-year-olds with Phelan-McDermid syndrome (PMS; N = 98), Tuberous Sclerosis Complex (TSC; N = 98), and PTEN Hamartoma Tumor syndrome (PHTS; N = 69). On average, intellectual disability (ID) severity was severe-to-profound in PMS, mild-to-moderate for TSC, and borderline (or absent) in PHTS. Severity of ID invalidated the use of many assessments, including standardized autism diagnostic measures. These results will inform trial planning for these and other similarly medically complex neurodevelopmental conditions.

In data from a multicenter prospective observational study, we assessed whether interictal epileptiform discharge metrics in the pre-seizure onset surveillance scalp electroencephalograms (EEGs) in children with tuberous sclerosis complex could predict seizure outcomes, specifically epileptic spasms. In 16 children with eligible EEG data (7 with epileptic spasms and 9 with other seizure types) and 16 controls, 2 spike metrics were calculated through automated detection followed by expert review: (1) spike rate (spikes per minute) and (2) number of unique spike foci. In patients who developed seizures, a combination of spike rate threshold of ≥2 per minute and ≥2 unique spike foci during sleep was highly predictive of impending epileptic spasms (100% positive predictive value, 2 false negatives). One control patient was falsely predicted to develop epileptic spasms, decreasing the overall positive predictive value to 83.3%. These findings suggest that EEG spike metrics could predict impending epileptic spasms in children with tuberous sclerosis complex, pending larger-scale validation.

OBJECTIVE:Patients with tuberous sclerosis complex (TSC), while considered genetically homogeneous, are clinically heterogeneous and present unique challenges for epilepsy surgery evaluation and treatment. Thus, the authors' goal was to identify factors associated with seizure outcomes in children with TSC who had undergone epilepsy surgery. METHODS:The PubMed, MEDLINE, Embase, CINAHL, and Web of Science databases were queried for relevant articles. Patients from the TSC Alliance registry and Children's of Alabama were also included. Eligible studies were those reporting individual participant data on the seizure outcomes of pediatric patients with TSC who had undergone epilepsy surgery. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and a meta-analysis was performed using a random-effects logistic regression model. Individual factors and seizure outcome following epilepsy surgery at the latest reported follow-up were tested for association. The primary outcome was a good seizure outcome, defined as Engel class I or II, International League Against Epilepsy class 1, 2, or 3, or ≤ 3 seizures per year following surgery. RESULTS:From 44 studies eligible for systematic review and 2 additional sources, there were 2058 patients. Of these, 1338 (65%) patients had available surgical outcome data and a median follow-up of 2.5 years (IQR 1.0-5.0 years). Overall, 878 (66%) patients had a good seizure outcome. Such an outcome was associated with ≤ 1 visible tuber on MRI (OR 4.8, p = 0.01, 95% CI 1.44-15.94, I2 = 0%); however, a good seizure outcome was less likely in patients with no or mild cognitive delay (OR 0.52, p = 0.02, 95% CI 0.30-0.09, I2 = 11%) or in those with no or unifocal interictal scalp EEG abnormality (OR 0.36, p = 0.01, 95% CI 0.16-0.80, I2 = 24%). Preoperative IQ (treated as a continuous variable, OR 0.98, p = 0.009, 95% CI 0.96-0.99, I2 = 0%) had little to no effect on seizure outcome. Two (5%) studies met the criteria for a low risk of bias, 28 (64%) met the criteria for a moderate risk of bias, and 14 (32%) met the criteria for a serious risk of bias. CONCLUSIONS:The authors identified several factors associated with seizure outcomes in TSC patients who had undergone epilepsy surgery. However, the study findings should be interpreted with caution, as they represent an aggregation of largely retrospective cohort or case studies with a high potential for bias. Systematic review registration no.: CRD42023393588 (www.crd.york.ac.uk/prospero/).

BACKGROUND:Tuberous sclerosis complex (TSC) is associated with higher risk of adaptive problems, behavior/emotional problems, and autism spectrum disorder (ASD). This study evaluated the adaptive and behavioral developmental trajectories of children with TSC with and without a diagnosis of ASD at 36 months. METHODS:The Tuberous Sclerosis Complex Autism Center of Excellence Research Network study longitudinally assessed infants with TSC. Developmental (Mullen Scales of Early Learning), adaptive (Vineland Adaptive Behavior Scales, 2nd Edition, Survey Interview), and behavior/emotional (Child Behavior Checklist) functioning at 18, 24, and 36 months were examined in relationship to an ASD clinical diagnosis at 36 months. RESULTS:Deficits in all adaptive functioning domains were observed starting at age 18 months among those ultimately diagnosed with ASD but were largely explained after adjustment for developmental functioning except for lower social functioning at 36 months among individuals with ASD. Behavior/emotional problems did not consistently differ at 18 or 24 months, but nearly all emotional/behavioral problem domains were more severe in the children with ASD, relative to their peers without ASD at 36 months, even after adjusting for developmental functioning. These findings were not attributable to seizure burden. CONCLUSIONS:Although children with TSC and ASD did not differ in their adaptive functioning compared with children with TSC without ASD before 36 months, by 36 months, their social adjustment and emotional/behavioral functioning was significantly poorer than their peers without ASD, underscoring the importance of early detection of developmental concerns and targeted treatments.

ABSTRACT Objective Autism spectrum disorder (ASD) affects 1 in 36 individuals in the United States and is characterized by impaired social communication and restrictive/repetitive behaviors. Individuals with tuberous sclerosis complex (TSC) have a high incidence of ASD (40%) and exhibit congenital brain lesions (tubers), offering a unique lesion‐based model to investigate the neural circuits underlying ASD symptoms. We tested whether tuber connectivity is associated with specific ASD symptom profiles in TSC patients. Methods Brain tuber locations were analyzed in 115 children with TSC from the TSC Autism Centers of Excellence Research Network. Lesion network mapping was performed using normative resting‐state functional magnetic resonance imaging data from 1000 typically developing 9‐year‐olds to identify brain networks functionally connected to tuber locations. Multivariable linear regression analyses assessed associations between these networks and specific domain subscores on the Autism Diagnostic Observation Schedule (ADOS). Results Greater severity of social affect symptoms was associated with tubers connected to bilateral deep cerebellar nuclei, particularly the right side, localizing to Crus V despite no cerebellar tubers being included in this analysis. No significant associations were found for total ADOS scores or repetitive/restrictive behavior subscores. These effects were independent of age, sex, lesion burden, epilepsy severity, and language ability. Interpretation Social affect impairments in TSC patients with ASD are associated with to functional connectivity between tubers and cerebellar crus V. This symptom‐specific neuroanatomical association supports the concept that different ASD features map to distinct brain circuits and highlights the role of cortico‐cerebellar pathways in early social development.

Background and Objectives Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. Methods The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18–60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. Results A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. Discussion In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

BACKGROUND AND OBJECTIVES:Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS:The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS:A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION:In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

Developmental domains, such as cognitive, language, and motor, are key concepts of interest in longitudinal studies of intellectual and developmental disabilities (IDD). Normative scores (e.g., IQ) are often used to operationalize performance on standardized tests of these concepts, but it is the interval-distributed person-ability scores that are intended for the assessment of within-individual change. Here we illustrate the use and interpretation of several Stanford Binet, 5th Edition score types (IQ, extended IQ, Z-normalized raw score, developmental quotient, raw sum score, age equivalent, and ability score) using data from two longitudinal studies of rare genetic conditions associated with IDD. We found that, although normality assumptions were tenuous for all score types, floor effects led to model unsuitability for longitudinal analysis of most types of norm-referenced scores, and that the validity of interpretation with respect to individual change was best for ability scores.

Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population. To evaluate common genetic modifiers of epilepsy, our study pooled phenotypic and genotypic data from 369 individuals with TSC to evaluate known and novel epilepsy common variants. We did not find evidence of enhanced genetic penetrance for known epilepsy variants identified across the largest genome-wide association studies of epilepsy in the general population, but identified support for novel common epilepsy variants in the context of TSC. Specifically, we have identified a novel signal in SLC7A1 that may be functionally involved in pathways relevant to TSC and epilepsy. Our study highlights the need for further evaluation of genetic modifiers in TSC to aid in further understanding of epilepsy in TSC and improve outcomes.

Developmental domains such as cognitive, language, and motor are key concepts of interest in longitudinal studies of intellectual and developmental disabilities (IDD). Normative scores (e.g., IQ) are often used to operationalize performance on standardized tests of these concepts, but it is the interval-distributed person-ability scores that are intended for the assessment of within-individual change. Here we illustrate the use and interpretation of several Stanford Binet, 5th Edition score types (IQ, extended IQ, Z-normalized raw score, developmental quotient, raw sum score, age equivalent, and ability score) using data from two longitudinal studies of rare genetic conditions associated with IDD. We found that while normality assumptions were tenuous for all score types, floor effects led to model unsuitability for longitudinal analysis of most types of norm-referenced scores, and that the validity of interpretation with respect to individual change was best for ability scores.

AbstractObjectiveTuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.MethodsWe conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age.ResultsThere were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder.InterpretationThese results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC‐STEPS).

Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the a-subunit of Ca2+/calmodulindependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.