Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a Longitudinal, Prospective, Multisite Study.

OBJECTIVE: Tuberous sclerosis complex (TSC) is highly associated with autism spectrum disorder (ASD). Objectives of the study were to characterize autistic features in young children with TSC. METHODS: Participants included 138 children followed from ages 3 to 36 months with TSC from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study aimed at understanding the underlying mechanisms of ASD in TSC. Developmental and autism-specific assessments were administered, and a clinical diagnosis of ASD was determined for all participants at 36 months. Further analyses were performed on 117 participants with valid autism assessments based on nonverbal mental age greater than 15 months. RESULTS: Prevalence of clinical diagnosis of ASD at 36 months was 25%. Nearly all autistic behaviors on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) were more prevalent in children diagnosed with ASD; however, autism-specific behaviors were also observed in children without ASD. Overall quality of social overtures, facial expressions, and abnormal repetitive interests and behaviors were characteristics most likely to distinguish children with ASD from those without an ASD diagnosis. Participants meeting ADOS-2 criteria but not a clinical ASD diagnosis exhibited intermediate developmental and ADOS-2 scores compared to individuals with and without ASD. INTERPRETATION: ASD is highly prevalent in TSC, and many additional individuals with TSC exhibit a broad range of subthreshold autistic behaviors. Our findings reveal a broader autism phenotype that can be identified in young children with TSC, which provides opportunity for early targeted treatments. ANN NEUROL 2021;90:874-886.

Fungi: Friend or Foe? A Mycobiome Evaluation in Children With Autism and Gastrointestinal Symptoms.

ABSTRACT: Gastrointestinal (GI) symptoms often affect children with autism spectrum disorders (ASD) and GI symptoms have been associated with an abnormal fecal microbiome. There is limited evidence of Candida species being more prevalent in children with ASD. We enrolled 20 children with ASD and GI symptoms (ASD + GI), 10 children with ASD but no GI symptoms (ASD - GI), and 20 from typically developing (TD) children in this pilot study. Fecal mycobiome taxa were analyzed by Internal Transcribed Spacer sequencing. GI symptoms (GI Severity Index [GSI]), behavioral symptoms (Social Responsiveness Scale -2 [SRS-2]), inflammation and fungal immunity (fecal calprotectin and serum dectin-1 [ELISA]) were evaluated. We observed no changes in the abundance of total fungal species (alpha diversity) between groups. Samples with identifiable Candida spp. were present in 4 of 19 (21%) ASD + GI, in 5 of 9 (56%) ASD - GI, and in 4 of 16 (25%) TD children (overall P = 0.18). The presence of Candida spp. did not correlate with behavioral or GI symptoms (P = 0.38, P = 0.5, respectively). Fecal calprotectin was normal in all but one child. Finally, there was no significance in serum dectin-1 levels, suggesting no increased fungal immunity in children with ASD. Our data suggest that fungi are present at normal levels in the stool of children with ASD and are not associated with gut inflammation.

Language predictors of autism spectrum disorder in young children with tuberous sclerosis complex.

BACKGROUND: Epilepsy has previously been implicated in the development of autism spectrum disorder (ASD) in the setting of tuberous sclerosis complex (TSC). However, the role of language in this relationship is unclear, and the specific relationship between ASD, epilepsy, and language development in this population has not been well-studied. OBJECTIVES: The objectives the study were to identify the role of early language in subsequent development of ASD, evaluate the impact of epilepsy as a covariate on language development, and evaluate the relationship between epilepsy, language development, and development of ASD. METHODS: This study included 154 children ages 3-36 months with TSC who were enrolled in the TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study to identify biomarkers of ASD. Developmental and autism-specific assessments were administered longitudinally. Appropriate variables from the Mullen Scales of Early Learning (MSEL), Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II), and Preschool Language Scales, 5th Edition (PLS-5) were used to assess patients' language skills. At 36 months, clinical best estimate, which was based on clinical assessment and observation, was used to determine a diagnosis of ASD. RESULTS: By 12 months, all language variables on the MSEL, PLS-5, and VABS-II significantly predicted an ASD diagnosis at 36 months. Age at seizure onset was associated with language scores in that later seizure onset was associated with improved language scores on the MSEL, VABS-II, and PLS-5. Seizure onset prior to 6 months was associated with a diagnosis of ASD at 36 months. Higher seizure frequency negatively correlated with language scores at 12 months and beyond. Higher seizure frequency was also associated with an ASD diagnosis at 36 months. When looking at the relationship between epilepsy, language, and ASD diagnosis, by 18 months, language scores were more associated with a later ASD diagnosis at 36 months compared with age at seizure onset, which was a better predictor of later ASD diagnosis earlier in development. CONCLUSION: Analysis of language variables and epilepsy characteristics from 6 to 36 months and ASD diagnosis at 36 months revealed significant relationships between all three variables. While the direction of these relationships needs further research, epilepsy, language, and the development of ASD are integrally related in young children with TSC.

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study.

OBJECTIVE: To determine if routine electroencephalography (EEG) in seizure-naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes. METHODS: Forty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1-hour awake and asleep video-EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland-II) were completed at 6, 12, and 24 months of age. RESULTS: Of 40 infants enrolled (mean age of 82.4 days), 32 completed the study. Two were lost to follow-up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation [SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control. SIGNIFICANCE: IEDs identify impending epilepsy in the majority (77%) of seizure-naive infants with TSC. The use of a 1-hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well-controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND).

Tuberous sclerosis complex (TSC) is associated with a wide range of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties, which are often underdiagnosed and undertreated. Here, we present a clinical update on TSC-associated neuropsychiatric disorders, abbreviated as "TAND," to guide screening, diagnosis, and treatment in practice. The review is aimed at clinical geneticists, genetic counselors, pediatricians, and all generalists involved in the assessment and treatment of children, adolescents and adults with TSC, and related disorders. The review starts with a summary of the construct and levels of TAND, before presenting up-to-date information about each level of investigation. The review concludes with a synopsis of current and future TAND research.

TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae. © 2017 Wiley Periodicals, Inc.

Influence of seizures on early development in tuberous sclerosis complex.

OBJECTIVE: Epilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC. METHODS: Analysis of 130 patients ages 0-36months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency. RESULTS: Data were analyzed at 6, 12, 18, and 24months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome. CONCLUSIONS: Results of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24months of age.

Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic.

Lead, mercury, and arsenic are neurotoxicants with known effects on neurodevelopment. Autism spectrum disorder (ASD) is a neurodevelopmental disorder apparent by early childhood. Using data on 4486 children with ASD residing in 2489 census tracts in five sites of the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring (ADDM) Network, we used multi-level negative binomial models to investigate if ambient lead, mercury, and arsenic concentrations, as measured by the US Environmental Protection Agency National-Scale Air Toxics Assessment (EPA-NATA), were associated with ASD prevalence. In unadjusted analyses, ambient metal concentrations were negatively associated with ASD prevalence. After adjusting for confounding factors, tracts with air concentrations of lead in the highest quartile had significantly higher ASD prevalence than tracts with lead concentrations in the lowest quartile (prevalence ratio (PR) = 1.36; 95 '% CI: 1.18, 1.57). In addition, tracts with mercury concentrations above the 75th percentile (>1.7 ng/m(3)) and arsenic concentrations below the 75th percentile (≤0.13 ng/m(3)) had a significantly higher ASD prevalence (adjusted RR = 1.20; 95 % CI: 1.03, 1.40) compared to tracts with arsenic, lead, and mercury concentrations below the 75th percentile. Our results suggest a possible association between ambient lead concentrations and ASD prevalence and demonstrate that exposure to multiple metals may have synergistic effects on ASD prevalence.

Are 'leaky gut' and behavior associated with gluten and dairy containing diet in children with autism spectrum disorders?

OBJECTIVES: Studies have suggested a link between diet and behavior in children with autism spectrum disorders (ASDs). Parental reports of behavioral changes upon exposure to gluten and/or casein are common in clinical practice. An association between diet type, intestinal permeability (IP) ('leaky gut'), and behavior has been long proposed but not substantiated. We explored this possible association in this trial. METHODS: This randomized double-blind, placebo-controlled study explored the effects of gluten and milk on IP and behavior in children with ASDs over a period of 4 weeks. IP assessed by lactulose:mannitol (L/M) sugar permeability test and behavior assessed by the Aberrant Behavior Checklist and Conners Parent Rating were measured. Gastrointestinal symptoms in both groups were also monitored. RESULTS: Neither the L/M ratio nor behavioral scores were different between groups exposed to gluten/dairy or placebo. The changes observed were noted to be small and not clinically significant. DISCUSSION: Our study although underpowered to show small differences does not support an association between dietary gluten/milk, IP, and behavioral changes in subjects with ASD.

Blood manganese concentrations in Jamaican children with and without autism spectrum disorders.

BACKGROUND: Manganese is an essential element for human health and development. Previous studies have shown neurotoxic effects in children exposed to higher levels of manganese. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impairs social interaction and communication. Several studies have hypothesized that ASD is caused through environmental exposures during crucial stages in brain development. We investigated the possible association between blood manganese concentrations (BMC) and ASD. We also identified factors associated with BMC in typically developing (TD) Jamaican children. METHODS: We used data from 109 ASD cases with their 1:1 age- and sex-matched TD controls to compare mean BMC in Jamaican children (2-8 years of age) with and without ASD. We administered a pre-tested questionnaire to assess demographic and socioeconomic information, medical history, and potential exposure to manganese. Finally, we collected 2 mL of whole blood from each child for analysis of manganese levels. Using General Linear Models (GLM), we assessed the association between BMC and ASD status. Furthermore, we used two independent sample t-tests to identify factors associated with BMC in TD children. RESULTS: In univariable GLM analysis, we found no significant association between BMC and ASD, (10.9 µg/L for cases vs. 10.5 µg/L for controls; P = 0.29). In a multivariable GLM adjusting for paternal age, parental education, place of child's birth (Kingston parish), consumption of root vegetables, cabbage, saltwater fish, and cakes/buns, there was still no significant association between BMC and ASD status, (11.5 µg/L for cases vs. 11.9 µg/L for controls; P = 0.48). Our findings also indicated TD children who ate fresh water fish had a higher BMC than children who did not (11.0 µg/L vs. 9.9 µg/L; P = 0.03) as younger TD children (i.e., 2 ≤ age ≤4), (12.0 µg/L vs. 10.2 µg/L; P = 0.01). CONCLUSIONS: While these results cannot be used to assess early exposure at potentially more susceptible time period, our findings suggest that there is no significant association between manganese exposures and ASD case status in Jamaica. Our findings also indicate that BMC in Jamaican children resemble those of children in the developed world and are much lower than those in the developing countries.

Risk factors and clinical profile of autism spectrum disorder in southern Brazil.

In Brazil, as in other countries, it is expected a significant variation of epidemiological and clinical characteristics among individuals with autism spectrum disorder (ASD). This study was performed to explore maternal risk factors and clinical characteristics of children with ASD in a population located in southern Brazil. Data were collected from medical records and analyzed to explore biomarkers associated with ASD. Out of 321 children with ASD, 86.5% were males with a male-to-female ratio of 5.7:1, 50.7% were mild/moderate while 49.3% presented severe ASD. Between the risk factors investigated, gestational infection was significantly associated with severe ASD patients. There was also an association between epilepsy and severe autism. Several gastrointestinal (GI) symptoms were significantly associated with severe ASD. Obesity, followed by lower levels of cholesterol, were also significant factors associated with an ASD diagnosis when compared to age-matched controls. Finally, severe ASD was associated with significantly higher serum serotonin levels when compared to age-matched controls and mild/moderate ASD cases. Our findings demonstrate that our population shares many features associated with ASD around the world, such as GI symptoms, epilepsy, and high serotonin levels. It is worth highlighting the low cholesterol levels associated with obesity as an unusual feature that deserves more attention.

Pancreatic Replacement Therapy for Maladaptive Behaviors in Preschool Children With Autism Spectrum Disorder.

Importance: There is an urgent unmet need for a treatment addressing the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in preschool populations. Objectives: To evaluate whether treatment of children with ASD aged 3 to 6 years treated with high-protease pancreatic therapy produces long- and short-term improvements in autism-associated maladaptive behaviors. Design, Setting, and Participants: This cohort study at 32 sites across the US used a double-blind parallel group, delayed-start design comprising a 2-week blinded placebo run-in, and a double-blind, randomized, placebo-controlled segment (12 weeks). Children were recruited into the study in 2015, with data collection continuing until 2021. The analyses were completed from June 2021 to February 2022. Interventions: All participants were randomly assigned to receive either 900 mg high-protease pancreatic replacement therapy or placebo with food 3 times a day for 12 weeks, followed by all receiving 900 mg high-protease pancreatic replacement therapy for 24 weeks. Main Outcomes and Measures: The primary outcome was the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I). All potential participants were screened using the Social Communication Questionnaire (SCQ) with diagnosis confirmed by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) for ASD and the Autism Diagnostic Inventory-Revised (ADI-R). Outcomes were measured at the conclusion of the 12-week double-blind segment and at the conclusion of the 24-week open-label segment (total 36 weeks). Results: A total of 190 participants (150 male [79%]), aged 3 to 6 (mean [SD] age, 4.5 [0.8]) years were randomized. Mixed model for repeated measures analysis performed on ABC-I demonstrated statistically significant differences of -2.49 (95% CI, -4.66 to -0.32; Cohen d = 0.364; P = .03) at the 12-week timepoint and -3.07 (95% CI, -5.81 to -0.33; Cohen d = 0.516; P = .03) at 36-week timepoint. No convergence was noted. Our high-protease pancreatic replacement (CM-AT) was well tolerated with no emergent safety concerns or related serious adverse events noted. Conclusions and Relevance: This cohort study of preschool children sustained cumulative reduction in the maladaptive behavior of irritability in autism. This delayed-start analysis, used to demonstrate disease and condition modification, may prove to be an important tool to evaluate treatments for ASD. Trial Registration: ClinicalTrials.gov Identifier: NCT02410902 and NCT02649959.

Executive Function in Autism: Association with ADHD and ASD Symptoms.

There is substantial comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), and there are well-documented executive functioning (EF) deficits in both populations. An important question concerns whether EF deficits in children with ASD are related to severity of ASD, ADHD, or both. We examined ADHD and ASD symptoms in relation to ratings of EF in the home and classroom. The sample comprised 64 children (55 males) diagnosed with ASD (mean age = 9.26 years; mean FSIQ = 92). Analyses indicated that parent and teacher ratings of EF (except Shift and Emotional Control) were consistently related to ADHD symptom severity, but not to ASD severity. Thus, functioning in the domains of Shift and Emotional control appear relatively spared, whereas performance in all other EF was impaired in relation to ADHD symptoms.

ADHD severity as a predictor of cognitive task performance in children with Autism Spectrum Disorder (ASD).

BACKGROUND: In recent years, a number of studies have begun to explore the nature of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with Autism Spectrum Disorder (ASD). In this study, we examined the relationship between both symptoms of ADHD and symptoms of ASD on cognitive task performance in a sample of higher-functioning children and adolescents with ASD. Participants completed cognitive tasks tapping aspects of attention, impulsivity/inhibition, and immediate memory. AIMS: We hypothesized that children with ASD who had higher levels of ADHD symptom severity would be at higher risk for poorer sustained attention and selective attention, greater impulsivity/disinhibition, and weaker memory. METHODS AND PROCEDURES: The sample included 92 children (73 males) diagnosed with ASD (Mean Age = 9.41 years; Mean Full Scale IQ = 84.2). OUTCOMES AND RESULTS: Using regression analyses, more severe ADHD symptomatology was found to be significantly related to weaker performance on tasks measuring attention, immediate memory, and response inhibition. In contrast, increasing severity of ASD symptomatology was not associated with higher risk of poorer performance on any of the cognitive tasks assessed. CONCLUSIONS AND IMPLICATIONS: These results suggest that children with ASD who have more severe ADHD symptoms are at higher risk for impairments in tasks assessing attention, immediate memory, and response inhibition-similar to ADHD-related impairments seen in the general pediatric population. As such, clinicians should assess various aspects of cognition in pediatric patients with ASD in order to facilitate optimal interventional and educational planning.

Two different genetic etiologies for tuberous sclerosis complex (TSC) in a single family.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic condition that involves abnormalities of the skin, hamartomas in the heart, brain, and kidneys, seizures, as well as TSC-associated neuropsychiatric disorders (TAND). About 90%-95% of individuals with TSC will have an identifiable pathogenic variant in either TSC1 or TSC2. We present here two family members with clinical diagnoses of TSC that were later determined to be due to two different genetic etiologies. METHODS: A 2-year-old Caucasian female (Patient 1) was born to non-consanguineous healthy parents and was determined to have a clinical diagnosis of TSC at 2 months old. Her paternal great-uncle (Patient 2) was also known to have a clinical diagnosis of TSC. Sequencing and deletion/duplication analysis for TSC1 and TSC2 were performed on both individuals. RESULTS: Mutation analysis revealed that both Patient 1 and Patient 2 had identifiable pathogenic variants in TSC2. Patient 1 had c.4800_4801delTG (p.Cys1600Trpfs*2), while Patient 2 had c.4470_4471delinsTT (p.Glu1490_Lys1491delinsAsp*). CONCLUSION: To our knowledge, our clinical report is of significance as it is the third kindred to be identified with affected members with two distinct genetic etiologies for TSC. Our case report highlights the importance of incorporating genetic testing into the clinical evaluation for individuals with features suggestive of TSC.

Effects of Extended-Release Methylphenidate Treatment on Cognitive Task Performance in Children with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

Objective: To examine the effectiveness of four doses of psychostimulant medication, combining extended-release methylphenidate (ER-MPH) in the morning with immediate-release MPH (IR-MPH) in the afternoon, on cognitive task performance. Method: The sample comprised 24 children (19 boys and 5 girls) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-R and the Autism Diagnostic Observation Schedule, and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age = 8.8 years, SD = 1.7; mean intelligence quotient = 85; SD = 16.8). Effects of placebo and three dose levels of ER-MPH (containing 0.21, 0.35, and 0.48 mg/kg equivalent of IR-MPH) on cognitive task performance were compared using a within-subject, crossover, placebo-controlled design. Each of the four MPH dosing regimens (placebo, low-dose MPH, medium-dose MPH, and high-dose MPH) was administered for 1 week; the dosing order was counterbalanced across children. Results: MPH treatment was associated with significant performance gains on cognitive tasks tapping sustained attention, selective attention, and impulsivity/inhibition. Dose/response was generally linear in the dose range studied, with no evidence of deterioration in performance at higher MPH doses in the dose range studied. Conclusion: The results of this study suggest that MPH formulations are associated with significant improvements on cognitive task performance in children with ASD and ADHD.

The Impact of Psychiatric Symptoms on Tuberous Sclerosis Complex and Utilization of Mental Health Treatment.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem, neurocutaneous disorder with a spectrum of TSC-associated neuropsychiatric disorders. The most common neuropsychiatric manifestations in the pediatric and adult populations are cognitive concerns, depression, and anxiety. Previous research suggests that while 90% of individuals with TSC have some TSC-associated neuropsychiatric disorders features, only 20% receive treatment, leading to a 70% treatment gap. METHODS: This web-based study used validated measures in conjunction with researcher-designed questions to evaluate perception of disease severity, presence of anxiety and depression, and the utilization and barriers toward mental health services among adults with TSC. RESULTS: The Beck Anxiety Inventory, Beck Depression Inventory-II, and Brief Illness Perception Questionnaire indicated that our overall study population had mild symptoms of anxiety, minimal depression, and a moderate perception of disease severity. Notably, the difference between the median depression score for men and women was statistically significant with men scoring higher than women (P = 0.02). Of 69 respondents, 57% (n = 39) reported receiving mental health treatment at some point over their lifetime. In both the mental health treatment group and the nonmental health treatment group, cost was more often indicated as a barrier to accessing mental health resources (treatment group: cost = 51% and stigma = 21%; nontreatment group: cost = 27% and stigma = 20%). CONCLUSIONS: TSC disease severity had a moderate and low-moderate association with anxiety and depression, respectively. Regardless of past utilization, respondents had a positive outlook towards the use of mental health services with the major barrier being cost.

Tuberous Sclerosis Complex Genotypes and Developmental Phenotype.

BACKGROUND: Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. METHODS: The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. RESULTS: T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. CONCLUSIONS: In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.

Impacting development in infants with tuberous sclerosis complex: Multidisciplinary research collaboration.

The Tuberous Sclerosis Complex Autism Center of Excellence Network (TACERN) is a 6-site collaborative conducting longitudinal research on infants with tuberous sclerosis complex (TSC), focused on identifying early biomarkers for autism spectrum disorder (ASD). A multidisciplinary research team that includes the specialties of psychology, neurology, pediatrics, medical genetics, and speech-language pathology, its members work together to conduct studies on neurological status, brain structure and function, neurodevelopmental phenotype, and behavioral challenges in this population. This article provides insights into the roles of the multidisciplinary multisite team and lessons learned from the collaboration, in terms of research as well as training of future researchers and clinicians. In addition, the authors detail the major findings to date, including those related to the identification and measurement of early symptoms of ASD, relationship between seizures and early development, and early biomarkers for epilepsy and developmental delay in infants and young children with TSC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Fronto-limbic functioning in children and adolescents with and without autism.

We used neuropsychological tasks to investigate integrity of brain circuits linking orbitofrontal cortex and amygdala (orbitofrontal-amygdala), and dorsolateral prefrontal cortex and hippocampus (dorsolateral prefrontal-hippocampus), in 138 individuals aged 7-18 years, with and without autism. We predicted that performance on orbitofrontal-amygdala tasks would be poorer in the Autism group compared to the Non-Autism group regardless of intellectual level (verbal mental age, VMA) and that performance on dorsolateral prefrontal-hippocampus tasks would be associated primarily with intellectual level. Predicted differences between Autism and Non-Autism groups on orbitofrontal-amygdala tasks were present but greater in individuals with higher VMA. On dorsolateral prefrontal-hippocampus tasks, poorer performance by the Autism compared to the Non-Autism group was found at all VMA levels. Group differences suggest both brain circuits are impaired in autism, but performance on all tasks is also associated with intellectual level.