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Neuropsychological Attention Skills and Related Behaviours in Adults with Tuberous Sclerosis Complex
Abstract and Figures
Tuberous sclerosis complex (TSC) is a genetic disorder associated with mTOR over-activation and disruption of MAPK, PI3K and AMPK signalling. Children with TSC have significant deficits on neuropsychological attention tasks, particularly dual tasking. Here we investigated attentional skills and related behaviours in daily life in normally intelligent adults with TSC and matched controls using the Test of Everyday Attention for Children (TEA-Ch) and the Attention-Deficit Scales for Adults (ADSA). No group differences were demonstrated on selective or sustained attention tasks carried out alone. However, adults with TSC performed significantly worse when these tasks were combined in a cross-modal dual task condition. On the ADSA the TSC group had significantly worse scores on several subscales (attention/concentration, behaviour/disorganization, academic and emotional behaviours) compared to controls and these correlated with dual task performance, indicating a clear impact of dual task deficits on attention-related behaviours in daily life. The presence or absence of epilepsy did not influence dual task performance or attention-deficits in daily life. Taken together with similar findings in children, results suggest that dual task difficulties are a core feature of the neuropsychological phenotype of TSC.
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... Intellectual ability is a very strong correlate of many TAND manifestations, and uneven intellectual profiles can be associated with many functional impairments. Even in people with above-average and high intellectual abilities, the rates of specific neuropsychological deficits (e.g., in attentional, memory, or executive skills) are very high and can be associated with significant challenges in daily life (e.g., in school, relationships, or the workplace) [43,44]. This is even more likely to be the case for those with TSC known to have neurodevelopmental disorders such as autism, attention deficit hyperactivity disorder (ADHD), or learning disorders. ...
Background
Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific.
Methods
The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community.
Results
At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to “screen” for TAND at least annually, to “act” using appropriate next steps for evaluation and treatment, and to “repeat” the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families.
Conclusions
The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a “TAND toolkit” of “what to seek” and “what to do” when difficulties are identified in TAND clusters.
... ADHD also frequently co-occurs [136] • Social communication differences more evident than RRBIs in infancy [101,102] ...
Purpose of Review
Elevated prevalence of autism characteristics is reported in genetic syndromes associated with intellectual disability. This review summarises recent evidence on the behavioural heterogeneity of autism in the following syndromes: Fragile X, Cornelia de Lange, Williams, Prader-Willi, Angelman, Down, Smith-Magenis, and tuberous sclerosis complex. Key considerations for assessment and support are discussed.
Recent Findings
The profile and developmental trajectory of autism-related behaviour in these syndromes indicate some degree of syndrome specificity which may interact with broader behavioural phenotypes (e.g. hypersociability), intellectual disability, and mental health (e.g. anxiety). Genetic subtype and co-occurring epilepsy within syndromes contribute to increased significance of autism characteristics. Autism-related strengths and challenges are likely to be overlooked or misunderstood using existing screening/diagnostic tools and criteria, which lack sensitivity and specificity within these populations.
Summary
Autism characteristics are highly heterogeneous across genetic syndromes and often distinguishable from non-syndromic autism. Autism diagnostic assessment practices in this population should be tailored to specific syndromes. Service provisions must begin to prioritise needs-led support.
... Tierney i wsp. [62] przeprowadzili systematyczne badanie 22 osób dorosłych z TSC bez niepełnosprawności intelektualnej. Wyniki wykazały zaburzenia przestrzennej pamięci operacyjnej oraz deficyty w procesie planowania u osób z TSC. ...
The aim of the study was to provide a state-of-the-art review with regard to neuropsychiatric disorders associated with tuberous sclerosis complex (TSC). TSC is a rare genetic disease
classified as a phacomatosis. Due to the wide spectrum of clinical symptoms of the disease, many cases remain undiagnosed. The vast majority of people with a mutation in the TSC1 or TSC2 genes develop some of the neuropsychiatric symptoms during their lifetime. Diagnostic criteria, neuroanatomical pathology and pathophysiology of psychiatric, neuropsychological, developmental and psychosocial symptoms present in TSC are described. The specificity of epilepsy in TSC and its role in neuropsychiatric and neuropsychological development are presented. All levels (intellectual, developmental, behavioral, psychiatric, school, neuropsychological and psychosocial) of tuberous sclerosis complex-associated neuropsychiatric disorders
(TAND) are discussed in detail. The TAND Checklist – a tool for assessing all potentially disturbed aspects of functioning – was presented. The importance of proper diagnosis of neuropsychiatric disorders and multidisciplinary patient care was emphasized.
... Bootstrapping supported the clustering with neuropsychological skills but confirmed a frequent co-occurrence with the scholastic cluster. Based on the existing TSC literature, the cluster maps very well onto the high rates of a range of neuropsychological attentional, executive, and memory deficits reported [16,17,[19][20][21]. Cluster 4. Mood/anxiety cluster Four items are included in this cluster -anxiety, depressed mood, mood swings and extreme shyness. ...
Background
Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders ( TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead to personalized identification and treatment of TAND. Two small-scale studies showed cluster and factor analysis could identify clinically meaningful natural TAND clusters. Here we set out to identify definitive natural TAND clusters in a large, international dataset.
Method
Cross-sectional, anonymized TAND Checklist data of 453 individuals with TSC were collected from six international sites. Data-driven methods were used to identify natural TAND clusters. Mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. Statistical robustness of clusters was evaluated with 1000-fold bootstrapping, and internal consistency calculated with Cronbach’s alpha.
Results
Ward’s method rendered seven natural TAND clusters with good robustness on bootstrapping. Cluster analysis showed significant convergence with an exploratory factor analysis solution, and, with the exception of one cluster, internal consistency of the emerging clusters was good to excellent. Clusters showed good clinical face validity.
Conclusions
Our findings identified a data-driven set of natural TAND clusters from within highly variable TAND Checklist data. The seven natural TAND clusters could be used to train families and professionals and to develop tailored approaches to identification and treatment of TAND. Natural TAND clusters may also have differential aetiological underpinnings and responses to molecular and other treatments.
... Οι ασθενείς με ΟΣ, ακόμα κι εκείνοι με φυσιολογικό νοητικό δυναμικό, έχουν αυξημένο κίνδυνο εμφάνισης διαταραχών σε ειδικές εγκεφαλικές δεξιότητες (15). Αυτές οι διαταραχές περιλαμβάνουν διαταραχές στη συγκέντρωση (40-90%) (ιδιαίτερα στην ικανότητα διπλήςπολλαπλής εργασίας) (42,43), στη μνήμη (44)(45)(46), στις διοικητικές δεξιότητες (ιδιαίτερα στην ευέλικτη σκέψη) (7,18,41) και στις οπτικοχωρικές εργασίες (18). ...
... Genotype-phenotype correlations show that ID is less frequent in patients with no mutation identified (NMI) compared to patients carrying demonstrable TSC2/TSC1 mutations (Kothare et al., 2014;Peron et al., 2018). Also in individuals with normal intellectual abilities, specific learning, and attention/memory/executive function deficits can interfere with academic achievements and social functioning (Tierney, McCartney, Serfontein, & de Vries, 2011). ...
Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into adulthood. The transition for patients with tuberous sclerosis complex (TSC) is complicated by the multisystemic nature of this condition, age‐dependent manifestations, and high clinical variability and by the presence of intellectual disability in at least half of the individuals. In this article, we address the medical needs regarding each TSC‐related manifestation in adulthood, and the services and support required. We review existing models of transition in different chronic conditions, discuss our experience in transitioning from the pediatric to the adult TSC Clinic at our Institution, and propose general rules to follow when establishing a transition program for TSC. Although a generalizable transition model for TSC is likely not feasible for all Institutions, a multidisciplinary TSC clinic is probably the best model, developed in accordance with the resources available and country‐specific healthcare systems. Coordination of care and education of the adult team should be always sought regardless of the transition model.
... Indeed, Tierney et al. (2011) reported that adults with TSC were rated as being significantly less functional on a behavioral questionnaire tap- (Hallett et al., 2011). In a qualitative study of parental experience and care needs performed in Italy (Graffigna, Bosio, & Cecchini, 2013), in-depth interviews and online discussions with 48 parents of individuals with TSC (aged 1-22) identified three themes. ...
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.
... Neuropsychological assessments and questionnaires were performed at baseline and 6 and 12 months, and were selected to assess specific problematic behaviors in TSC. 20 Blood samples were taken at baseline and 6 and 12 months for all participants and every visit during sirolimus treatment. Sirolimus trough levels were measured by high-performance liquid chromatography-mass spectrometry/mass spectrometry chromatography at the Erasmus MC pharmacy. ...
Objective:
To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC).
Methods:
Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment.
Results:
Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely.
Conclusions:
We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation.
Classification of evidence:
This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.
Objective
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families.
Method
We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided.
Results
There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups.
Conclusions
Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification.
Background
Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead to personalized identification and treatment of TAND. Two small-scale studies showed cluster and factor analysis could identify clinically meaningful natural TAND clusters. Here we set out to identify definitive natural TAND clusters in a large, international dataset.
Method
Cross-sectional, anonymized TAND Checklist data of 453 individuals with TSC were collected from six international sites. Data-driven methods were used to identify natural TAND clusters. Mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. Statistical robustness of clusters was evaluated with 1000-fold bootstrapping, and internal consistency calculated with Cronbach’s alpha.
Results
Ward’s method rendered seven natural TAND clusters with good robustness on bootstrapping. Cluster analysis showed significant convergence with an exploratory factor analysis solution, and, with the exception of one cluster, internal consistency of the emerging clusters was good to excellent. Clusters showed good clinical face validity.
Conclusions
Our findings identified a data-driven set of natural TAND clusters from within highly variable TAND Checklist data. The seven natural TAND clusters could be used to train families and professionals and to develop tailored approaches to identification and treatment of TAND. Natural TAND clusters may also have differential aetiological underpinnings and responses to molecular and other treatments.
FORMAT The TEA consists of eight sub-tests delivered and scored using a variety of mediums. The assessment pack comes in a black portable carry-case which contains: one manual, which covers Standardisation, Validation, Interpretation and Administration guidelines, one A4 ring-bound stimulus book covering three parallel versions, three audio tapes covering three parallel versions for all aurally presented material, two A3 maps covering three parallel versions of the Map Search sub-test, three A3 scoring templates for the Map Search sub-test, three A3 fictitious Yellow Pages extracts covering three parallel versions, two clear plastic wallets for overlaying maps and Yellow Pages while being drawn on, a set of non-permanent markers, one stapled examiner scored answer booklet and one 30 minute Training Video.
The tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) proteins act as integrators of a range of intracellular signalling pathways. Various genetic disorders associated with learning and behavioural deficits, including TSC, Fragile X, Neurofibromatosis Type 1, Noonan and Leopard syndromes, are associated with abnormalities in TSC-mTOR signalling. Based on the assumption that signalling proteins and their structural and functional components are widely conserved, a number of animal models are used to study aspects of the physical and behavioural phenotypes of these human disorders. Model organisms include rat (Rattus norvegicus), mouse (Mus musculus), zebrafish (Danio rerio), fruitfly (Drosophila melanogaster) and fission yeast (Schizosaccharomyces pombe). Here we used a bioinformatic approach to examine the presence of structural and functional elements of TSC1 and TSC2 across these organisms, together with Strongylocentrotus purpuratus and Dictyostelium discoideum. Results suggest that while Rattus norvegicus and Mus musculus TSC1 and TSC2 showed very high similarity to the human sequences, this was not the case for Danio rerio, Drosophila melanogaster, Strongylocentrotus purpuratus, Schizosaccharomyces pombe or Disctyostelium discoideum. Findings indicate that caution should be exercised in detailed interpretation of results from some model organisms.
The only comprehensive overview of the molecular basis and clinical features of the genetic disorder tuberous sclerosis, which affects approximately 50,000 people in the US alone. Special focus is placed on novel insights into the signal transduction pathways affected by the disease as well as genotype phenotype correlations, while existing and potential therapies are also discussed in depth. The editors are leading experts in research and treatment of the disease as well as the Vice President of the Tuberous Sclerosis Alliance, the only voluntary health organization for TSC in the US.
“Attention” is not a unitary brain process. Evidence from adult studies indicates that distinct neuroanatomical networks perform specific attentional operations and that these are vulnerable to selective damage. Accordingly, characterising attentional disorders requires the use of a variety of tasks that differentially challenge these systems. Here we describe a novel battery, the Test of Everyday Attention for Children (TEA-Ch), comprising nine subtests adapted from the adult literature. The performance of 293 healthy children between the ages of 6 and 16 is described together with the relationships to IQ, existing measures of attention, and scholastic attainment. This large normative sample also allows us to test the fit of the adult model of functionally separable attention systems to the observed patterns of variance in children's performance. A Structural Equation Modelling approach supports this view. A three-factor model of sustained and selective attention and higher-level “executive” control formed a good fit to the data, even in the youngest children. A single factor model was rejected.
There are behavioural and anatomical grounds to believe that Attention Deficit Disorder ADD) is particularly associated with poor self-sustained attention and behavioural control. The TEA-Ch performance of 24 boys diagnosed with ADD presented here is consistent with this view. When performance levels on WISC-I11 subtests were taken into account, specific deficits in sustained attention were apparent while selective attention performance was within the normal range.
IntroductionHistorical Review of Linkage Analysis and Positional Cloning of the TSC1 and TSC2 GenesThe TSC1 and TSC2 Genes: Genomic Structure, Splicing, Predicted Sequences, and DomainsMutational Spectrum of TSC1 and TSC2Frequency and Significance of Mosaicism in TSCConsiderations in Patients in Whom No Mutation Can Be IdentifiedThe Role of TSC1 and TSC2 in Tumor DevelopmentThe Future of Molecular Diagnostics in TSCReferences
IntroductionDifferent Levels of InvestigationAssessment and Management of Neurocognitive and Neurobehavioral Difficulties in TSCCauses of the Neurocognitive and Neurobehavioral Features of TSCAnimal Models for Behavioral, Psychiatric, Intellectual, Learning, and Neuropsychological Deficits in TSCFuture Directions for the Understanding of Behavioral, Psychiatric, Intellectual, Academic, and Neuropsychological Deficits in TSCHow to Live a Positive Life with TSCReferences
SUMMARY32 families informative for the segregation of Tuberous sclerosis (TSC) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4·7 at θ= 0) but other families were too small to give individually convincing lodscores. Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2·63) and with D16S291 on chromosome 16 (max lod 3·98) at values of theta of 0·2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the families linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC1 but in each case a single affected individual appeared to exclude the whole of the candidate region. Preliminary analysis of clinical features did not reveal any definite differences in incidence of mental handicap between individuals in different linkage groups or with different sex of the parent of origin. The frequencies of periungual fibromas and facial angiofibromas were also similar in both linkage groups. The difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be helpful in this respect.