Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist

doi:10.1016/j.pediatrneurol.2014.10.004

Pediatric Neurology

Volume 52, Issue 1, January 2015, Pages 25-35

https://doi.org/10.1016/j.pediatrneurol.2014.10.004 Get rights and content

Abstract

Background

Tuberous sclerosis complex is a multisystem genetic disorder with a range of physical manifestations that require evaluation, surveillance, and management. Individuals with tuberous sclerosis complex also have a range of behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial difficulties. These may represent the greatest burden of the disease. Around 90% of individuals with tuberous sclerosis complex will have some of these difficulties during their lifetime, yet only about 20% ever receive evaluation and treatment. The Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference expressed concern about the significant “treatment gap” and about confusion regarding terminology relating to the biopsychosocial difficulties associated with tuberous sclerosis complex.

Methods

The Tuberous Sclerosis Complex Neuropsychiatry Panel coined the term TAND—tuberous sclerosis complex-associated neuropsychiatric disorders—to bring together these multidimensional manifestations of the disorder, and recommended annual screening for TAND. In addition, the Panel agreed to develop a TAND Checklist as a guide for screening.

Results

Here, we present an outline of the conceptualization of TAND, rationale for the structure of the TAND Checklist, and include the full US English version of the TAND Checklist.

Conclusion

We hope that the unified term TAND and the TAND Checklist will raise awareness of the importance of tuberous sclerosis complex-associated neuropsychiatric disorders and of the major burden of disease associated with it, provide a shared language and a simple tool to describe and evaluate the different levels of TAND, alert clinical teams and families or individuals of the importance of screening, assessment, and treatment of TAND, and provide a shared framework for future studies of tuberous sclerosis complex-associated neuropsychiatric disorders.

Introduction

Tuberous sclerosis complex (TSC) is a multisystem disorder associated with multiorgan involvement, including the brain, kidneys, heart, eyes, and lung.1, 2 The disorder has a birth incidence of approximately 1:6000 and is seen at similar prevalence rates around the globe.³ In approximately 85% of cases, a mutation is identified in the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13.3) genes. The TSC1-TSC2 protein complex acts as an upstream regulator of mammalian target of rapamycin (mTOR).1, 2, 4 Disruption of this regulatory role leads to mTOR overactivation and to dysregulated growth control, thus explaining the fundamental pathophysiological mechanism of the disorder.1, 2, 4 In recent years, molecularly targeted treatments using mTOR inhibitors have been introduced for some of the specific organ systems involved, such as subependymal giant cell astrocytomas of the brain and angiomyolipomas of the kidney.5, 6, 7, 8

Given the significant progress in understanding the pathophysiology of TSC over the last 2 decades, the International Consensus Conference was convened in 2012 to revise the diagnostic criteria and to refine the assessment, surveillance, and treatment guidelines for TSC. Revised diagnostic and surveillance guidelines were published in 2013.9, 10

Apart from the range of physical manifestations of TSC, individuals with the disorder may also be affected by a wide array of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties.11, 12 In both clinical practice and scientific publications, these multiple levels of difficulties have been referred to by many different terms, including “neurocognitive issues,” “neurobehavioral difficulties,” “learning issues,” “mental health issues,” “neuropsychiatric disorders,” “cognitive and behavioral difficulties,” and so on. Most individuals who live with TSC will experience some of these difficulties in their lifetime. Similar to the physical manifestations of TSC, there is also growing evidence that specific elements of neuropsychiatric disorders in TSC may be directly attributable to dysregulation of mTOR signaling and that mTOR inhibitors might therefore also become molecularly targeted treatments for some of these aspects of TSC.11, 12, 13, 14, 15

In 2003 an international consensus panel was convened to develop guidelines for the assessment of “cognitive and behavioral problems” in individuals with TSC. The recommendations were published in 2005.¹⁶ The panel made two main recommendations. The first was to perform regular assessment of cognitive development and behavior in all children and adolescents with TSC to establish a baseline for evaluating changes in developmental trajectories and to identify and treat emerging difficulties. The second was to perform a comprehensive assessment (particularly a comprehensive physical evaluation) in response to sudden or unexpected changes in cognitive development or behavior to identify and treat the underlying cause of neurobehavioral change.¹⁶

In a survey of members of the UK Tuberous Sclerosis Association 5 years after the publication of these guidelines, only 18% of all families had ever received any of the evaluations or treatments recommended in the 2005 guidelines. Given that more than 90% of all individuals with TSC are likely to have some of these challenges,¹⁷ the “treatment gap” (the difference between clinical need and services provided) was therefore in excess of 70%. This finding is in keeping with global findings of treatment gaps in mental health where it is not uncommon for 70%-80% of individuals who have mental disorders not to receive any treatment.¹⁸

Given the multidimensional nature of these difficulties associated with TSC across multiple levels, the clinical and scientific confusion about different terminologies used, and the significant treatment gaps identified, the Neuropsychiatry Panel at the 2012 International Consensus Conference were keen to identify a strategy that would increase awareness of the need to screen for these difficulties, simplify and clarify the terminology used around behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial aspects of TSC, and develop a simple tool to facilitate clinical teams and families to screen for these challenges to identify areas that require more in-depth evaluation or treatment.

The Neuropsychiatry Panel commented that the “treatment gaps” observed in TSC were similar to those observed in the human immunodeficiency virus (HIV) community, where there used to be an overemphasis on physical treatment of HIV-positive individuals without consideration of the major neurocognitive and neuropsychiatric features of HIV.¹⁹ The HIV community introduced the concept of HAND (HIV-associated neurocognitive disorders) as a strategy to raise awareness of such concerns. Inspired by the HIV example, the TSC Neuropsychiatry Panel therefore decided to coin the term TAND (TSC-associated neuropsychiatric disorders) and recommended that all individuals with TSC should be screened for TAND at least once per year. To facilitate the process, a TAND Checklist was developed. Pilot validation of the TAND Checklist was performed and is presented elsewhere.¹⁷

Here, we outline the conceptualization of the multidimensional nature of TAND and present a TAND Checklist for clinical use.

Section snippets

The multiple dimensions of TAND

Infants, children, adolescents, and adults with TSC may present with a varied and variable range of challenges across multiple “levels or dimensions.”11, 20

The concept of TAND

TAND aims to bring together under a single term the multiple levels of involvement that relate to the neurobiological, psychological, and social aspects of TSC. The term was coined to generate a unifying rubric to be used as a “short-hand” to capture all the possible functional manifestations, complications, and consequences of TSC that relate to behavior, mental health or psychiatric disorders, neurodevelopment, intellectual, academic, neuropsychologic, and psychosocial abilities.

The term is

The TAND Checklist

Given the attempt of the Neuropsychiatry Panel to unify terminology and delineate a shared language to describe the multiple dimensions of TAND, we agreed to develop a short, freely accessible TAND Checklist to aid health-care professionals and families in screening for TAND.

The purpose of the TAND Checklist is to act as a memory aid or a basic structure to guide a conversation between the clinician and family or individual with TSC. The conversation that flows from the TAND Checklist should

The structure of the TAND Checklist

The overall structure of the TAND Checklist is outlined in the Table. Conceptually, the 12 items (referred to as questions) follow the levels of investigation outlined previously and require simple YES or NO responses to most questions.

The introductory items (questions 1 and 2) aim to get a general sense of developmental milestones and of the current level of functioning of the individual about whom the conversation is taking place. These items were placed first to ensure that the interviewer

Pilot validation of the TAND Checklist

The pilot validation of the TAND Checklist, using a mixed-method approach, is presented in detail elsewhere.¹⁷ In phase I of the pilot validation, expert professionals (n = 20) and expert parents or caregivers (n = 42) from 28 countries were asked to comment on the clarity, comprehensiveness, ease of use, and likely use of the TAND Checklist. Results suggested that the TAND Checklist was clear, comprehensive, and easy to use. Participants generally felt that clinical teams would use it, but

How does the TAND Checklist fit into the 2012 International TSC consensus recommendations for the assessment and management of TAND?

As outlined elsewhere,¹⁰ the Neuropsychiatry Panel recommended screening for TAND at least annually. We suggest that the TAND Checklist might be a useful guide to perform this task. Any areas of concern identified should lead to appropriate next-step evaluations or treatment.

In addition, we also recommended that comprehensive formal assessments for TAND should be performed at key developmental time points. These include infancy (age 0-3), pre-school years (age 3-6), primary school years (age

Next steps with the TAND Checklist

The TAND Checklist is provided here in English. Next steps will include working with local organizations in various countries to prepare translations of the TAND Checklist. Translations will be done using a standardized procedure including translation, blind back-translation, and authorization by the authors of the TAND Checklist. The TAND Checklist was developed to be freely available to increase the likelihood of its uptake in real-life settings.

Further studies using the current version of

Conclusion

Here the Neuropsychiatry Panel of the 2012 International Consensus Conference for TSC presented the rationale for and conceptualization of a new term, TAND. The overall purpose of this new term was to define a unifying construct to describe the multidimensional biopsychosocial manifestations seen in TSC. We hope that this unified term will raise awareness of the importance of TAND and of the major burden of disease associated with it, provide a shared language to describe and evaluate the

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Measurement of Developmental and Behavioral Concerns in Toddlers With Tuberous Sclerosis Complex
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The TAND (Tuberous Sclerosis Complex [TSC]-Associated Neuropsychiatric Disorders) Checklist was developed as a clinical screener for neurodevelopmental disorders in TSC. Most studies have described patterns in older children and adults. This study sought to better understand behavioral concerns as measured by the TAND Checklist in young children with TSC.
We examined patterns of caregiver responses to the TAND Checklist in 90 toddlers with TSC (12 to 23 months n = 60; 24 to 36 months n = 30) through data collected during baseline visits across two TSC early intervention studies.
Over 90% of caregivers reported at least one behavioral concern related to TAND. The number of concerns increased with age. Delayed language was the most frequently reported concern across ages (12 to 23 months: 58.3%, 24 to 36 months: 86.7%). Questions related to behavioral concerns were largely relevant in this age range, but questions in other areas, such as neuropsychological or academic function, were not.
TAND symptoms are very common in toddlers with TSC, and these symptoms may increase with age. The TAND Checklist is a useful tool for identifying behavioral concerns efficiently, but several items and sections are not suited to younger children. Results support the development of an abbreviated form of the TAND Checklist for toddlers.
Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ)
2023, Pediatric Neurology
Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) are often present but underidentified and undertreated in individuals with tuberous sclerosis complex (TSC). The clinician-completed TAND-Lifetime Checklist (TAND-L) was developed to address this identification and treatment gap. Stakeholder engagement identified the need for a TAND Checklist that can (1) be completed by caregivers or individuals with TSC and (2) quantify TAND difficulties. The aim of this study was to develop a self-report quantified TAND Checklist (TAND-SQ) and conduct feasibility and acceptability testing.
This aim was addressed in three phases: (1) development of the TAND-SQ Checklist, (2) feasibility and acceptability testing of the “near-final” TAND-SQ Checklist, and (3) preparation of the final TAND-SQ Checklist. Participants included 23 technical experts from the TAND consortium in all phases and 58 lived experts (caregivers and individuals with TSC) in phase 2. All participants completed a TAND-SQ Checklist and a checklist feedback form.
Phase 1 additions to the TAND-SQ, when compared with the TAND-L, included four new items and a quantification rating. Phase 2 showed high ratings for the “near-final” TAND-SQ Checklist on comprehensiveness, clarity, ease of use, and overall acceptability. In phase 3, questions on strengths, strategies, and a TAND Cluster Profile were added.
The TAND-SQ Checklist is presented here for use by individuals with TSC and their caregivers. The next steps as part of the TANDem project include internal and external validation of the checklist and linking of TAND Cluster Profiles generated from the checklist to evidence-informed consensus recommendations within a smartphone application.
Paradigm shift in the treatment of tuberous sclerosis: Effectiveness of everolimus
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Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.
Mild TSC phenotype and non-penetrance associated with a frameshift variant in TSC2 prompts caution in evaluating pathogenicity of frameshift variants
2023, Gene
Technological advances in genetic testing, particularly the adoption of noninvasive prenatal screening (NIPS) for single gene disorders such as tuberous sclerosis complex (TSC, OMIM# 613254), mean that putative/possible pathogenetic DNA variants can be identified prior to the appearance of a disease phenotype. Without a phenotype, accurate prediction of variant pathogenicity is crucial. Here, we report a TSC2 frameshift variant, NM_000548.5(TSC2):c.4255_4256delCA, predicted to result in nonsense-mediated mRNA decay (NMD) and cessation of TSC2 protein production and thus pathogenic according to ACMG criteria, identified by NIPS and subsequently detected in family members with few or no symptoms of TSC. Due to the lack of TSC-associated features in the family, we hypothesized that the deletion created a non-canonical 5′ donor site resulting in cryptic splicing and a transcript encoding active TSC2 protein. Verifying the predicted effect of the variant was key to designating pathogenicity in this case and should be considered for other frameshift variants in other genetic disorders.
Phenotypic information on the family members was collected via review of the medical records and patient reports. RNA studies were performed using proband mRNA isolated from blood lymphocytes for RT-PCR and Sanger sequencing. Functional studies were performed by transient expression of the TSC2 variant proteins in cultured cells, followed by immunoblotting.
No family members harboring the variant met any major clinical diagnostic criteria for TSC, though a few minor features non-specific to TSC were present. RNA studies supported the hypothesis that the variant caused cryptic splicing, resulting in an mRNA transcript with an in-frame deletion of 93 base pairs r.[4255_4256del, 4251_4343del], p.[(Gln1419Valfs*104), (Gln1419_Ser1449del)]. Expression studies demonstrated that the canonical function of the resulting truncated TSC2 p.Gln1419_Ser1449del protein product was maintained and similar to wildtype.
Although most frameshift variants are likely to result in NMD, the NM_000548.5(TSC2):c.4255_4256delCA variant creates a cryptic 5′ splice donor site, resulting in an in-frame deletion that retains TSC2 function, explaining why carriers of the variant do not have typical features of TSC. The information is important for this family and others with the same variant. Equally important is the lesson that predictions can be inaccurate, and that caution should be used when designating frameshift variants as pathogenic, especially when phenotypic information to corroborate testing results is unavailable. Our work demonstrates that functional RNA- and protein-based confirmation of the effects of DNA variants improves molecular genetic diagnostics.
Role of Type I Interferon Signaling and Microglia in the Abnormal Long-term Potentiation and Object Place Recognition Deficits of Male Mice With a Mutation of the Tuberous Sclerosis 2 Gene
2023, Biological Psychiatry Global Open Science
Tuberous sclerosis complex is a genetic disorder associated with high rates of intellectual disability and autism. Mice with a heterozygous null mutation of the Tsc2 gene (Tsc2^+/−) show deficits in hippocampal-dependent tasks and abnormal long-term potentiation (LTP) in the hippocampal CA1 region. Although previous studies focused on the role of neuronal deficits in the memory phenotypes of rodent models of tuberous sclerosis complex, the results presented here demonstrate a role for microglia in these deficits.
To test the possible role of microglia and type I interferon in abnormal hippocampal-dependent memory and LTP of Tsc2^+/− mice, we used field recordings in CA1 and the object place recognition (OPR) task. We used the colony stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia in Tsc2^+/− mice and interferon alpha/beta receptor alpha chain null mutation (Ifnar1^−/−) to manipulate a signaling pathway known to modulate microglia function.
Unexpectedly, we demonstrate that male, but not female, Tsc2^+/− mice show OPR deficits. These deficits can be rescued by depletion of microglia and by the Ifnar1^−/− mutation. In addition to rescuing OPR deficits, depletion of microglia also reversed abnormal LTP of the Tsc2^+/− mice. Altogether, our results suggest that altered IFNAR1 signaling in microglia causes the abnormal LTP and OPR deficits of male Tsc2^+/− mice.
Microglia and IFNAR1 signaling have a key role in the hippocampal-dependent memory deficits and abnormal hippocampal LTP of Tsc2^+/− male mice.
Systematic Review: Emotion Dysregulation in Syndromic Causes of Intellectual and Developmental Disabilities
2023, Journal of the American Academy of Child and Adolescent Psychiatry
To summarize the current state of the literature regarding emotion dysregulation (ED) in syndromic intellectual disabilities (S-IDs) in 6 of the most common forms of S-IDs—Down syndrome, fragile X syndrome (FXS), tuberous sclerosis complex, Williams syndrome, Prader-Willi syndrome, and Angelman syndrome—and to determine future research directions for identification and treatment of ED.
PubMed bibliographic database was searched from date of inception to May 2021. PRISMA 2020 guidelines were followed with the flowchart, table of included studies, list of excluded studies, and checklist provided. Filters applied included human research and English. Only original research articles were included in the final set, but review articles were used to identify secondary citations of primary studies. All articles were reviewed for appropriateness by 2 authors and summarized. Inclusion criteria were met by 145 articles (Down syndrome = 29, FXS = 55, tuberous sclerosis complex = 11, Williams syndrome = 18, Prader-Willi syndrome = 24, Angelman syndrome = 8).
Each syndrome review was summarized separately and further subdivided into articles related to underlying neurobiology, behaviors associated with ED, assessment, and targeted intervention. FXS had the most thorough research base, followed by Down syndrome and Prader-Willi syndrome, with the other syndromes having more limited available research. Very limited research was available regarding intervention for all disorders except FXS.
Core underlying characteristics of S-IDs appear to place youth at higher risk for ED, but further research is needed to better assess and treat ED in S-IDs. Future studies should have a standard assessment measure of ED, such as the Emotion Dysregulation Inventory, and explore adapting established curricula for ED from the neurotypical and autism spectrum disorder fields.

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Original ArticleTuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

The multiple dimensions of TAND

The concept of TAND

The TAND Checklist

The structure of the TAND Checklist

Pilot validation of the TAND Checklist

How does the TAND Checklist fit into the 2012 International TSC consensus recommendations for the assessment and management of TAND?

Next steps with the TAND Checklist

Conclusion

Lancet

Lancet

Lancet

Lancet

Pediatr Neurol

Pediatr Neurol

Neurotherapeutics

Trends Mol Med

Curr Opin Neurobiol

Pediatr Neurol

Epilepsy Behav

Mechanism-based treatment in tuberous sclerosis complex

Pediatr Neurol

Tuberous sclerosis: a GAP at the crossroad of multiple signaling pathways

Hum Mol Genet

Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial

Clin Cancer Res

Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis

N Engl J Med

Neurodevelopmental, psychiatric and cognitive aspects of tuberous sclerosis complex

From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis

J Intellect Disabil Res

Consensus clinical guidelines for the assessment of cognitive and behavioural problems in tuberous sclerosis

Eur Child Adolesc Psychiatry

PRIME: a programme to reduce the treatment gap for mental disorders in five low- and middle-income countries

PLoS Med

Updated research nosology for HIV-associated neurocognitive disorders

Neurology

Original Article
Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist