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Pediatric Neurology Jul 2019Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to...
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.
Topics: Child, Preschool; Cognition; Developmental Disabilities; Female; Genotype; Humans; Language Development; Learning; Male; Phenotype; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 31005478
DOI: 10.1016/j.pediatrneurol.2019.03.003 -
Pediatric Neurology Oct 2013Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and...
BACKGROUND
Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices.
METHODS
The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly.
RESULTS
The updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established.
CONCLUSIONS
The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex.
Topics: Disease Management; Humans; Internationality; Population Surveillance; Practice Guidelines as Topic; Tuberous Sclerosis
PubMed: 24053983
DOI: 10.1016/j.pediatrneurol.2013.08.002 -
Pediatric Neurology Apr 2014Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes,... (Review)
Review
BACKGROUND
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most frequent neurological symptoms are seizures, which occur in up to 90% of patients and often are intractable, followed by autism spectrum disorders, intellectual disability, attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment has frequently proven insufficient for neurological and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation and recent mechanism-based treatment approaches.
METHODS
We performed a literature review to identify ongoing therapeutic challenges and novel strategies.
RESULTS
To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Studies in animals have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using magnetic resonance diffusion tensor imaging and electroencephalogram support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors.
CONCLUSIONS
Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutic approach.
Topics: Animals; Brain; Child Development Disorders, Pervasive; Humans; Synaptic Transmission; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 24486221
DOI: 10.1016/j.pediatrneurol.2013.12.002 -
JAMA Dermatology Oct 2014The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are...
IMPORTANCE
The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are common in tuberous sclerosis complex (TSC) and are a frequent concern for patients. Recognition of these lesions is imperative for early diagnosis, given the treatment advances that may improve patient outcomes.
OBJECTIVE
To detail recommendations for the diagnosis, surveillance, and management of skin and dental lesions in TSC.
EVIDENCE REVIEW
The TSC Dermatology and Dentistry Subcommittee, 1 of 12 subcommittees, reviewed the relevant literature from 1997 to 2012.
FINDINGS
A consensus on skin and dental issues was achieved within the Dermatology and Dentistry Subcommittee before recommendations were presented, discussed, and agreed on in a group meeting of all subcommittees from June 14 to 15, 2012.
CONCLUSIONS AND RELEVANCE
Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor.
Topics: Age Factors; Consensus Development Conferences as Topic; Dental Enamel; Fibroma; Humans; Mouth Neoplasms; Practice Guidelines as Topic; Sensitivity and Specificity; Skin Diseases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 25029267
DOI: 10.1001/jamadermatol.2014.938 -
American Journal of Medical Genetics.... Sep 2018Tuberous sclerosis complex (TSC) is associated with a wide range of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties,... (Review)
Review
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.
Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Depressive Disorder; Humans; Memory Disorders; Mental Disorders; Tuberous Sclerosis
PubMed: 30117265
DOI: 10.1002/ajmg.c.31637 -
Developmental Dynamics : An Official... Jan 2020Recent advances in human stem cell and genome engineering have enabled the generation of genetically defined human cellular models for brain disorders. These models can... (Review)
Review
Recent advances in human stem cell and genome engineering have enabled the generation of genetically defined human cellular models for brain disorders. These models can be established from a patient's own cells and can be genetically engineered to generate isogenic, controlled systems for mechanistic studies. Given the challenges of obtaining and working with primary human brain tissue, these models fill a critical gap in our understanding of normal and abnormal human brain development and provide an important complement to animal models. Recently, there has been major progress in modeling the neuropathophysiology of the canonical "mTORopathy" tuberous sclerosis complex (TSC) with such approaches. Studies using two- and three-dimensional cultures of human neurons and glia have provided new insights into how mutations in the TSC1 and TSC2 genes impact human neural development and function. Here we discuss recent progress in human stem cell-based modeling of TSC and highlight challenges and opportunities for further efforts in this area.
Topics: Animals; Brain; Humans; Neurons; Organoids; Pluripotent Stem Cells; Stem Cells; Tuberous Sclerosis
PubMed: 31070828
DOI: 10.1002/dvdy.60 -
Pediatric Neurology Oct 2016Tuberous sclerosis complex is a dominantly inherited disorder that variably affects the brain, skin, kidneys, heart, and other organs. Its neurological manifestations... (Review)
Review
Tuberous sclerosis complex is a dominantly inherited disorder that variably affects the brain, skin, kidneys, heart, and other organs. Its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. A mutation of either TSC1 or TSC2 can cause tuberous sclerosis complex. Their two gene products, hamartin and tuberin, form a physical complex which normally inhibits protein synthesis mediated through the mechanistic target of rapamycin, so a TSC1 or TSC2 mutation results in overactivation of the mechanistic target of rapamycin cascade. In addition to their tumor suppressor roles, TSC1 and TSC2 help to regulate cell size, neuronal migration, axon formation, and synaptic plasticity. Clinical trials of two different the mechanistic target of rapamycin inhibitors have demonstrated substantial improvement of tuberous sclerosis complex-related tumors, and a recent trial also showed a benefit from the mechanistic target of rapamycin inhibitor everolimus in the treatment of refractory epilepsy due to tuberous sclerosis complex. Effective mechanism-based therapy is now available for some manifestations of tuberous sclerosis complex.
Topics: Awards and Prizes; Brain Neoplasms; Congresses as Topic; Epilepsy; Humans; Mutation; Tuberous Sclerosis
PubMed: 27543366
DOI: 10.1016/j.pediatrneurol.2016.07.003 -
The European Respiratory Journal Mar 1996
Review
Topics: Female; Humans; Lymphangioleiomyomatosis; Male; Tuberous Sclerosis
PubMed: 8729994
DOI: 10.1183/09031936.96.09030399 -
Journal of Neurodevelopmental Disorders Sep 2023Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management...
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.
Topics: Humans; Affect; Anxiety; Autistic Disorder; Consensus; Tuberous Sclerosis
PubMed: 37710171
DOI: 10.1186/s11689-023-09500-1 -
Respiratory Medicine Jul 2020Lymphangioleiomyiomatosis (LAM) is a rare disease affecting women in childbearing age. A sporadic form (S-LAM) affecting previously healthy women, and a form associated... (Comparative Study)
Comparative Study
Lymphangioleiomyiomatosis (LAM) is a rare disease affecting women in childbearing age. A sporadic form (S-LAM) affecting previously healthy women, and a form associated with Tuberous Sclerosis Complex (TSC-LAM) are described. Some data suggested that TSC-LAM could be a milder disease compared to S-LAM. To investigate whether the different disease behavior is real or due to overdiagnosis of screened TSC women, we compared the natural history of S-LAM and TSC-LAM in patients with incidental diagnosis. Clinical, and functional data from 52 patients (23 with S-LAM and 29 with TSC-LAM) were analysed. At diagnosis functional impairment was mild without differences between groups [FEV1 % pred was 97% (88-105) and 94% (82-106) in TSC-LAM and S-LAM, respectively, p = 0.125]. Patients with S-LAM had less renal angiomyolipoma, and lower VEGF-D serum levels than TSC-LAM. There was no difference in the baseline extent of pulmonary cysts on CT scan and no difference in yearly rate of functional decline between TSC-LAM, and S-LAM patients [e.g. yearly rate of decline of FEV1 % pred was -0.51 (-1.59-2.24) and -0.90 (-1.92--0.42) in TSC-LAM and S-LAM, respectively, p = 0.265]. In conclusion, the natural history of TSC-LAM and S-LAM, when a potential selection bias due to screening in the latter group is balanced, is similar. Our study suggests that the prevalence of S-LAM can be significantly underestimated due to a tendency to diagnosis more frequently patients with more severe impairment, without identifying several ones with asymptomatic disease.
Topics: Adult; Female; Forced Expiratory Volume; Humans; Lymphangioleiomyomatosis; Male; Middle Aged; Prevalence; Rare Diseases; Severity of Illness Index; Tuberous Sclerosis
PubMed: 32469709
DOI: 10.1016/j.rmed.2020.105993