Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well

Implementing a Multidisciplinary Approach to Treating Tuberous Sclerosis Complex

Objective: Tuberous sclerosis complex is expressed throughout the body, resulting in a range of clinical manifestations that can be challenging to manage. Results: The authors report a patient who presented at age 3.5 years with several suspected seizures and was diagnosed with tuberous sclerosis complex following the discovery of numerous bilateral cortical tubers and subependymal nodules on magnetic resonance imaging. Interdisciplinary, comprehensive care was recommended; this included ongoing surveillance to monitor for the development of tuberous sclerosis complex–associated conditions. Approximately 2 years later, the patient began exhibiting aggressive and self-injurious behavior, and a subependymal giant cell astrocytoma was discovered. After everolimus was initiated, he demonstrated less aggression, had ceased self-injurious behavior, and subependymal giant cell astrocytoma growth stabilized. Conclusions: This case highlights the importance of a multidisciplinary approach to care in tuberous sclerosis complex, which ensures the early detection and appropriate treatment of clinical manifestations that may arise during the course of the patient’s life

Early Vocal Development in Tuberous Sclerosis Complex

Background: Our goal was to assess for the first time early vocalizations as precursors to speech in audio-video recordings of infants with tuberous sclerosis complex (TSC). Methods: We randomly selected 40 infants with TSC from the TSC Autism Center of Excellence Research Network data set. Using human observers, we analyzed 74 audio-video recordings within a flexible software-based coding environment. During the recordings, infants were engaged in developmental testing. We determined syllables per minute (volubility), the number of consonant-vowel combinations, such as ‘ba’ (canonical babbling), and the canonical babbling ratio (canonical syllables/total syllables) and compared the data with 2 groups of typically developing (TD) infants. One comparison group\u27s data had come from a laboratory setting, while the other\u27s had come from all-day Language Environment Analysis recordings at home. Results: Compared with TD infants in laboratory and all-day Language Environment Analysis recordings, entry into the canonical babbling stage was delayed in the majority of infants with TSC, and the canonical babbling ratio was low (TD mean = 0.346, SE = 0.19; TSC mean = 0.117, SE = 0.023). Volubility level in infants with TSC was less than half that of TD infants (TD mean = 9.82, SE = 5.78; TSC mean = 3.99, SE = 2.16). Conclusions: Entry into the canonical stage and other precursors of speech development were delayed in infants with TSC and may signal poor language and developmental outcomes. Future studies are planned to assess prediction of language and developmental outcomes using these measures in a larger sample and in more precisely comparable recording circumstances

International consensus recommendations for the identification and treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)

Abstract 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