Everolimus for treatment of tuberous sclerosis complex‐associated neuropsychiatric disorders

Wilde

American J of Med Genetics Pt C

et al. 2018

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.

Section: Current Research and Future Directionsmentioning

confidence: 99%

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

Wilde

American J of Med Genetics Pt C

et al. 2018

American J of Med Genetics Pt C

“…Whenever diagnosed, TAND should be treated with specific symptomatic therapies. The potential role of mTOR inhibitors for improving neurocognitive functioning and behavior is still debated (Kilincaslan et al, ; Krueger et al, ).…”

Section: Clinical Manifestations Of Tsc In Adulthoodmentioning

confidence: 99%

Healthcare transition from childhood to adulthood in Tuberous Sclerosis Complex

Peron

Canevini

Ghelma

et al. 2018

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.

“…Several recent studies have addressed whether everolimus treatment could have positive effects on cognition and autistic behaviour in TSC patients, but have so far produced controversial results (Hwang et al, 2016, Kilincaslan et al, 2017, Krueger et al, 2017, Mizuguchi et al, 2019, Ess and Franz, 2019, Overwater et al, 2019. One important point is that children younger than 4 years old were excluded from these studies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

Choudhury

Amegandjin

Jadhav

et al. 2020

Preprint

Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.