Tuberous sclerosis complex is associated with a novel human tauopathy

Hwang, Jihye; Perloff, Olga S.; Gaus, Stephanie E.; Benitez, Camila; Alquézar, Carolina; Cosme, Celica Q.; Nana, Alissa L.; Vatsavayai, Sarat C.; Ramos, Eliana Marisa; Geschwind, Daniel H.; Miller, Bruce L.; Kao, Aimee W.; Seeley, William W.

doi:10.1007/s00401-022-02521-5

Cited by 5 publications

(4 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While dementia in FXTAS is reported to share features with AD and APP-upregulation, 32 both neuropathologic 33 and neuropsychological 34 FXTAS characteristics primarily resemble a white matter dementia. The psychiatric manifestations in a man with tuberous sclerosis complex (TSC) were reported to resemble the behavioral variant of frontotemporal dementia (bvFTD), consistent with recent neuropathologic findings of an aging-associated TSC tauopathy , 35 , 36 in which the mTOR pathway hyperactivation and elevated phosphorylated tau aggregates are associated with premature neurodegeneration. Because psychiatric manifestations are part of TSC-associated neuropsychiatric disorders, 37 this underlines the necessity of systematic monitoring of the behavioral adult phenotypes to identify new-onset disorders.…”

Section: Discussionsupporting

confidence: 69%

“…Neuropsychological deficits are almost always reported in epilepsy, but the differential effects of seizures and the underlying neuronal abnormalities are unclear. A growing body of literature shows relations between epilepsy, mTOR pathways, tauopathy, 35 , 36 , 45 and neuronal activity–dependent synaptic release of dementia biomarkers, 46 , 47 suggesting a link between neurodevelopmental disorders, epilepsy, and neurodegeneration. A developmental and epileptic encephalopathy is sometimes considered a (partly) reversible dementia, exemplified by the cohort with late-diagnosed Dravet adults in which some individuals improved cognitively even after decades of treatment resistance.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dementia in Rare Genetic Neurodevelopmental Disorders

Kwetsie,

van Schaijk,

Van Der Lee

et al. 2024

Neurology

View full text Add to dashboard Cite

Background and Objectives Knowledge of young-onset Alzheimer disease in adults with Down syndrome has greatly improved clinical care. However, little is known about dementia in rare genetic neurodevelopmental disorders (RGNDs). In this review, a comprehensive overview is provided of reports on dementia and cognitive/adaptive trajectories in adults with RGNDs. Methods A systematic literature review was conducted in Embase, Medline ALL, and PsycINFO on December 6, 2022. The protocol was registered in PROSPERO (CRD42021223041). Search terms for dementia, cognitive and adaptive functioning, and RGNDs were combined using generic terms and the Orphanet database. Study characteristics and descriptive data on genetic diagnosis, clinical and neuropathologic features, comorbidities, and diagnostic methods were extracted using a modified version of the Cochrane Data Extraction Template. Results The literature search yielded 40 publications (17 cohorts, 23 case studies) describing dementia and/or cognitive or adaptive trajectories in adults with 14 different RGNDs. Dementia was reported in 49 individuals (5 cohorts, 20 cases) with a mean age at onset of 44.4 years. Diagnostics were not disclosed for half of the reported individuals (n = 25/49, 51.0%). A total of 44 different psychodiagnostic instruments were used. MRI was the most reported additional investigation (n = 12/49, 24.5%). Comorbid disorders most frequently associated with cognitive/adaptive decline were epilepsy, psychotic disorders, and movement disorders. Discussion Currently available literature shows limited information on aging in RGNDs, with relatively many reports of young-onset dementia. Longitudinal data may provide insights into converging neurodevelopmental degenerative pathways. We provide recommendations to optimize dementia screening, diagnosis, and research.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Dementia in Rare Genetic Neurodevelopmental Disorders

Kwetsie,

van Schaijk,

Van Der Lee

et al. 2024

Neurology

View full text Add to dashboard Cite

show abstract

“… 36 , 37 She showed that Tsc1 haploinsufficiency is associated with an increased risk of the primary tauopathy, progressive supranuclear palsy, and the secondary tauopathy, Alzheimer’s disease. 38 , 39 In Tsc1 haploinsufficiency, tau becomes abnormally acetylated and stabilized, thereby increasing steady-state levels of this protein and leading to abnormal protein aggregation. Chris Prodromou (University of Sussex, UK) revealed the structure of the LA1011-Hsp90 C-terminal domain complex.…”

Section: Co-chaperone Codementioning

confidence: 99%

Second international symposium on the chaperone code, 2023

Buchner,

Alasady,

Backe

et al. 2024

Cell Stress and Chaperones

Self Cite

View full text Add to dashboard Cite

“… 114 A recent study has provided additional evidence for a specific pattern of post-translational modifications in TSC (with differences between TSC1 and TSC2 mutation carriers), suggesting that individuals with TSC may have increased risk for tauopathy in mid-life. 113 …”

Section: Mechanisms Of Developmental Encephalopathymentioning

confidence: 99%

Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy

Aronica

Specchio

Luinenburg

et al. 2023

Brain

View full text Add to dashboard Cite

Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process leading to early onset and difficult-to-treat seizures. Several cellular, molecular, and pathophysiologic mechanisms, including mammalian target of rapamycin (mTOR) dysregulation, GABAergic dysfunction, and abnormal connectivity, may play a role in this epileptogenic process, and may also contribute to the associated developmental encephalopathy. Disease specific antiseizure medications or drugs targeting the mTOR pathway have proved to be effective in TSC-associated epilepsy. Pre-symptomatic administration of vigabatrin, a GABAergic drug, delays seizure onset and reduces the risk of a subsequent epileptic encephalopathy, such as infantile spasms syndrome or Lennox-Gastaut syndrome. Everolimus, a rapamycin-derived mTOR inhibitor, reduces seizures frequency especially in younger patients. This evidence suggests that everolimus should be considered early in the course of epilepsy. Future trials are needed to optimize the use of everolimus and to determine whether earlier correction of the mTOR dysregulation can prevent the progression to developmental and epileptic encephalopathies or mitigate their severity in infants with TSC. Clinical trials of several other potential antiseizure drugs (cannabidiol and ganaxolone) that target contributing mechanisms are also underway. This review provides an overview of the different biological mechanisms occurring in parallel and interacting throughout the life course, even beyond the epileptogenic process, in individuals with TSC. These complexities highlight the facing challenges in the prevention and treatment of TSC-related developmental and epileptic encephalopathy.

show abstract

Tuberous sclerosis complex is associated with a novel human tauopathy

Cited by 5 publications

References 27 publications

Dementia in Rare Genetic Neurodevelopmental Disorders

Dementia in Rare Genetic Neurodevelopmental Disorders

Second international symposium on the chaperone code, 2023

Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy

Contact Info

Product

Resources

About