Causes of mortality in individuals with tuberous sclerosis complex

Amin, Sam; Lux, Andrew; Calder, Nuala; Laugharne, Matthew; Osborne, J. P.; O'Callaghan, Finbar

doi:10.1111/dmcn.13352

Cited by 101 publications

(96 citation statements)

References 28 publications

(67 reference statements)

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“…The presence of LAM affected overall mortality; of the patients who had LAM, 40% (4 out of 10 patients) died, a higher proportion than any other organ involvement from TSC (Shepherd, Gomez, Lie, & Crowson, 1991). Another recent single-center experience from the UK reported similar findings where renal involvement from TSC was the most common cause of death, and LAM accounted for 12.5% (2 out of 16) of all TSC-related deaths in this cohort (Amin et al, 2017). In another study, 12.5% (6 out of 48) of the TSC-LAM patients progressed and died because of LAM (Cudzilo et al, 2013).…”

Section: Introductionsupporting

confidence: 70%

Pulmonary manifestations in tuberous sclerosis complex

Gupta

Henske

2018

American J of Med Genetics Pt C

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Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.

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Section: Introductionsupporting

confidence: 70%

Pulmonary manifestations in tuberous sclerosis complex

Gupta

Henske

2018

American J of Med Genetics Pt C

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“…Moreover, the lethal seizure was also not longer than the very first seizure. Importantly, SUDEP is one of the leading causes of seizure‐related death and contributes substantial to the cause of death in patients who die from complications of TSC . Besides, SUDEP cases were described in 10% of the families who carried mutations in genes of the GATOR1 complex, a regulator of the mTOR pathway .…”

Section: Discussionmentioning

confidence: 99%

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

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“…Premature decline of glomerular filtration rate (GFR) occurs in ~40% of patients with TSC (Bissler & Kingswood, ; Kingswood, Bolton, et al, ), and can occur in the absence of angiomyolipomata bleeding or interventions and is, in part, due to the renal cystic disease (Janssens et al, ). The importance of renal disease in TSC is highlighted by two studies that showed it was the leading cause of death in those clinic populations (Amin et al, ; Shepherd & Gomez, ).…”

Section: Introductionmentioning

confidence: 99%

Renal manifestation of tuberous sclerosis complex

Bissler

Kingswood

2018

American J of Med Genetics Pt C

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Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. It commonly causes several types of cystic disease and benign tumors (angiomyolipomata) in the kidneys that can both lead to significant premature loss of glomerular filtration rate. The main risks of angiomyolipomata, severe bleeding, loss of renal function, and pulmonary lymphangioleiomyomatosis, can be ameliorated by active surveillance and preemptive therapy with mTOR inhibitors. The cystogenic mechanism may involve primary cilia, but also appears to also involve a majority of normal tubular cells and may be driven by a minority of cells with mutations inactivating both their TSC1 or TSC2 genes. Malignant tumors are rare.

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Causes of mortality in individuals with tuberous sclerosis complex

Cited by 101 publications

References 28 publications

Pulmonary manifestations in tuberous sclerosis complex

Pulmonary manifestations in tuberous sclerosis complex

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Renal manifestation of tuberous sclerosis complex

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