Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.

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Tuberous Sclerosis and Bilateral Renal Angiomyolipomas: A Case Report and Literature Review of Emerging Treatment Strategies

Case Reports in Nephrology ◽

10.1155/2016/4595014 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5

Author(s):

Francois Jo-Hoy ◽

Omar Tolaymat ◽

Ryan Kunjal ◽

Leighton R. James

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Genetic Disorder ◽

Treatment Options ◽

Treatment Strategies ◽

Left Renal Artery ◽

Specific Patient ◽

Characteristic Finding ◽

Complex Patients ◽

Renal Artery Embolization

Tuberous sclerosis complex is a rare multisystemic genetic disorder associated with the development of benign hamartomas. Angiomyolipomas are one such characteristic finding that may be seen in 55–80% of tuberous sclerosis complex patients. While being normally asymptomatic, they can also cause significant morbidity and mortality. We present the case of a patient with tuberous sclerosis complex and recently discovered bilateral renal angiomyolipomas, admitted for hematuria who underwent left renal artery embolization; however, worsening renal function necessitated subsequent nephrectomy. Despite still being mainstays of treatment, invasive interventions are now being recommended for specific patient populations as demonstrated in our case. Emerging strategies targeting the PI3K/AKT/mTOR pathway have been shown to reduce the size of angiomyolipomas and are now used to treat asymptomatic cases >3 cm. Our review discusses these treatment options with the intention of increasing awareness of current recommendations and hopefully leading to increased application of these novel therapies that will reduce the need for invasive interventions.

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TUBEROUS SCLEROSIS: PRESENTATION OF A CASE AND REVIEW OF THE LITERATURE

10.36106/gjra/4910349 ◽

2021 ◽

pp. 95-96

Author(s):

Fabricio Andrés Lasso Andrade ◽

Jorge Alejandro Cadena Arteaga ◽

Ángela Maria Fajardo Arteaga ◽

Viviana Lizeth Echeverry Morillo ◽

David Alfredo Acevedo Vargas ◽

...

Keyword(s):

Nervous System ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Causal Link ◽

Benign Tumors ◽

Review Of The Literature ◽

Dominant Inheritance ◽

Variable Expression

Tuberous Sclerosis Complex (TSC) also known as Bournneville disease. TSC is a multisystemic genetic disorder with autosomal dominant inheritance, of variable expression, which is mainly characterized by the presence of benign tumors or hamartomas in the nervous system and skin, but which may also be present in the heart, kidney, lung and other organs. The most frequent symptom is epilepsy, affecting 80-90% of patients with TSC which manifests itself in childhood between 1 to 3 years of age. We present a case of sporadic onset tuberous sclerosis with epilepsy that had a causal link with TSC after admission to the emergency room in a convulsive status.

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The Impact of Psychiatric Symptoms on Tuberous Sclerosis Complex and Utilization of Mental Health Treatment

Pediatric Neurology ◽

10.1016/j.pediatrneurol.2018.10.011 ◽

2019 ◽

Vol 91 ◽

pp. 41-49 ◽

Cited By ~ 2

Author(s):

Kate E. Mowrey ◽

Myla Ashfaq ◽

Deborah A. Pearson ◽

Syed S. Hashmi ◽

Steven L. Roberds ◽

...

Keyword(s):

Mental Health ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Mental Health Treatment ◽

Psychiatric Symptoms ◽

Health Treatment ◽

The Impact

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Mosaicism in Tuberous Sclerosis Complex: A Case Report, Literature Review, and Original Data from Danish Hospitals

EMJ Dermatology ◽

10.33590/emjdermatol/21-00082 ◽

2021 ◽

pp. 98-105

Author(s):

Julie Loft Nagel ◽

Maja Patricia Smerdel ◽

Lisbeth Birk Møller ◽

Lotte Andreasen ◽

Anette Bygum

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Original Data ◽

Hereditary Disease ◽

Loss Of Function ◽

Low Level ◽

Multiple Organs ◽

Organ Systems

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disease with hamartomatous growths in multiple organs due to loss-of-function variants in TSC1 or TSC2. In approximately 15% of patients with clinical TSC, no pathogenic variant can be identified, and low-level mosaicism is suggested to be one of the reasons. Mosaicism is well-known in TSC and challenges the molecular genetic diagnosis. The advent of next-generation sequencing has improved the diagnostics in TSC including in patients with mosaicism. The TSC phenotype varies widely, and mosaic patients with TSC are often considered to have a milder phenotype. Here, the authors describe a patient with mosaic TSC with a 10% variant allele fraction and manifestations in three organ systems (skin, eyes, and kidneys). Furthermore, the authors studied existing literature about phenotypic organ manifestations in patients with mosaic TSC. No clear definition of the phenotype of patients with mosaic TSC could be established, but unilateral angiofibromas and the absence of tubers and a subependymal nodule could indicate mosaicism. The case shows that patients with low-level mosaic TSC can have multiple affected organ systems though still a mild clinical picture.

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The Connectivity Fingerprint of the Fusiform Gyrus Captures the Risk of Developing Autism in Infants with Tuberous Sclerosis Complex

Cerebral Cortex ◽

10.1093/cercor/bhz233 ◽

2019 ◽

Vol 30 (4) ◽

pp. 2199-2214

Author(s):

Benoit Scherrer ◽

Anna K Prohl ◽

Maxime Taquet ◽

Kush Kapur ◽

Jurriaan M Peters ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Face Processing ◽

Genetic Disorder ◽

Neuropsychiatric Symptoms ◽

Autism Spectrum ◽

The Body ◽

Fusiform Gyrus ◽

Benign Tumors ◽

Anatomical Connectivity

Abstract Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by benign tumors throughout the body; it is generally diagnosed early in life and has a high prevalence of autism spectrum disorder (ASD), making it uniquely valuable in studying the early development of autism, before neuropsychiatric symptoms become apparent. One well-documented deficit in ASD is an impairment in face processing. In this work, we assessed whether anatomical connectivity patterns of the fusiform gyrus, a central structure in face processing, capture the risk of developing autism early in life. We longitudinally imaged TSC patients at 1, 2, and 3 years of age with diffusion compartment imaging. We evaluated whether the anatomical connectivity fingerprint of the fusiform gyrus was associated with the risk of developing autism measured by the Autism Observation Scale for Infants (AOSI). Our findings suggest that the fusiform gyrus connectivity captures the risk of developing autism as early as 1 year of age and provides evidence that abnormal fusiform gyrus connectivity increases with age. Moreover, the identified connections that best capture the risk of developing autism involved the fusiform gyrus and limbic and paralimbic regions that were consistent with the ASD phenotype, involving an increased number of left-lateralized structures with increasing age.

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Tuberous sclerosis complex renal disease

10.1093/med/9780199592548.003.0330 ◽

2015 ◽

Cited By ~ 1

Author(s):

Bradley P. Dixon ◽

J. Christopher Kingswood ◽

John J. Bissler

Keyword(s):

Renal Failure ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Mammalian Target Of Rapamycin ◽

Cystic Disease ◽

Pulmonary Lymphangioleiomyomatosis ◽

Brain Involvement ◽

Almost All

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting almost all organs. It has wider phenotypic variation than often appreciated, with less than half showing the combination of characteristic facial angiofibromas, epilepsy, and mental retardation. Renal angiomyolipomata or cysts are found in 90% and renal failure was historically a common mode of adult death from the disease. Pulmonary lymphangioleiomyomatosis is restricted to females. Angiomyolipomata or cystic disease, or both, may cause renal failure. Angiomyolipomata may also haemorrhage, especially from larger lesions. Manifestations of brain involvement substantially complicate management of many patients with TSC. The causative genes TSC1 and TSC2 encode tuberin and hamartin which are involved in control of the mammalian target of rapamycin pathway. Inhibitors of that pathway, such as sirolimus and everolimus, are therefore logical approaches to therapy and have been shown to be effective in reducing angiomyolipomata volume. It remains to be seen whether they can protect renal function.

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Description of a multidisciplinary model of care in a French cohort of adult patients with tuberous sclerosis complex

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106607 ◽

2020 ◽

Vol 58 (1) ◽

pp. 25-31

Author(s):

Pierre Pfirmann ◽

Jerome Aupy ◽

Eva Jambon ◽

Laetitia Idier ◽

Mathilde Prezelin-Reydit ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Multidisciplinary Approach ◽

Genetic Disorder ◽

Multidisciplinary Care ◽

Adult Patients ◽

Bone Lesions ◽

Interdisciplinary Management ◽

Cutaneous Lesions ◽

High Level

BackgroundTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Due to the various manifestations of TSC and their potential complications, a multidisciplinary care approach is recommended by consensus guidelines.ObjectivesOur study aimed to give a complete description of our TSC adult cohort and to evaluate the multidisciplinary and interdisciplinary management model.MethodsData on each adult patient diagnosed with TSC, including disease manifestations, interventions and outcomes, were collected at baseline and updated annually. A multidisciplinary TSC approach with all the recommended explorations was carried out annually.Results90 patients were enrolled in Centre Hospitalier Universitaire de Bordeaux, between January 2000 and September 2018. Median age of patients at inclusion was 37 years (range, 27–47) and 20 years old at diagnosis of TSC. Regarding the occurrence of TSC manifestations, 97% of the patients had cutaneous lesions, 89% had neurological manifestations, 83% had renal manifestations and 100% had dental lesions with pits. More than half the patients had sclerotic bone lesions (68%), TSC-associated neuropsychiatric disorders (64%) and lymphangioleiomyomatosis (59%). A TSC multidisciplinary approach was developed including a global follow-up and an evaluation of TSC targeting organs, according to the recommendations. A satisfaction survey revealed global and entire satisfaction of patients with TSC.ConclusionWe obtained an accurate description of a cohort of adult patients with TSC. Our multidisciplinary approach model allowed us to provide optimal management of patients with TSC with a high level of patient satisfaction.

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Fetal Echocardiographic Detection of Cardiac Tumors: A Case Report of Multiple Fetal Cardiac Rhabdomyomas

Journal of Diagnostic Medical Sonography ◽

10.1177/8756479319847641 ◽

2019 ◽

Vol 35 (5) ◽

pp. 426-430

Author(s):

Bailey Sarff ◽

Randall Floyd ◽

Amy Bildner ◽

Janell Stormo ◽

Kelsy Fisher

Keyword(s):

Case Report ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cardiac Tumor ◽

Genetic Disorder ◽

Cardiac Tumors ◽

Size Number

Cardiac rhabdomyomas are the most common fetal cardiac tumor. They can be detected in the second and third trimesters. Rhabdomyomas are most commonly associated with the genetic disorder tuberous sclerosis complex. When associated with tuberous sclerosis complex, cardiac rhabdomyomas usually regress within the first few years of life, without complications. Symptoms depend on the size, number, and location of the rhabdomyomas. A case report of multiple cardiac rhabdomyomas that was found at 35 weeks’ gestation and is discussed.

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