Tuberous Sclerosis Complex Manifesting With Massive Angiomyolipomas in Multiple Organs

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.

Download Full-text

Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812943116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 2977-2986 ◽

Cited By ~ 4

Author(s):

Rituraj Pal ◽

Yan Xiong ◽

Marco Sardiello

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Mammalian Target Of Rapamycin ◽

Glycogen Storage ◽

Tumor Formation ◽

Negative Regulator ◽

Multiple Organs ◽

Genes Encoding

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.

Download Full-text

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

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211031100 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110311

Author(s):

Susanne Schubert-Bast ◽

Adam Strzelczyk

Keyword(s):

Precision Medicine ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Targeted Therapies ◽

Genetic Disorder ◽

Treatment Options ◽

Clinical Syndrome ◽

Adjunctive Treatment ◽

Multiple Organs ◽

The Impact

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.

Download Full-text

Tuberous sclerosis complex

Anais Brasileiros de Dermatologia ◽

10.1590/s0365-05962012000200001 ◽

2012 ◽

Vol 87 (2) ◽

pp. 184-196 ◽

Cited By ~ 11

Author(s):

Daniela Araujo Rodrigues ◽

Ciro Martins Gomes ◽

Izelda Maria Carvalho Costa

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Autosomal Dominant ◽

Multisystem Disorder ◽

Therapeutic Trials ◽

Multiple Organs ◽

Tissue Replacement ◽

History Of ◽

Neurocutaneous Syndrome ◽

Made In

Tuberous Sclerosis Complex, also known as Epiloia or Bourneville-Pringle disease is an autosomal dominant neurocutaneous syndrome with variable clinical expression. It is a multisystem disorder that may be associated with hamartomas in multiple organs in an unpredictable manner. The dermatologist plays an essential role in the history of the disease, since skin manifestations represent the most prevalent clinical features, enabling early diagnosis and intervention in its natural course. This article aims to inform the scientific community about advances made in the study of genetics and molecular biology. Recent findings regarding stimulation of tumor growth have been changing the history of this condition, making therapeutic trials with topical and systemic drugs possible. Knowledge of these topics enables better management of the patients affected, since tissue replacement by tumors can result in significant morbidity and mortality.

Download Full-text

Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2020190118 ◽

2021 ◽

Vol 118 (6) ◽

pp. e2020190118

Author(s):

Sharon Barone ◽

Kamyar Zahedi ◽

Marybeth Brooks ◽

Elizabeth P. Henske ◽

Yirong Yang ◽

...

Keyword(s):

Transcription Factor ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cyst Formation ◽

Benign Tumors ◽

Intercalated Cells ◽

Forkhead Transcription Factor ◽

Double Knockout ◽

Multiple Organs ◽

Expression Studies

Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl−/H+ exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H+-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H+-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H+-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H+-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC.

Download Full-text

Valproic Acid Induced Pancreatitis Presenting With Decreased Level of Consciousness in a Child With Tuberous Sclerosis Complex

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-25.3.256 ◽

2020 ◽

Vol 25 (3) ◽

pp. 256-260 ◽

Cited By ~ 1

Author(s):

Pierre-Charles Deschenes ◽

Julie Autmizguine ◽

Philippe Major ◽

Niina Kleiber

Keyword(s):

Emergency Department ◽

Valproic Acid ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Clinical Presentation ◽

Gastrointestinal Symptoms ◽

Drug Reactions ◽

Multiple Organs ◽

Level Of Consciousness ◽

New Onset

A 2-year-old Caucasian boy with tuberous sclerosis complex presented to the emergency department with lethargy and new onset myoclonias. Pancreatitis, thrombocytopenia, and coagulopathy associated to a decreased level of consciousness were diagnosed. Valproic acid had been initiated 13 months before and had been slowly increased to a dose of approximately 38 mg/kg/day. All the symptoms resolved after discontinuation of the medication. The clinical presentation of this child highlights that valproic acid-related pancreatitis can present with decreased level of consciousness without associated gastrointestinal symptoms. Adverse drug reactions associated with valproic acid can lead to damage of multiple organs and may prove fatal if not promptly recognized and managed.

Download Full-text

TUBEROUS SCLEROSIS : ITS VARIED PRESENTATION

10.36106/paripex/1901465 ◽

2020 ◽

pp. 1-2

Author(s):

Puja D. Nandaniya

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Autosomal Dominant ◽

Benign Tumors ◽

Gingival Hyperplasia ◽

Oral Manifestations ◽

Enamel Hypoplasia ◽

Multiple Organs ◽

Neurocutaneous Syndrome ◽

The Brain

Tuberous sclerosis complex is an unusual autosomal dominant neurocutaneous syndrome characterized by the development of benign tumors affecting different body systems affecting the brain, skin, retina, and viscera. It is characterized by cutaneous changes, neurologic conditions, and the formation of hamartomas in multiple organs leading to morbidity and mortality. The most common oral manifestations are fibromas, gingival hyperplasia, and enamel hypoplasia. The management of these patients is often multidisciplinary involving specialists from various fields. Here, we present a case report of a 26-old-year male patient with characteristic clinical, radiological, and histological features of tuberous sclerosis complex.

Download Full-text