bims-tubesc 2021-11-07 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–11–07
eleven papers selected by

Epilepsy Management in Tuberous Sclerosis Complex: Existing and Evolving Therapies and Future Considerations.
Could prevention of infantile spasms have been possible in a historical cohort of 31 tuberous sclerosis patients?
Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies.
Spectacular Effect of Massive Facial Angiofibromas Removal With a Carbon Dioxide Laser as a Manifestation of a Tuberous Sclerosis Complex.
Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances.
Anti-NMDA Receptor Encephalitis in a Patient with Tuberous Sclerosis-Related Brain Tumor: A Case Report.
Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis.
Multifocal micronodular pneumocyte hyperplasia with a novel mutation in TSC1: a case report.
The epilepsy-autism spectrum disorder phenotype in the era of molecular genetics and precision therapy.
Hayatine inhibits amino acid-induced mTORC1 activation as a novel mTOR-Rag A/C interaction disruptor.
MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants.

Pediatr Neurol. 2021 Sep 30. pii: S0887-8994(21)00214-9. [Epub ahead of print]126 11-19

Epilepsy Management in Tuberous Sclerosis Complex: Existing and Evolving Therapies and Future Considerations.

Maryam Nabavi Nouri, Maria Zak, Puneet Jain, Robyn Whitney.

  Tuberous sclerosis complex (TSC) is a rare autosomal dominant condition that affects multiple body systems. Disruption of the mammalian target of rapamycin (mTOR) pathway results in abnormal cell growth, proliferation, protein synthesis, and cell differentiation and migration in TSC. In the central nervous system, mTOR disruption is also believed to influence neuronal excitability and promote epileptogenesis. Epilepsy is the most common neurological manifestation of TSC and affects 80% to 90% of individuals with high rates of treatment resistance (up to 75%). The onset of epilepsy in the majority of individuals with TSC occurs before the age of two years, which is a critical time in neurodevelopment. Both medically refractory epilepsy and early-onset epilepsy are associated with intellectual disability in TSC, while seizure control and remission are associated with lower rates of cognitive impairment. Our current knowledge of the treatment of epilepsy in TSC has expanded immensely over the last decade. Several new therapies such as preemptive vigabatrin therapy in infants, cannabidiol, and mTOR inhibitors have emerged in recent years for the treatment of epilepsy in TSC. This review will provide clinicians with a comprehensive overview of the pharmacological and nonpharmacological therapies available for the treatment of epilepsy related to TSC.

Keywords:  Electroencephalogram surveillance; Epilepsy; Management; Preventative therapy; Tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.1016/j.pediatrneurol.2021.09.017
Eur J Paediatr Neurol. 2021 Oct 29. pii: S1090-3798(21)00192-6. [Epub ahead of print]35 153-157

Could prevention of infantile spasms have been possible in a historical cohort of 31 tuberous sclerosis patients?

Raili Riikonen.

  Efforts to prevent epilepsy in infants with tuberous sclerosis complex (TSC) has been the focus of EPISTOP.
PURPOSE: The present study was carried out to evaluate whether prevention could have been realistic.
METHODS: A retrospective analysis by hospital chart review of 31 patients with TSC and infantile spasms (practically all patients) admitted to two tertiary hospitals, Children's Hospital, University of Helsinki and Kuopio in 1980-2000. Clinical history, early cognitive development, early clinical signs of TSC, clinical signs of suspicious seizures, first seizures and EEG, response to adrenocorticotropic hormone (ACTH) therapy, EEG and brain imaging were evaluated.
RESULTS: Early development prior the spasms was apparently normal in 25 (80%). The first EEG ever performed for a child showed hypsarrhythmia in 16 (51%) or modified hypsarrhythmia in 10 (32%). Treatment lag was short (0-4, mean 2 weeks) and the primary response to ACTH favorable in 19 (64%). Etiological diagnostic workup of IS revealed TSC. In one single case (3%) the diagnosis of TSC could be made at birth due to a congenital cardiac rhabdomyoma. Three other rhabomyomas were diagnosed later. In brain imaging, subependymal periventricular calcifications or hypodense areas were seen in every patient at onset of IS. Other organ manifestations of TSC were retinal phakomas (6), polycystic kidneys (2), and renal angiolipomatosis (1).
CONCLUSIONS: Preventive treatment of epileptic discharges could have been possible in a single case of neonatal rhabdomyoma suggesting that preventive treatment is challenging in everyday practice. The main obstacle is the delay of TSC diagnosis.

Keywords:  Infantile spasms; Prevention; Retrospective study; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.ejpn.2021.10.010
Seizure. 2021 Oct 17. pii: S1059-1311(21)00339-3. [Epub ahead of print]93 111-119

Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies.

Gert Wiegand, Theodor W May, Irene Lehmann, Ulrich Stephani, Navah E Kadish.

   PURPOSE: To investigate the efficacy and tolerability of long-term treatment with Everolimus (EVO) in patients with tuberous sclerosis complex (TSC) and therapy-resistant epilepsy in a compassionate use trial.
METHODS: After a 3-month baseline, patients were treated with EVO. Treatment was divided into treatment phases each lasting at least 9 months. Patients started with one of three target serum levels. In case of insufficient seizure control, subsequent treatment phases with other target serum levels followed. The accompanying antiseizure medication (ASM) remained stable during the baseline phase and for at least the initial three treatment phases. We evaluated changes in seizure frequency and seizure-free days compared to baseline for each patient (Cox-Stuart-test).
RESULTS: Fifteen patients were followed up for up to 10 years (minimum 0.6 years, median 5.8 years). Twelve patients (80%) experienced a significant reduction in seizure frequency or an increase in seizure-free days: Six (40%) patients became seizure-free and four patients (26.7%) remained seizure free for > 7 years, of which three required no additional ASM. All participants reported at least one adverse effect, the vast majority (92.5%) of which were mild or moderate.
CONCLUSION: Long-term treatment with EVO was highly efficacious, safe and well tolerated. While EVO can be a therapeutic option for therapy-resistant epilepsy in TSC, it can take a long time for seizure relief to manifest.

Keywords:  Children; Epilepsy; Long-term treatment; Tuberous sclerosis complex (TSC); mTOR, Everolimus

DOI:  https://doi.org/10.1016/j.seizure.2021.10.011
J Lasers Med Sci. 2021 ;12 e24

Spectacular Effect of Massive Facial Angiofibromas Removal With a Carbon Dioxide Laser as a Manifestation of a Tuberous Sclerosis Complex.

Adam Borzęcki, Katarzyna Chyl-Surdacka, Monika Turska.

  Introduction: Tuberous sclerosis complex (TSC) is a rare, genetic disease which leads to neurological, cardiological, nephrological, ophthalmic, pulmonary and skin disorders. Case Presentation: Here, we describe a case of a 64-year-old man with the presence of giant angiofibromas located on his chin and nasolabial folds which caused inconvenience and unaesthetic appearance. All angiofibromas were removed with the use of a CO2 laser. The patient was extremely satisfied with the obtained result. No side effects were observed after a 6-month follow-up. Conclusion: Despite the fact that giant facial angiofibromas may be troublesome not only for patients but also for medical doctors, adequate CO2 laser usage with local anesthesia and control of massive bleeding is a promising treatment option for patients with TSC.

Keywords:  Angiofibromas; Carbon dioxide laser; Lasers; Tuberous sclerosis; Tuberous sclerosis complex

DOI:  https://doi.org/10.34172/jlms.2021.24
Anim Nutr. 2021 Dec;7(4): 1009-1023

Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances.

Shizhe Zhang, Xueyan Lin, Qiuling Hou, Zhiyong Hu, Yun Wang, Zhonghua Wang.

  The mechanistic target of rapamycin complex 1 (mTORC1) integrates various types of signal inputs, such as energy, growth factors, and amino acids to regulate cell growth and proliferation mainly through the 2 direct downstream targets, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase 1 (S6K1). Most of the signal arms upstream of mTORC1 including energy status, stress signals, and growth factors converge on the tuberous sclerosis complex (TSC) - Ras homologue enriched in brain (Rheb) axis. Amino acids, however, are distinct from other signals and modulate mTORC1 using a unique pathway. In recent years, the transmission mechanism of amino acid signals upstream of mTORC1 has been gradually elucidated, and some sensors or signal transmission pathways for individual amino acids have also been discovered. With the help of these findings, we propose a general picture of recent advances, which demonstrates that various amino acids from lysosomes, cytoplasm, and Golgi are sensed by their respective sensors. These signals converge on mTORC1 and form a huge and complicated signal network with multiple synergies, antagonisms, and feedback mechanisms.

Keywords:  Amino acids; Leucine; Mammal; Signaling pathway; mTORC1

DOI:  https://doi.org/10.1016/j.aninu.2021.05.003
Case Rep Neurol. 2021 Sep-Dec;13(3):13(3): 656-663

Anti-NMDA Receptor Encephalitis in a Patient with Tuberous Sclerosis-Related Brain Tumor: A Case Report.

Thomas Ihl, Friederike A Arlt, Marie-Luise Machule, Harald Prüss, Heinrich J Audebert.

  Anti-NMDA receptor (NMDAR) encephalitis (NMDARE) is an important treatable cause of autoimmune psychosis in all age-groups, which is sometimes associated with tumors, especially ovarian teratomas. Tuberous sclerosis complex (TSC) is an autosomal dominant inherited neurocutaneous disease predisposing for development of benign tumors. We present a case of a 35-year-old woman with recurrent episodes of schizophrenia-like symptoms. Accidentally, MRI revealed TSC-related brain tumors. NMDAR antibody titers were strongly positive in serum and cerebrospinal fluid. This is the first case describing an overlap of NMDARE and TSC-related brain tumors. A review of brain tumors and NMDARE is given in the supplementary material. Although a causal link seems interesting from a pathophysiological point of view, we are in favor of a coincidence.

Keywords:  Case report; NMDA receptor encephalitis; Primary brain tumor; Tuberous sclerosis complex

DOI:  https://doi.org/10.1159/000518642
Nat Commun. 2021 Nov 03. 12(1): 6332

Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis.

Alison E Jarmas, Eric W Brunskill, Praneet Chaturvedi, Nathan Salomonis, Raphael Kopan.

Mammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that translatome analysis in Tsc1+/- nephron progenitor cells from mice with elevated nephron numbers reveals how differential translation of Wnt antagonists over agonists tips the balance between self-renewal and differentiation. Wnt agonists are poorly translated in young niches, resulting in an environment with low R-spondin and high Fgf20 promoting self-renewal. In older niches we find increased translation of Wnt agonists, including R-spondin and the signalosome-promoting Tmem59, and low Fgf20, promoting differentiation. This suggests that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and possibly clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving synchronized differentiation. As predicted by these findings, removing one Rspo3 allele in nephron progenitors delays cessation and increases nephron numbers in vivo.

DOI: https://doi.org/10.1038/s41467-021-26626-9
Croat Med J. 2021 Oct 31. 62(5): 523-527

Multifocal micronodular pneumocyte hyperplasia with a novel mutation in TSC1: a case report.

Ai Li, Rong Jiang, Yongxia Li, Xixian Teng, Kaijun Ding, Bingqian Yang.

We report on a 34-year-old woman diagnosed with tuberous sclerosis complex. The patient was admitted for respiratory manifestations, while multi-organ involvement made the diagnostic process challenging. Genetic testing revealed a novel mutation TSC1 c.2094_2110del (p.His699Ter), which expands the disease-causing variant spectrum. Our results may facilitate the disease diagnostics and help to devise genetic counseling and targeted gene therapy.
Epilepsia. 2021 Nov 06.

The epilepsy-autism spectrum disorder phenotype in the era of molecular genetics and precision therapy.

Nicola Specchio, Valentina Di Micco, Marina Trivisano, Alessandro Ferretti, Paolo Curatolo.

  Autism spectrum disorder (ASD) is frequently associated with infants with epileptic encephalopathy, and early interventions targeting social and cognitive deficits can have positive effects on developmental outcome. However, early diagnosis of ASD among infants with epilepsy is complicated by variability in clinical phenotypes. Commonality in both biological and molecular mechanisms have been suggested between ASD and epilepsy, such as occurs with tuberous sclerosis complex. This review summarizes the current understanding of causal mechanisms between epilepsy and ASD, with a particularly genetic focus. Hypothetical explanations to support the conjugation of the two conditions include abnormalities in synaptic growth, imbalance in neuronal excitation/inhibition, and abnormal synaptic plasticity. Investigation of the probable genetic basis has implemented many genes, although the main risk supports existing hypotheses in that these cluster to abnormalities in ion channels, synaptic function and structure, and transcription regulators, with the mammalian target of rapamycin (mTOR) pathway and "mTORpathies" having been a notable research focus. Experimental models not only have a crucial role in determining gene functions but are also useful instruments for tracing disease trajectory. Precision medicine from gene therapy remains a theoretical possibility, but more contemporary developments continue in molecular tests to aid earlier diagnoses and better therapeutic targeting.

Keywords:  autistic spectrum disorders; developmental and epileptic encephalopathy; genes; precision medicine; tuberous sclerosis

DOI:  https://doi.org/10.1111/epi.17115
Biochem Biophys Res Commun. 2021 Oct 21. pii: S0006-291X(21)01412-1. [Epub ahead of print]583 71-78

Hayatine inhibits amino acid-induced mTORC1 activation as a novel mTOR-Rag A/C interaction disruptor.

Meiling Lu, Lei Yu, Yanrong Yang, Jiali Zhu, Sujing Qiang, Xinbo Wang, Jia Wang, Xiao Tan, Weifeng Wang, Yue Zhang, Weichao Wang, Jian Xie, Xinyan Chen, Hongbing Wang, Xianghuan Cui, Xin Ge.

  Abnormal activation of the mechanistic target of rapamycin (mTOR) signaling is commonly observed in many cancers and attracts extensive attention as an oncology drug discovery target, which is encouraged by the success of rapamycin and its analogs (rapalogs) in treatment of mTORC1-hyperactive cancers in both pre-clinic models and clinical trials. However, rapamycin and existing rapalogs have typically short-lasting partial responses due to drug resistance, thereby triggering our interest to investigate a potential mTORC1 inhibitor that is mechanistically different from rapamycin. Here, we report that hayatine, a derivative from Cissampelos, can serve as a potential mTORC1 inhibitor selected from a natural compound library. The unique properties owned by hayatine such as downregulation of mTORC1 activities, induction of mTORC1's translocation to lysosomes followed by autophagy, and suppression on cancer cell growth, strongly emphasize its role as a potential mTORC1 inhibitor. Mechanistically, we found that hayatine disrupts the interaction between mTORC1 complex and its lysosomal adaptor RagA/C by binding to the hydrophobic loop of RagC, leading to mTORC1 inhibition that holds great promise to overcome rapamycin resistance. Taken together, our data shed light on an innovative strategy using structural interruption-based mTORC1 inhibitors for cancer treatment.

Keywords:  Hayatine; Rag A/C; Rapamycin; mTOR

DOI:  https://doi.org/10.1016/j.bbrc.2021.10.014
Ther Adv Psychopharmacol. 2021 ;11 20451253211036814

MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants.

Tomasz Cholewinski, Diana Pereira, Matthijs Moerland, Gabriel E Jacobs.

  Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of the mammalian target of rapamycin complex 1 (mTORC1) in MDD. No well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. This review aims to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials on mTORC1 modulating ADs. Therefore, a PubMed-based narrative literature review of the mTORC1 involvement in MDD was performed. We have summarized recent pre-clinical and clinical findings linking the MDD to the impaired activity of several key biomarkers related to mTORC1. Also, cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs are summarized. The presented biomarkers may be used to monitor pharmacological effects by novel rapid-acting mTORC1-targeting ADs. Based on findings in the peripheral blood mononuclear cells, we argue that those may serve as an ex vivo model for evaluation of mTORC1 activity and propose the use of the summarized biomarkers for this purpose. This could both facilitate the selection of a pharmacodynamically active dose and guide future early clinical efficacy studies in MDD. In conclusion, this review provides a blueprint for the rational development of rapid-acting mTORC1-targeting ADs.

Keywords:  CNS drug development; biomarker-based drug development; mTORC1; major depressive disorder (MDD); pharmacological biomarkers; rapid-acting antidepressants

DOI:  https://doi.org/10.1177/20451253211036814