bims-tubesc 2021-08-01 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–08–01
fourteen papers selected by

Leucyl-tRNA synthetase 1 is required for proliferation of TSC-null cells.
Multiple cardiac fatty deposits in a patient with tuberous sclerosis complex.
Low-level mosaicism in tuberous sclerosis complex in four unrelated patients: Comparison of clinical characteristics and diagnostic pathways.
Endovascular treatment of intrarenal aneurysms bleeding and angiomyolipomas in a patient with tuberous sclerosis and polycystic kidney disease.
The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia.
Epilepsy associated with tuberous sclerosis complex in childhood: Long-term outcome in children after epilepsy surgery and children non-eligible for epilepsy surgery.
Ectopic pregnancy of the fundal myometrium in a patient with tuberous sclerosis.
Tuberous Sclerosis.
Systematic review of sirolimus in dermatological conditions.
[Tuberous sclerosis complex: analysis of areas of involvement, treatment progress and translation to routine clinical practice in a cohort of paediatric patients].
ubtor Mutation Causes Motor Hyperactivity by Activating mTOR Signaling in Zebrafish.
Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1.
[Musculoskeletal manifestations of neurofibromatosis type 1 (von Recklinghausen's disease) and tuberous sclerosis (Bourneville's disease)].
A Dramatic Response to Sirolimus Therapy in a Premature Infant With Massive Cardiac Rhabdomyoma.

Biochem Biophys Res Commun. 2021 Jul 26. pii: S0006-291X(21)01119-0. [Epub ahead of print]571 159-166

Leucyl-tRNA synthetase 1 is required for proliferation of TSC-null cells.

Ji-Hyun Bae, Jong Hyun Kim.

  Uncontrolled cell proliferation associated with cancer depends on the functional abrogation of at least one of tumor suppressor. In response to nutrient cue, tuberous sclerosis complex (TSC) works as a tumor suppressor which inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). However, the regulation mechanism of nutrient-dependent cell proliferation in TSC-null cells remains unclear. Here, we demonstrate that leucine is required for cell proliferation through the activation of leucyl-tRNA synthetase (LARS1)-mTORC1 pathway in TSC-null cells. Cell proliferation and survival were attenuated by LARS1 knock-down or inhibitors in TSC-null cells. In addition, either rapamycin or LARS1 inhibitors significantly decreased colony formation ability while their combined treatment drastically attenuated it. Taken together, we suggest that LARS1 inhibitors might considered as novel tools for the regression of tumor growth and proliferation in TSC-null tumor cells which regrow upon discontinuation of the mTORC1 inhibition.

Keywords:  Amino acids; Cell proliferation; LARS1; TSC; mTORC1

DOI:  https://doi.org/10.1016/j.bbrc.2021.07.080
BMJ Case Rep. 2021 Jul 27. pii: e244366. [Epub ahead of print]14(7):

Multiple cardiac fatty deposits in a patient with tuberous sclerosis complex.

Masahiro Kimura, Takao Kato, Kanae Miyake, Takeshi Kimura.



Keywords:  cardiovascular medicine; radiology

DOI:  https://doi.org/10.1136/bcr-2021-244366
Am J Med Genet A. 2021 Jul 30.

Low-level mosaicism in tuberous sclerosis complex in four unrelated patients: Comparison of clinical characteristics and diagnostic pathways.

Héctor Hugo Manzanilla-Romero, Denisa Weis, Simon Schnaiter, Sabine Rudnik-Schöneborn.

  Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by either TSC1 or TSC2 gene mutations. About 15% of TSC patients remain without genetic diagnosis by conventional analysis despite clinical evidence. It is important to identify somatic mosaics, as therapeutic options are now available in patients with TSC1 or TSC2 mutations. Here, we describe the clinical and genetic characteristics of four male TSC patients with low-level mosaicism. Patients presented at ages between 9 months and 32 years. Clinical manifestations varied considerably and included brain lesions in all four patients, cardiac rhabdomyomas in two young patients, skin involvement in two patients, and retinal hamartomas and renal angiomyolipomas in three patients. One patient presented with epileptic seizures and psychomotor delay. Low levels of mosaicism for TSC1 or TSC2 mutation were found in different tissue samples employing next generation sequencing and multiple ligation-dependent probe amplification. The five disease-associated variants, including one second-hit mutation, include three truncating mutations and one deletion in TSC2, and one truncating mutation in TSC1. Sanger sequencing, allele-specific oligonucleotide PCR (ASO-PCR), and droplet digital PCR were used to confirm and quantify the disclosed mutations. Genetic identification of low-level mosaicism for TSC remains challenging but is important for optimal surveillance and management.

Keywords:  genetic diagnosis; next generation sequencing; somatic mosaicism; tuberous sclerosis complex

DOI:  https://doi.org/10.1002/ajmg.a.62433
J Bras Nefrol. 2021 Jul 30. pii: S0101-28002021005062301. [Epub ahead of print]

Endovascular treatment of intrarenal aneurysms bleeding and angiomyolipomas in a patient with tuberous sclerosis and polycystic kidney disease.

Túlio Leite, Lucas Vatanabe Pazinato, Maria Juliana de Aquino Vidal, Danielo de Freitas, Joaquim Mauricio da Motta Leal Filho.

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are conditions related to renal failure that can rarely occur in association as a contiguous gene syndrome. Angiomyolipomas (AMLs) are renal tumors strongly related to TSC that may rupture and cause life-threatening bleedings. We present a patient with TSC, ADPKD, and renal AMLs with persistent hematuria requiring blood transfusion. The persistent hematuria was successfully treated through endovascular embolization, a minimally invasive nephron sparing technique.

DOI: https://doi.org/10.1590/2175-8239-JBN-2021-0023
Epilepsia Open. 2021 Jul 30.

The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia.

Hanna M Hulshof, Barbora Benova, Pavel Krsek, Martin Kyncl, Maarten H Lequin, Anezka Belohlavkova, Petr Jezdik, Kees P J Braun, Floor E Jansen.

   OBJECTIVE: Patients with tuberous sclerosis complex (TSC) present with drug-resistant epilepsy in about 60% of cases, and evaluation for epilepsy surgery may be warranted. Correct delineation of epileptogenic zone (EZ) amongst multiple dysplastic lesions on MRI represents a challenging step in pre-surgical evaluation.
METHODS: Two experienced neuroradiologists evaluated pre- and post-surgical MRIs of 28 epilepsy surgery patients with TSC, assessing characteristics of tubers, cysts, calcifications, and focal cortical dysplasia (FCD) - resembling lesions. Utilizing multiple metrics, we compared MRI features of the EZ - defined as the resected area in TSC patients who achieved seizure-freedom two years after epilepsy surgery - with features of other brain areas. Using combinatorial analysis, we identified combinations of dysplastic features that are most frequently observed in the epileptogenic zone in TSC patients.
RESULTS: All TSC- associated dysplastic features were more frequently observed in the EZ than in other brain areas (increased cortical thickness, grey-white matter blurring, transmantle sign, calcifications, tubers; Kendal's tau 0.35, 0.25, 0.27, 0.26, 0.23 respectively; p value <0.001 in all). No single feature could reliably and independently indicate the EZ in all patients. Conversely, the EZ was indicated by the presence of the combination of three of the following features: tubers, transmantle sign, increased cortical thickness, calcifications, and the largest FCD-affected area. Out of these, the largest FCD-affected area emerged as the most reliable indicator of the EZ, combined either with calcifications or tubers.
SIGNIFICANCE: The epileptogenic zone in TSC patients harbors multiple dysplastic features, consistent with focal cortical dysplasia. A specific combination of these features can indicate the EZ and aid in pre-surgical MRI evaluation in epilepsy surgery candidates with TSC.

Keywords:  epilepsy surgery; focal cortical dysplasia; magnetic resonance imaging; pre-surgical evaluation; tuberous sclerosis complex

DOI:  https://doi.org/10.1002/epi4.12529
Epilepsy Behav. 2021 Jul 23. pii: S1525-5050(21)00471-6. [Epub ahead of print]122 108210

Epilepsy associated with tuberous sclerosis complex in childhood: Long-term outcome in children after epilepsy surgery and children non-eligible for epilepsy surgery.

Marion Stomberg, Christian G Bien, Thilo Kalbhenn, Tilman Polster, Theodor W May.

   OBJECTIVE: Drug-resistant epilepsy is one of the major disease burdens in patients with tuberous sclerosis complex (TSC). Epilepsy surgery has been shown to be effective in TSC, but making a decision for surgery is often more complex than in other surgically amenable epilepsy syndromes and not all patients with TSC are eligible. We investigated long-term outcomes (after ≥one year; median, 6.4 years) with a special interest in general developmental level, health-related quality of life, parental concerns due to epilepsy, impact on family, and social adaptation in children who underwent epilepsy surgery and in children who were not eligible for surgery.
METHODS: Eighty-five children (median age at intervention: 3.3 years, interquartile range [IQR]: 1.8-6.3 years) with TSC-related epilepsy had a presurgical investigation, and 34 of this group underwent epilepsy surgery. At follow-up (median age: 11.5 years, IQR: 7.8-15.5 years), we assessed seizure outcome, health-related quality of life, social adaptation, parental concerns due to epilepsy, and general developmental level based on established questionnaires and a standardized interview. Generalized linear models were performed for statistical evaluation.
RESULTS: At follow-up, 53% (18/34) of the operated patients were seizure free for ≥12 months and 30% (15/50) of the patients non-eligible for epilepsy surgery (p = 0.037). In the surgical group, developmental level was significantly higher in seizure-free patients, in comparison to non-seizure-free patients (p = 0.004); this was also observed in the non-surgical group, but less marked (p = 0.089). Furthermore, developmental level was significantly (p ≤ 0.001) related to quality of life, social adaptation, impact on family, and parental concerns. In both cohorts, parental concerns were less pronounced if children became seizure free (p < 0.001 and p = 0.018, respectively).
SIGNIFICANCE: In children with TSC-related epilepsy, quality of life, social adaptation, and impact on family were related to general developmental level, which in turn was significantly related to seizure freedom. Consequent epilepsy management aiming at seizure freedom, including presurgical evaluation and, if indicated, epilepsy surgery in a center specifically experienced with TSC-related epilepsy, is a worthwhile effort to improve quality of life in patients with TSC and their families.

Keywords:  Children; Epilepsy surgery; Outcome; Quality of life; TSC

DOI:  https://doi.org/10.1016/j.yebeh.2021.108210
Clin Case Rep. 2021 Jul;9(7): e04303

Ectopic pregnancy of the fundal myometrium in a patient with tuberous sclerosis.

Neha Sharma, Michele Agustin, Ariel Polonsky, Lance Bruck.

  A myometrial ectopic pregnancy is a rare and potentially fatal diagnosis. This diagnosis should be considered when presented with large increases in serum beta-hCG with no evidence of an intrauterine pregnancy, particularly with altered myometrium.

Keywords:  acute medicine; general surgery; genetics; obstetrics and gynaecology

DOI:  https://doi.org/10.1002/ccr3.4303
Skinmed. 2021 ;19(3): 179-185

Tuberous Sclerosis.

Bruna Dücker Bastos Amorim, David Azulay, Marcia Ramos-E-Silva.

Tuberous sclerosis is a rare autosomal dominant genetic disorder. It is characterized by the appearance of benign tumors, known as hamartomas, which can affect multiple organs, including the skin. Cutaneous manifestations are present in almost all patients; therefore, the dermatologist has a fundamental role in the history and evolution of the disease in spite of being a multisystemic disorder. Two tumor suppressor genes, CET1 and CET2, involved in tissue growth and cell proliferation, show mutation in this disease, which leads to the appearance of various benign tumors, hamartomas. Clinical characteristics are more than three hypomelanotic macules, more than three angiofibromas or face or scalp cephalic fibrotic plaque, more than two ungual fibromas, shagreen plaque, multiple retinal hamartomas, etc. Treatment is basically symptomatic, and genetic counseling is very important. This is an autosomal dominant disorder, although there is spontaneous mutation and no familial history in 65% of patients. When one of the parents is affected, genetic study is useful for prenatal diagnosis.
Australas J Dermatol. 2021 Jul 30.

Systematic review of sirolimus in dermatological conditions.

Andrew W Swarbrick, Aaron J Frederiks, Rachael S Foster.

  Sirolimus is a mammalian target of rapamycin inhibitor (mTORI) with anti-proliferative, antiangiogenic and immunosuppressive properties. While approved in Australia as an anti-rejection medication for renal transplant patients, there is mounting evidence regarding the utility of oral and topical sirolimus in treating a plethora of dermatological conditions or conditions with cutaneous manifestations. Our aim was to present an overview of the evidence for current usage and breadth of the application of sirolimus in dermatology. We carried out a systematic review of all the literature published up to 31 August 2019 on oral and topical sirolimus with respect to dermatological conditions or conditions otherwise relevant to dermatology. While 3368 papers were initially produced in our search, 238 papers met our inclusion criteria and were examined in our review. The conditions examined were categorised into genodermatoses (9 conditions), infection (1 condition), inflammatory/autoimmune (10 conditions), neoplasm (3 conditions) and vascular (17 conditions). We extracted data on first author, publication year, journal, characteristics of the study and study patients, condition, drug modalities, drug efficacy, side effects, blood level of mTORI, co-interventions and follow-up. While there is level 1 evidence for the efficacy of sirolimus in conditions such as tuberous sclerosis complex (TSC) and GVHD prophylaxis, for many other conditions, the evidence is limited to level 4 evidence. Regarding oral systemic therapy, dosing regimens varied with the most common for children 0.8mg/m2 twice daily and for adults 1 mg twice daily. Doses were often adjusted to reach a typical trough level of between 5 and 15 ng/mL, though targets often varied. In the overall majority of cases, side effects were minimal or tolerable, including mucositis, cytopenias, lipid abnormalities and nausea/vomiting, and only a few cases had to stop due to adverse effects. Regarding topical therapy, concentration of formulations varied from 0.1% to 1% and were compounded into creams, ointments or gels and administered typically once or twice per day. The most common side effect was skin irritation. There were a number of limitations to our study. In particular, many of the published studies were case reports or case series with no comparator arm, leading to susceptibility of bias in conclusions drawn, in particular a high likelihood of publication bias. Given the heterogeneity amongst studies, comparisons or aggregation of results was difficult. There continues to be growing use of oral and topical sirolimus in dermatological conditions. It provides new therapeutic options to patients where previous therapies have either failed or are limited due to toxicity. However, further studies are warranted.

Keywords:  dermatology; mTOR inhibitor; rapamycin; sirolimus; systematic review

DOI:  https://doi.org/10.1111/ajd.13671
Rev Neurol. 2021 Sep 01. 73(5): 141-150

[Tuberous sclerosis complex: analysis of areas of involvement, treatment progress and translation to routine clinical practice in a cohort of paediatric patients].

V Cantarín-Extremera, B Bernardino-Cuesta, C Martín-Villaescusa, J Melero-Llorente, A Hernández-Martín, C Aparicio-López, C de Lucas-Collantes, A Tamariz Martel-Moreno, A Duat-Rodríguez, M L Ruiz-Falcó-Rojas.

INTRODUCTION: Tuberous sclerosis complex (TSC) displays great phenotypic variability. Increasingly early diagnosis, including prenatal identification, entails the need for the paediatrician and neuropaediatrician to establish early suspicion and identification of factors that may influence prognosis and treatment.
AIM: To determine the clinical criteria for early diagnosis, initial complementary tests, actions and treatments to prevent different comorbidities, so as to improve the prognosis of these patients.
PATIENTS AND METHODS: Descriptive, retrospective study of = 18-year-olds with a definitive diagnosis of TSC in a tertiary hospital from 1998 to 2019. We collected variables referring to epidemiological data, multisystem involvement, complementary tests and genetics.
RESULTS: Ninety-four patients were analysed. The main diagnostic reasons were epilepsy and rhabdomyomas. The frequency of occurrence of clinical criteria was determined, and neuropathological findings were the main findings, followed by cutaneous stigmata, rhabdomyomas and renal lesions. Statistical relationships were found between clinical, radiological and genetic aspects, the influence of preventive activities on the occurrence of epilepsy and the relevance of everolimus use were tested.
CONCLUSIONS: Rhabdomyomas and skin stigmata in patients and parents are major diagnostic signs in infants. Tubers and subependymal nodules are statistically associated with the development of epilepsy. Early epileptic spasms, refractory to treatment in the first months, increase the risk of cognitive deficits and autism spectrum disorder. Epileptic abnormalities need to be closely monitored in the first year of life. Everolimus is an alternative treatment for several comorbidities, but its early use (< 3 years) requires further study.

DOI: https://doi.org/10.33588/rn.7305.2020665
Neurosci Bull. 2021 Jul 26.

ubtor Mutation Causes Motor Hyperactivity by Activating mTOR Signaling in Zebrafish.

Tiantian Wang, Mingshan Zhou, Quan Zhang, Cuizhen Zhang, Gang Peng.

  Mechanistic target of rapamycin (mTOR) signaling governs important physiological and pathological processes key to cellular life. Loss of mTOR negative regulators and subsequent over-activation of mTOR signaling are major causes underlying epileptic encephalopathy. Our previous studies showed that UBTOR/KIAA1024/MINAR1 acts as a negative regulator of mTOR signaling, but whether UBTOR plays a role in neurological diseases remains largely unknown. We therefore examined a zebrafish model and found that ubtor disruption caused increased spontaneous embryonic movement and neuronal activity in spinal interneurons, as well as the expected hyperactivation of mTOR signaling in early zebrafish embryos. In addition, mutant ubtor larvae showed increased sensitivity to the convulsant pentylenetetrazol, and both the motor activity and the neuronal activity were up-regulated. These phenotypic abnormalities in zebrafish embryos and larvae were rescued by treatment with the mTORC1 inhibitor rapamycin. Taken together, our findings show that ubtor regulates motor hyperactivity and epilepsy-like behaviors by elevating neuronal activity and activating mTOR signaling.

Keywords:  Epilepsy; Hyperactivity; Ubtor; Zebrafish; mTOR

DOI:  https://doi.org/10.1007/s12264-021-00755-z
Sci Rep. 2021 Jul 29. 11(1): 15490

Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1.

Patricia Soriano Roque, Mehdi Hooshmandi, Laura Neagu-Lund, Shelly Yin, Noosha Yousefpour, Hiroaki Sato, Tamaki Sato, Yosuke Nakadate, Akiko Kawakami, Soroush Tahmasebi, Alfredo Ribeiro-da-Silva, Christos G Gkogkas, Masha Prager-Khoutorsky, Thomas Schricker, Linda Wykes, Arkady Khoutorsky.

Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

DOI: https://doi.org/10.1038/s41598-021-94849-3
Radiologe. 2021 Jul 26.

[Musculoskeletal manifestations of neurofibromatosis type 1 (von Recklinghausen's disease) and tuberous sclerosis (Bourneville's disease)].

Markus Uhl.

   CLINICAL PROBLEM: Neurofibromatosis type 1 (NF1) and tuberous sclerosis (TS) are among the most common genetic diseases. Bone and soft tissue manifestations are common disease manifestations.
STANDARD RADIOLOGICAL PROCEDURE AND EVALUATION: The standard radiological procedure is magnetic resonance imaging (MRI). All macroscopic disease manifestations can be diagnosed radiologically and observed during the course. Specific complications such as plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) in NF1 are readily visible on MRI. Differentiation of plexiform neurofibromas and MPNST is uncertain and requires follow-up.
RECOMMENDATION FOR PRACTICE: MRI is the most important procedure for the investigation of soft tissue and bone manifestations of NF1 and TS.

Keywords:  Café-au-lait macules; Genetic disorders; Neurofibroma; Plexiform neurofibromas; Tuberous sclerosis

DOI:  https://doi.org/10.1007/s00117-021-00892-6
JACC Case Rep. 2019 Oct;1(3): 327-331

A Dramatic Response to Sirolimus Therapy in a Premature Infant With Massive Cardiac Rhabdomyoma.

Claire Lawley, Himanshu Popat, Melanie Wong, Nadia Badawi, Julian Ayer.

  Cardiac rhabdomyomas in neonates may cause significant cardiac risk. Recently, sirolimus has been used to treat these lesions. The dose, duration, and monitoring for therapy are unknown. A case of sirolimus use in a premature neonate is presented. No significant adverse effects were seen. Review of published cases is included. (Level of Difficulty: Advanced.).

Keywords:  LVOT, left ventricular outflow tract; TSC, tuberous sclerosis complex; cancer; congenital heart defect; echocardiography; mTOR, mammalian target of rapamycin

DOI:  https://doi.org/10.1016/j.jaccas.2019.07.030