bims-tubesc 2022-06-05 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–06–05
nine papers selected by

Tsc1 Haploinsufficiency Leads to Pax2 Dysregulation in the Developing Murine Cerebellum.
Cannabidiol treatment for seizures in tuberous sclerosis complex.
Analysis of renal lesions in Chinese tuberous sclerosis complex patients with different types of TSC gene mutations.
Reading Ability in Patients With Tuberous Sclerosis Complex: Results of Chinese Character Reading and Reading Comprehension Tests.
Preliminary Screening of a Familial Tuberous Sclerosis Complex Pathogenic Gene.
Sclerosing perivascular epithelioid cell tumour (PEComa) of the testis in a patient with tuberous sclerosis complex.
Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study.
Non-canonical mTORC1 signaling at the lysosome.
Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison.

Front Mol Neurosci. 2022 ;15 831687

Tsc1 Haploinsufficiency Leads to Pax2 Dysregulation in the Developing Murine Cerebellum.

Ines Serra, Ana Stravs, Catarina Osório, Maria Roa Oyaga, Martijn Schonewille, Christian Tudorache, Aleksandra Badura.

  Tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that promotes the inhibition of mechanistic target of rapamycin (mTOR) pathway, and mutations in TSC1 lead to a rare complex disorder of the same name. Despite phenotype heterogeneity, up to 50% of TSC patients present with autism spectrum disorder (ASD). Consequently, TSC models are often used to probe molecular and behavioral mechanisms of ASD development. Amongst the different brain areas proposed to play a role in the development of ASD, the cerebellum is commonly reported to be altered, and cerebellar-specific deletion of Tsc1 in mice is sufficient to induce ASD-like phenotypes. However, despite these functional changes, whether Tsc1 haploinsufficiency affects cerebellar development is still largely unknown. Given that the mTOR pathway is a master regulator of cell replication and migration, we hypothesized that dysregulation of this pathway would also disrupt the development of cell populations during critical periods of cerebellar development. Here, we used a mouse model of TSC to investigate gene and protein expression during embryonic and early postnatal periods of cerebellar development. We found that, at E18 and P7, mRNA levels of the cerebellar inhibitory interneuron marker paired box gene 2 (Pax2) were dysregulated. This dysregulation was accompanied by changes in the expression of mTOR pathway-related genes and downstream phosphorylation of S6. Differential gene correlation analysis revealed dynamic changes in correlated gene pairs across development, with an overall loss of correlation between mTOR- and cerebellar-related genes in Tsc1 mutants compared to controls. We corroborated the genetic findings by characterizing the mTOR pathway and cerebellar development on protein and cellular levels with Western blot and immunohistochemistry. We found that Pax2-expressing cells were largely unchanged at E18 and P1, while at P7, their number was increased and maturation into parvalbumin-expressing cells delayed. Our findings indicate that, in mice, Tsc1 haploinsufficiency leads to altered cerebellar development and that cerebellar interneuron precursors are particularly susceptible to mTOR pathway dysregulation.

Keywords:  Pax2; autism spectrum disorder (ASD); cerebellar development; mouse model; tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.3389/fnmol.2022.831687
Epilepsy Behav. 2022 May 27. pii: S1525-5050(22)00210-4. [Epub ahead of print]132 108761

Cannabidiol treatment for seizures in tuberous sclerosis complex.

Simona Lattanzi.



Keywords:  Antiseizure medications; Cannabidiol; Epilepsy; Seizures

DOI:  https://doi.org/10.1016/j.yebeh.2022.108761
Genet Mol Biol. 2022 ;pii: S1415-47572022000200104. [Epub ahead of print]45(2): e20200387

Analysis of renal lesions in Chinese tuberous sclerosis complex patients with different types of TSC gene mutations.

Wenda Wang, Yang Zhao, Xu Wang, Zhan Wang, Yi Cai, Hanzhong Li, Yushi Zhang.

We sought to explore the relationship between renal lesion features and genetic mutations in tuberous sclerosis complex (TSC) patients. TSC patients with renal lesions were subjected to TSC1/2 gene next-generation sequencing (NGS). TSC1/2 mutation types and imaging examinations were screened for combined analysis of genetic and clinical features. Seventy-three probands among TSC patients with renal lesions were included. Twenty affected relatives were also included. In total, 93 patients were included. Eighty patients (86.0%) had bilateral renal angiomyolipomas (AMLs), and one had epithelioid AML. Two patients had polycystic kidney disease, one had renal cell carcinoma, and one had Wilms tumor. Among the 73 probands, four had TSC1 mutations, 53 had TSC2 mutations, and 16 had no mutations identified (NMI). There was no statistically significant difference between TSC1 mutation, TSC2 mutation and NMI group (P= 0.309), or between familial and sporadic groups (P= 0.775) when considering AML size. There was no statistically significant difference between pathogenic/likely pathogenic and benign/likely benign/NMI groups (P= 0.363) or among patients with different mutation types of TSC2 (P= 0.906). The relationship between the conditions of TSC gene mutations and the severity of renal lesions still needs more analysis. Patients with NMI, particularly those with familial disease, need more attention because the pathogenesis remains unknown.

DOI: https://doi.org/10.1590/1678-4685-GMB-2020-0387
Front Psychol. 2022 ;13 849334

Reading Ability in Patients With Tuberous Sclerosis Complex: Results of Chinese Character Reading and Reading Comprehension Tests.

Hom-Yi Lee, Sheng-Hui Yang, Ji-Nan Sheu, Jeng-Dau Tsai.

   Background: Most tuberous sclerosis complex (TSC) patients have neurological disorders and are at high risk of academic difficulties. Among academic skills, reading ability is the most important academic skill. The study applied the Chinese character fluency test to measure the word recognition and reading comprehension of TSC children to observe whether they have the characteristics of reading disability, as an indicator of the spectrum of reading ability in TSC patients.
Methods: The patients were assessed using the Chinese character fluency test and reading comprehension test to explore the differences in reading ability in terms of gender, age, epilepsy history, genotype, and intelligence level.
Results: Of the 27 patients, the assessment of reading accuracy showed statistical differences between intellectual level > 80, PR (p = 0.024), and pass numbers (p = 0.018). For the fluency assessment, there was a difference between different intellectual level (p = 0.050). In the reading comprehension test, there was differences for intellectual level in positivity (p = 0.07) and pass numbers (p = 0.06).
Conclusion: The Chinese character fluency and reading comprehension test measure the word recognition and reading comprehension and the spectrum of reading ability in TSC patients. All individuals with TSC, especially those with below average of intellectual ability, should be considered for potential academic difficulties.

Keywords:  comprehension test; fluency test; neuropsychiatric disorders; reading ability; reading tests; tuberous sclerosis

DOI:  https://doi.org/10.3389/fpsyg.2022.849334
Int J Gen Med. 2022 ;15 5247-5252

Preliminary Screening of a Familial Tuberous Sclerosis Complex Pathogenic Gene.

Yuting Wang, SongNian Hu, XinYu Tan, Qingqing Sang, Peng Shi, Chun Wang, Daoqian Sang.

   Purpose: The aim of this study was to screen the possible pathogenic genes of one family with tuberous sclerosis complexes (TSCs).
Patients and Methods: All family members were examined through detailed clinical evaluations, auxiliary examinations and CT. Then, we selected five members from this TSC family as the test samples. They were analysed by a new exon group sequencing method. Single nucleotide polymorphisms (SNPs) were screened by using databases, such as dbSNP and HAPMAP, and then the candidate genes were selected. Genes were analysed, and finally, the most likely mutation sites were screened. The results were examined by Sanger sequencing.
Results: In this TSC family, we identified c.913+2T>G, a splicing site mutation in the 9th intron region of TSC1. Family members without TSC did not have this mutation.
Conclusion: The mutations in the intron regions cannot be ruled out as a pathogenic factor for TSC.

Keywords:  intron mutation; pathogenic genes; tuberous sclerosis complex; whole exon sequencing

DOI:  https://doi.org/10.2147/IJGM.S359702
Pathology. 2022 May 26. pii: S0031-3025(22)00137-4. [Epub ahead of print]

Sclerosing perivascular epithelioid cell tumour (PEComa) of the testis in a patient with tuberous sclerosis complex.

Laurence A Galea, Michael S Hildebrand, Amber Boys, Christopher Joy, Justin Chee, Gordon White.

DOI: https://doi.org/10.1016/j.pathol.2022.02.012
Front Neurosci. 2022 ;16 879451

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study.

Erika L Juarez-Martinez, Dorinde M van Andel, Jan J Sprengers, Arthur-Ervin Avramiea, Bob Oranje, Floortje E Scheepers, Floor E Jansen, Huibert D Mansvelder, Klaus Linkenkaer-Hansen, Hilgo Bruining.

  Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide-a chloride-regulating agent-improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8-21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC.
Clinical Trial Registration: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

Keywords:  EEG; bumetanide; excitation-inhibition balance; irritability; open-label study; repetitive behavior; tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.3389/fnins.2022.879451
Trends Cell Biol. 2022 May 30. pii: S0962-8924(22)00117-9. [Epub ahead of print]

Non-canonical mTORC1 signaling at the lysosome.

Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio.

  The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.

Keywords:  FLCN; Rag GTPases; TFEB; lysosome; mTORC1

DOI:  https://doi.org/10.1016/j.tcb.2022.04.012
Front Psychiatry. 2022 ;13 852208

Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison.

ENCORE Expertise Center

   Objective: The etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation.
Methods: We assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates.
Results: Overall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain.
Conclusion: The syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

Keywords:  Angelman Syndrome; Fragile X Syndrome; Neurofibromatosis Type 1; Tuberous Sclerosis Complex; autism spectrum disorder; autistic traits

DOI:  https://doi.org/10.3389/fpsyt.2022.852208