bims-tubesc 2022-08-28 papers

Acta Neurol Scand. 2022 Aug 24.

Progress of clinical research studies on tuberous sclerosis complex-related epilepsy in China.

Tinghong Liu, Feng Chen, Feng Zhai, Shuli Liang.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome, with 75.6%-83.5% and 54.1% patients presenting with epilepsy and drug-resistant epilepsy (DRE), respectively. Clinical studies on TSC, particularly surgical interventions, have achieved rapid and substantial progress. The TSC-Task Force Committee of the China Association Against Epilepsy (CAAE-TFTSC) was founded in 2012, and annual academic conferences on the surgical treatment of TSC-related epilepsy have been held since 2013. 'China experts' consensus on surgical treatment of TSC-related epilepsy' was published in 2019. This review focuses on surgical treatment, including resective surgery, neuromodulations, corpus callosotomy and mini-invasive ablations, as well as studies on phenotype, genotype and anti-seizure therapies of mammalian target of rapamycin inhibitor, vigabatrin and ketogenic diet in patients with TSC-related DRE in China.

Keywords: China; epilepsy; progression; surgery; tuberous sclerosis complex (TSC)

DOI: https://doi.org/10.1111/ane.13692

Epilepsia Open. 2022 Jul 31.

Epidemiology and disease burden of tuberous sclerosis complex in France: A population-based study based on national health insurance data.

Francis Fagnani, Caroline Laurendeau, Marie de Zelicourt, Jade Marshall.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a rare multisystem disorder, often associated with epilepsy. This retrospective study aimed to identify patients with TSC, including those with epilepsy, from a French healthcare claims database, and to report incidence, prevalence, and healthcare costs and resource utilization.
METHODS: The anonymized French health insurance database (SNDS) covers almost the entire French population. Patients with TSC were identified as having ≥1 International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code Q85.1 or a long-term disease (LTD) registration over the inclusion period (2006-2017). Patients with an ICD-10 epilepsy code or who were dispensed ≥1 antiseizure medication (ASM) in the same year or after their TSC diagnosis were identified as having TSC with epilepsy. Newly diagnosed patients over the inclusion period constituted the incident cohort. Healthcare costs (patients with recorded costs only), healthcare resource use, and ASM dispensation are reported for patients with 2018 data.
RESULTS: In 2018, 3139 prevalent patients with TSC were identified (crude prevalence, 4.69 per 100 000); the incident cohort comprised 2988 patients (crude incidence, 0.44 per 100 000). Among patients with TSC, 67% (2101/3139) had epilepsy (mean [standard deviation, SD] age: 28.8 [18.8] years; male: 48%). Among patients with epilepsy, total mean (SD) annual healthcare costs were €11 413 (27 620) per capita (outpatient, 63%; inpatient, 37%), 46% were hospitalized during 2018 (mean [SD]: 1.8 [10.9] acute care visits per patient), and 65% visited a hospital specialist. Among patients with epilepsy, medication (mean [SD]: €4518 [12 102] per capita) was the greatest contributor (63%) to outpatient costs, and in 2018, 74% were dispensed ≥1 different ASM and 9% were dispensed ≥4 ASMs.
SIGNIFICANCE: TSC with epilepsy was associated with substantial healthcare costs and resource utilization, particularly outpatient and medication costs. Many patients with TSC with epilepsy were prescribed multiple ASMs, suggesting refractory epilepsy.

Keywords: TSC; healthcare cost; healthcare resource utilization; prevalence; refractory epilepsy

DOI: https://doi.org/10.1002/epi4.12636

Biomedicines. 2022 Jul 29. pii: 1838. [Epub ahead of print]10(8):

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

Keywords: autism spectrum disorder; biomarkers; epilepsy; intellectual disability; serum; tuberous sclerosis complex

DOI: https://doi.org/10.3390/biomedicines10081838

Science. 2022 Aug 25. eabg6621

Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.

Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified LYsosomal CHOlesterol Signaling (LYCHOS, previously annotated as G-protein coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1). Cholesterol bound to the N-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a GTPase-activating protein for the Rag guanosine triphosphatases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing, and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.

DOI: https://doi.org/10.1126/science.abg6621