Sara Baldassari
A5048078515- Genetics and Neurodevelopmental Disorders
- Genomics and Rare Diseases
- Epilepsy research and treatment
- Cellular transport and secretion
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Glioma Diagnosis and Treatment
- Neuroscience and Neuropharmacology Research
- Advanced biosensing and bioanalysis techniques
- Ion channel regulation and function
- Glycogen Storage Diseases and Myoclonus
- RNA and protein synthesis mechanisms
- Metabolism and Genetic Disorders
- Renal and related cancers
- PI3K/AKT/mTOR signaling in cancer
- Fetal and Pediatric Neurological Disorders
- RNA regulation and disease
- Autoimmune Neurological Disorders and Treatments
- Genomic variations and chromosomal abnormalities
- Hedgehog Signaling Pathway Studies
- Neurological disorders and treatments
- Drug Solubulity and Delivery Systems
- Pharmacological Effects and Toxicity Studies
- Amino Acid Enzymes and Metabolism
- Diet and metabolism studies
Institut du Cerveau
2018-2025
Inserm
2018-2025
Pitié-Salpêtrière Hospital
2022-2025
Sorbonne Université
2018-2025
Centre National de la Recherche Scientifique
2018-2025
Istituto delle Scienze Neurologiche di Bologna
2015-2025
Institute of Neurological Sciences
2018-2025
Assistance Publique – Hôpitaux de Paris
2018-2024
Université Paris Cité
2018-2024
NeuroDiderot
2024
Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal dysplasia (FCD), and hemimegalencephaly (HME), are major causes severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) balloon cells (BCs). Here, we provide a comprehensive assessment the contribution germline somatic variants in large cohort surgical MCD cases. We enrolled monocentric study 80...
Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations DEPDC5 as a cause of familial focal epilepsy. In this study, investigated whether mammalian target rapamycin (mTOR) regulators, NPRL2 NPRL3, also contribute cases epilepsy.We used targeted capture next-generation sequencing analyze 404 unrelated probands with We performed exome on two families multiple members affected epilepsy linkage analysis...
DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch mTORC1 pathway. So far, its function in brain remains largely unknown. Germline loss-of-function mutations DEPDC5 have emerged as major cause familial refractory focal epilepsies, with case reports sudden unexpected death epilepsy (SUDEP). Remarkably, fraction patients also develop cortical dysplasia (FCD), neurodevelopmental malformation. We therefore hypothesized that somatic...
PurposeTo define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 NPRL3 genes encoding GATOR1 complex, a negative regulator mTORC1 pathwayMethodsWe analyzed clinical genetic data 73 novel probands (familial sporadic) with epilepsy-related variants in GATOR1-encoding proposed new guidelines for interpretation variants.ResultsThe seizure phenotype consisted mostly focal seizures (e.g., hypermotor or frontal lobe 50%), mean age at onset 4.4 years, often...
Abstract Focal malformations of cortical development (MCD) are linked to somatic brain mutations occurring during neurodevelopment. Mild malformation with oligodendroglial hyperplasia in epilepsy (MOGHE) is a newly recognized clinico-pathological entity associated pediatric drug-resistant focal epilepsy, and amenable neurosurgical treatment. MOGHE histopathologically characterized by clusters increased cell densities, patchy zones hypomyelination, heterotopic neurons the white matter. The...
Abstract Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset dysmorphic cells clustered within healthy brain tissue. Here we show correlation between epileptiform activity acute slices obtained human surgical tissues and density neurons. We uncovered multiple...
Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 8. Using whole genome sequencing repeat primed PCR, we provide evidence that chr2-linked (FAME2) caused an expansion ATTTC pentamer within first intron STARD7. The expansions segregate 158/158 individuals typically affected 22 pedigrees...
Abstract Objective Focal cortical dysplasia (FCD) is a major cause of difficult‐to‐treat epilepsy in children and young adults, the diagnosis currently based on microscopic review surgical brain tissue using International League Against Epilepsy classification scheme 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas diagnostic challenges this widely used scheme. Methods Four web‐based digital pathology trials were completed by 20...
Brain mosaic mutations are a major cause of refractory focal epilepsies with cortical malformations such as dysplasia, hemimegalencephaly, malformation development oligodendroglial hyperplasia in epilepsy, and ganglioglioma. Here, we collected cerebrospinal fluid (CSF) during epilepsy surgery to search for somatic variants cell‐free DNA (cfDNA) using targeted droplet digital polymerase chain reaction. In 3 12 epileptic patients known previously identified brain tissue, here provide evidence...
The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings assess possible predictors of postoperative seizure cognitive outcome in 47 patients with refractory epilepsy brain somatic gene variants.This is retrospective multicenter study where we performed descriptive analysis classical hypothesis testing. included the variables interest significantly associated...
Brain-restricted somatic variants in genes of the mechanistic target rapamycin signalling pathway cause focal epilepsies associated with cortical dysplasia type II. We hypothesized that could be identified from trace tissue adherent to explanted stereoelectroencephalography electrodes used presurgical epilepsy workup localize epileptogenic zone. investigated three paediatric patients drug-resistant subjected neurosurgery. In resected brain tissue, we low-level mosaic mutations AKT3 and...
Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There significant lack of effective treatment for these disorders. Here, following the identification somatic PIK3CA gain-of-function mutation in podocytes patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics crucial role played by this pathway proliferative development promoting podocyte proliferation, dedifferentiation...
To identify novel genes implicated in epilepsy with auditory features (EAF) phenotypically heterogeneous families unknown molecular basis.We identified 15 probands EAF whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all and available affected relatives. used whole-exome sequencing (WES) 20 individuals (including the 5 relatives) to single nucleotide variants, small insertions/deletions, copy number variants.WES revealed likely pathogenic variants that not...
Abstract Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients a spectrum of associated pathogenic brain‐specific somatic Ras homolog enriched in brain ( RHEB) variants. The variant load directly correlated the size malformation, upregulated mTOR activity confirmed dysplastic tissues. Laser capture microdissection showed enrichment RHEB variants dysmorphic neurons balloon cells. Our findings support role...
Abstract Focal cortical dysplasia type II (FCDII) is a malformation causing refractory epilepsy. FCDII arises from developmental somatic mutations in mTOR pathway genes, leading to focal dyslamination and abnormal cytomegalic cells. Which cell types carry pathogenic how they affect cell-type-specific transcriptional programs remains unknown. To address this question, here we combined single-nucleus genotyping transcriptomics morphologically-identified cells using surgical samples...
Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology these lesions can inform medical surgical treatment. We conducted somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent surgery, 599 previously unpublished with ultra-deep ( > 1600x) targeted panel sequencing. Here we...
Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for largest number cases. The genetic alterations involved in are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants PIK3C2B, encoding class II phosphatidylinositol 3-kinase PI3K-C2β, underlie humans. We demonstrate patients' act as loss-of-function alleles, leading to impaired synthesis rare 3,4-bisphosphate, resulting mTORC1...
Abstract Objective This study aimed to identify prescribing behaviors in women of childbearing potential (WOCP) with epilepsy already taking valproate (VPA), and investigate the relationship between VPA maintenance, substitution, reduction, or withdrawal as part polytherapy, seizure worsening relapse. Methods We retrospectively reviewed prescription outcomes WOCP (16–50 years age) epilepsy, referred eight Italian centers, who were for at least 1 year 2014 2019. Results Among 750 (~12% all...