Polygenic risk heterogeneity among focal epilepsies

Macnee, Marie; Leu, Costin; Pérez‐Palma, Eduardo; Ferguson, Lisa; Jehi, Lara; Daly, Mark J.; Najm, Imad; Busch, Robyn M.; Lal, Dennis

doi:10.1111/epi.16717

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…Focal epilepsies, in spite of being the most commonly encountered in the clinic, 63 remain largely elusive to genetic dissection and are thought to be characterized by oligogenic/polygenic architecture as other neuropsychiatric conditions. 64 , 65 Combining multiple layers of genetic, functional and animal data, we provide here compelling arguments that defects in an mTORC1 inhibitor, previously unlinked to human disease, represent a piece in the heterogeneous genetic puzzle of FE.…”

Section: Discussionmentioning

confidence: 74%

Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Gozzelino

Kochlamazashvili

Baldassari

et al. 2022

Brain

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Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

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Section: Discussionmentioning

confidence: 74%

Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Gozzelino

Kochlamazashvili

Baldassari

et al. 2022

Brain

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show abstract

“…Furthermore, various types of alterations in non-coding and intronic regions (including the intron-exon boundaries and their mutations, which could potentially result in splicing disorders including poison exons) (17,18), as well as epigenetic variations ( 19) (e.g., in Angelman syndrome) (20), have emerged in the last decades and should not be dismissed as potentially disease-causing mechanisms. Along these lines, beyond monogenic epilepsies, oligo-and polygenic substrates are emerging as phenotype-modifying factors in genetic epilepsies, converging in the latest polygenic risk scores (21,22). Finally, certain concepts with respect to patterns of inheritance are also worthy of a quick reminder (9).…”

Section: Basic Concepts About Types Of Genetic Variantsmentioning

confidence: 99%

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Beltrán‐Corbellini

Aledo‐Serrano

Møller³

et al. 2022

Front. Neurol.

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This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

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Polygenic burden and its association with baseline cognitive function and postoperative cognitive outcome in temporal lobe epilepsy

Arrotta,

Ferguson,

Thompson

et al. 2024

Epilepsy & Behavior

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Polygenic risk heterogeneity among focal epilepsies

Cited by 3 publications

References 21 publications

Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Polygenic burden and its association with baseline cognitive function and postoperative cognitive outcome in temporal lobe epilepsy

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