Mos-FED (Mosaicism in Focal Epilepsy Cortical Dysplasia Tissue)

Study Overview
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Brief Summary
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Focal cortical dysplasia (FCD) is a malformation of brain development, the most common cause of drug-resistant epilepsy and often caused by mutations in mammalian target of rapamycin (mTOR) pathway genes. Patients with FCD develop drug-resistant seizures. This study will look at FCD tissue removed during epilepsy surgery and aims to detect mutations in mTOR pathway genes in brain cells. Secondly, the investigators will establish if evidence of mutations found in brain cells can also be detected as circulating free DNA (cfDNA) in blood. By looking at which genes are made into proteins in individual cells found in epilepsy surgical tissue (single cell expression profiling),the investigators will attempt to identify new genetic targets in FCD. The main outcome will be finding new causes of epilepsy with FCD and the development of new diagnostic and screening tools.

Detailed Description
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Primary Objectives: To identify if somatic mosaicism for mTOR is present in resected tissue from patients with FCDIIA/B, and can be detected in DNA from patient's serum as circulating free DNA (cfDNA) or from nasal epithelial cells collected non-invasively by olfactory mucosal brush swab. To establish if single cell expression profiling from resected fresh frozen tissue reveals novel FCD causing pathways and single cell RNA sequencing increases the yield of mTOR pathway variant detection. To determine if phosphorylated upstream and downstream mTOR pathway components can be characterised by immunohistochemistry and Western blot as novel biomarkers of mTOR activation in human FCDII tissue. Secondary Objectives: To engage with patients, representatives and charitable organisations to assess feasibility and develop plan to set up a future trial of mTOR inhibitor treatment.

Official Title
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Dissecting mTOR Pathway Mosaicism in FCDII-Harbouring Epileptic Brain and Peripheral Tissue.

Conditions
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Focal Cortical Dysplasia, Epilepsy

Intervention / Treatment
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* Genetic: Blood and nasal swab sampling


Participation Criteria
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Eligibility Criteria
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Epilepsy in Focal Cortical Dysplasia Type IIA/B Key Inclusion Criteria: Adult and Paediatric Patients (male and female) A histologically proven diagnosis of FCDIIA/B or a suspected diagnosis of FCDIIA/B (on MRI/EEG and PET grounds) awaiting resective Epilepsy surgery. Able to attend appointment/hospital and undergo sampling of serum and nasal swab Informed Consent Available Key Exclusion Criteria: Any acute or chronic conditions that could limit the ability of the patient to participate in the study. Refusal to give informed consent.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with histologically confirmed FCDIIA/B undergoing or post Epilepsy Surgery<br>Genetic screening of DNA samples (blood, mucosal swab, brain tissue) | Genetic: Blood and nasal swab sampling<br>* Genetic screening of DNA samples (blood, mucosal swab, brain tissue) from 60-100 patients with histologically confirmed diagnosis of FCDIIA/B identified from Epilepsy Surgery Databases.<br>* Other names: Analysis of Epilepsy Surgical tissue;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| somatic mosaicism | This study will measure and report the rate of somatic mosaicism for mTOR pathway genes in resected brain tissue and peripheral blood and nasal mucosal cells from patients with FCDIIA/B assessed by panel genetic sequencing of genomic and free circulating DNA . | 2 years | 
| single cell expression profiling | This study will measure and report novel FCD causing mutations through single cell expression profiling from resected fresh frozen tissue. | 2 years | 
| phosphorylated targets | This study will measure phosphorylation of upstream and downstream mTOR pathway components by immunohistochemistry and Western blot in human FCDII tissue. | 2 years |