FOCAL CORTICAL DYSPLASIA

The most common etiology in medically refractory focal epilepsies in the pediatric population

FOCAL CORTICAL DYSPLASIA

Focal cortical dysplasia (FCD) is an abnormal formation of a focal area in the brain and represents the most common etiology in medically refractory focal epilepsies in the pediatric population.

GENE LIST AND PHENOTYPES

During brain development, special cells called neuronal and glial progenitor cells

transition towards their mature form in the brain. There, they become part of complex networks that help the brain work. Sometimes, small changes called somatic variants happen in these cells later in development. These changes usually affect only a small part of the brain or just a few cells, depending on how many times the changed cells divide and multiply.

HOW CAN THE FCD TEST BENEFIT A PATIENT?

While most epilepsy patients achieve good seizure control with appropriate medical treatment, epilepsy patients with structural brain malformations (approx. 30% of all epilepsy patients) often experience severe and intractable epileptic seizures despite proper medical treatment. Epilepsy surgery is an effective treatment option for these patients with drug-resistant focal epilepsy.In cases where the magnetic resonance imaging (MRI) result is unclear, presurgical implantation of electrodes (stereo electroencephalography electrodes – SEEG) in the brains record the EEG activity and therebyidentify the epileptogenic focushas shown promising results and is associated with minimallyinvasiveepilepsy surgery[1]. 

Genetic analyses of resected brain tissue and of cells from SEEG electrodes have led to the identification of genetic variants in approximately30 candidate genes associated with structural malformations in the cerebral cortex [2-3] and has paved the way for the development of precision medicine treatment therapies. Particularly genetic variants in genes that regulate cell growth, like the genes involved in the mTOR and Ras/Raf/MAPK signalling pathways have been associated with structural brain malformations [1, 3-7]. Findings of somatic variants in the SLC35A2 gene have also shed light on the pathogenesis of an otherwise poorly understood disease mechanism leading to mild cortical malformations with oligodendroglial hyperplasia and epilepsy (MOGHE) [8-9].

Knowledge of the specific genetic cause can improve the patients’ diagnostic journey and guide towards targeted treatment as a promising supplementary to epilepsy surgery [9-11].

Genetic testing with our FCD panel solution is relevant for patients suffering from:

  • Treatment resistant focal epilepsy
  • Focal cortical dysplasia (FCD) 
  • Malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) 

GENE LIST & PHENOTYPES Sample Requirements

  • DNA from brain biopsy + blood sample
  • Test Specifications
  • The test is performed as targeted panel test.
  • Chemistry: Twist Biosystems customized gene panel
  • Hardware: Illumina Novaseq 6000 Sequencer
  • Data processing: An in-house bioinformatic pipeline performs variable calling and filtering calling
  • Metrics: Average read depth >1000-fold. On target coverage,>97% at a >20-fold read depth.

Limitations of the Analysis Low-grade mosaicism lower than 5% is not detected. The analysis is limited to the protein coding regions and 10bp from the exon-intron boundaries including splice sites. Non-coding regions: 5’-UTR, 3’ UTR, introns, and promoter regions are sparsely analyzed (only known pathogenic variants are reported), and large rearrangements (complex inversions, gene conversions, balanced translocations) as well as single exon deletions or duplications will not be detected. The method is also not appropriate for the analysis of pseudogene regions/duplicated segments or repeat regions.Low-grade mosaicism lower than 5% is not detected. The analysis is limited to the protein coding regions and 10bp from the exon-intron boundaries including splice sites. Non-coding regions: 5’-UTR, 3’ UTR, introns, and promoter regions are sparsely analyzed (only known pathogenic variants are reported), and large rearrangements (complex inversions, gene conversions, balanced translocations) as well as single exon deletions or duplications will not be detected. The method is also not appropriate for the analysis of pseudogene regions/duplicated segments or repeat regions.

MORE INFORMATION

Terms

By ordering an analysis at Amplexa Genetics A/S, the requester confirms to have obtained the necessary informed consent for the performance of the requested analyses and accepts Amplexa Genetics Terms and Conditions. A hard-copy requisition or an e-mail stating the specific study together with the receipt of a sample is considered an order to conduct the analysis. 

From the day of order receipt, the turnaround time is five weeks.

You can expect a response no later than four weeks after we have received your sample.

REFERENCES

[1] Klein, KM. et al., Identification of a mosaic MTOR variant in purified neuronal DNA in a patient with focal cortical dysplasia using a novel depth electrode harvesting technique. Epilepsia. 2024 Jun;65(6):1768-1776.

[2] Baldassari, S. et al. Dissecting the genetic basis of focal cortical dysplasia: a large cohortstudy. Acta Neuropathol. 138:885-900 (2019).

[3] López-Rivera, J. A. et al.The genomic landscape across 474 surgically accessible epileptogenic human brain lesions. Brain 146, 1342–1356 (2023).

[4] Khoshkhoo S. et al., Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy. JAMA Neurol. 80:578-587 (2023).

[5] Represa, A. Why Malformations of Cortical Development Cause Epilepsy. Front. Neurosci. 13, 250 (2019).

[6] Najm, I. et al. The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission. Epilepsia 63, 1899–1919 (2022).

[7] Honke, J. et al. Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type IIdifferentiates between the GATOR1‑alteredautophagocytic subtype IIa and MTOR‑alteredmigration deficient subtype IIb. Acta NeuropathologicaCommunications 11:179 (2023).

[8] Barba, C. et al.Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene. Neurology 100, e528–e542 (2023).

[9] Aledo-Serrano, Á. et al.D-galactose Supplementation for the Treatment of Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE): A Pilot Trial of Precision Medicine After Epilepsy Surgery. Neurotherapeutics 20, 1294–1304 (2023).

[10] Almacellas Barbanoj, A. et al.Anti-seizure gene therapy for focal cortical dysplasia. Brain 147, 542–553 (2024).

[11] Auvin, S. & Baulac, S. mTOR-therapy and targeted treatment opportunities in mTOR-related epilepsies associated with cortical malformations. Rev. Neurol. (Paris). 179, 337–344 (2023).

[12] Richards, S.et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 17, 405-24 (2015).

[13] Durkie, M.et al.ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024. Recommendations ratified by Association for Clinical Genomic Science (ACGS) Quality Subcommittee. (https://www.acgs.uk.com/media/12533/uk-practice-guidelines-for-variant-classification-v12-2024.pdf) (2024).