Mosaic Recurrent MTOR Pathogenic Variant in a Patient with Stable Sleep Related Frontal Lobe Epilepsy Despite Striking Progression of Diffuse Cortical and Subcortical T2 Hyper-Intensity MRI
Abstract number :
1.356
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
100
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Michael Hildebrand, PhD – University of Melbourne
Timothy Green, BSc – Epilepsy Research Centre, Department of Medicine, Austin Health – University of Melbourne; Mark Bennett, PhD – Population Health and Immunity Division – The Walter and Eliza Hall Institute of Medical Research; Melanie Bahlo, PhD – Population Health and Immunity Division – The Walter and Eliza Hall Institute of Medical Research; Ingrid Scheffer, MBBS, PhD – Epilepsy Research Centre, Department of Medicine, Austin Health – University of Melbourne; Samuel Berkovic, MD – Epilepsy Research Centre, Department of Medicine, Austin Health – University of Melbourne; Saul Mullen, MBBS, PhD – Epilepsy Research Centre, Department of Medicine, Austin Health – University of Melbourne; Patrick Carney, MBBS, PhD – Neurosciences, Eastern Health – Monash University
Rationale: We present a thirty two year old patient with sleep-related focal to bilateral tonic-clonic seizures arising from the left frontal lobe commencing at eighteen years of age. Initial MRI was considered normal. Despite a stable clinical course and examination, progressive MRI changes were observed over fourteen years, involving extensive ill-defined cortical and subcortical T2 hyper-intensity of the entire left cerebral hemisphere with gyral expansion.
Methods: High resolution MRI, histopathological analysis, deep gene panel and exome sequencing, and droplet digital PCR were employed to characterize the clinical progression and molecular architecture.
Results: Serial MRI imaging confirmed enlargement of the lesion over a 12-year period during early adulthood. Histopathological analysis of a left frontal lobe biopsy involving cortex and white matter showed features (e.g., dysmorphic neurons, balloon cells) in white matter most suggestive of focal cortical dysplasia (FCD) type IIb. Genetic analysis of formalin-fixed paraffin-embedded brain tissue revealed a recurrent mosaic pathogenic MTOR missense c.4448G >A (p.Cys1483Tyr) gain-of-function variant at 8.5% variant allele fraction. The variant was not detected in peripheral tissue. This variant has been previously reported in patients with hemimegalencephaly (HME).
Conclusions: Our findings extend the spectrum of brain lesions associated with MTOR variants beyond stable FCDs and HMEs. Gain-of-function variants in mTOR pathway genes are the most frequently identified genetic cause of FCDs and HME, and are often mosaic in sporadic cases. MTOR hyperactivation leads to neuronal migration defects and development of focal dysplasias which are typically static lesions. In our patient, there is evidence of a progressive lesion on imaging, despite a stable clinical picture more consistent with a long term epilepsy associated tumour (LEAT). These findings may have significant clinical implications for this patient as LEAT may become malignant. The patient therefore requires monitoring with regular imaging long term.
Funding: National Health & Medical Research Council Australia Ideas Grant 2012287. (CIA Hildebrand)
Genetics