Authors :
Presenting Author: Benjamin Edmonds, MD – University of Washington
Bianca Russel, MD – Assistant Professor, Genetics, UCLA; Aran Groves, MD, PhD – Pediatric Neurology Fellow, Pediatrics, UCLA; Jacqueline Ngo, MD – Pediatric Neurology Fellow, Pediatrics, UCLA; Aria Fallah, MD, MS – Pediatric Neurosurgeon, Neurosurgery, UCLA; Noriko Salamon, MD, PhD – Chief of Neuroradiology, Radiology, UCLA; Hiroki Nariai, MD, PhD – Assistant Professor, Pediatric Neurology, UCLA
Rationale:
Recent application of a multi-disciplinary approach to cortical malformations with genetic testing in patients with neurodevelopmental syndromes has led to a discovery of germline and mosaic variants within the PI3K-mTOR and GATOR1 signaling pathways that result in hyperactivation of mTORC1. Our aim is to optimize diagnosis and treat patients at UCLA with hemimegalencephaly. By identifying the genetic etiology, we provide accurate recurrence risk counseling, information on range of outcomes, and the opportunity for precision therapeutics when indicated.
Methods:
A retrospective study of all pediatric patients at UCLA with hemimegalencephaly from March 2019 to October 2022 who underwent brain tissue analysis after surgical resection and/or had evaluation with blood or serum testing for germline mutations associated with hemimegalencephaly was conducted. When affected brain tissue was available, samples were tested using established molecular diagnostic panels designed to identify low level mosaic variants
1. The extent of mosaicism was evaluated. Findings were correlated with histopathology, clinical history, and neuroimaging. There was no exclusion criteria.
Results:
Six patients met inclusion criteria (two with germline variants in
NPRL3, and four with mosaic
MTOR,
AKT3, and
PIK3CA variants). One child with a somatic
MTORvariant had medication-resistant epilepsy after hemispherectomy but with a decrease in seizure frequency of ~80% after initiation of everolimus (afinitor). Another patient with clinical hemihypertrophy was diagnosed with a
PIK3CA mosaic variant found on buccal tissue testing and was offered targeted
PIK3CA inhibitor treatment alpelisib (vijoice) for their overgrowth. A third individual with a germline
NPRL3 variant, had epilepsy at birth and subsequent testing identified the variant was inherited from their unaffected mother. The older brother also had the same variant and later developed seizures with bilateral cranial malformations.
Conclusions:
A multi-disciplinary approach to the diagnosis and management of patients with hemimegalencephaly that includes neurology, genetics, neuroradiology, and histopathology with routine brain parenchymal tissue for low level mosaic variants, can facilitate discovery of the underlying etiology of brain malformations, which can lead to novel therapeutic options and accurate genetic risk counseling. Implementation of this type of program provides important guidance in prognostication, surveillance, and therapeutics.
References:
1 Pirozzi F, Berkseth M, Shear R, et al. Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care [published correction appears in Brain. 2023 Jan 5;146(1):e7-e8]. Brain. 2022;145(3):925-938. doi:10.1093/brain/awab376
Funding:
Epilepsy Foundation Greater Los Angeles and the UCLA Children’s Discovery and Innovation Institute.