Multi-disciplinary team approach for pediatric hemimegalencephaly: Insights from a single institutional case series

Benjamin Edmonds; Jacqueline P Ngo; Aran Groves; Beck Reyes; Rolanda A Gott; Dennis J Chia; Hilda Mirbaha; Shino Magaki; Negar Khanlou; Stacy L Pineles; Noriko Salamon; Rachel M Thompson; Maya Newman; Rajsekar R Rajaraman; Shaun A Hussain; Aria Fallah; Bianca Russell; Hiroki Nariai

doi:10.1002/epi4.13079

Multi-disciplinary team approach for pediatric hemimegalencephaly: Insights from a single institutional case series

Epilepsia Open. 2024 Oct 23. doi: 10.1002/epi4.13079. Online ahead of print.

Authors

Benjamin Edmonds¹, Jacqueline P Ngo², Aran Groves², Beck Reyes², Rolanda A Gott³, Dennis J Chia⁴, Hilda Mirbaha⁵, Shino Magaki⁵, Negar Khanlou⁵, Stacy L Pineles⁶, Noriko Salamon⁷, Rachel M Thompson⁸, Maya Newman⁹, Rajsekar R Rajaraman², Shaun A Hussain², Aria Fallah¹⁰, Bianca Russell¹¹, Hiroki Nariai^{2

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Affiliations

¹ Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, Washington, USA.
² Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
³ Division of Developmental Pediatrics, Department of Pediatrics, David Geffen School of Medicine, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
⁴ Division of Pediatric Endocrinology, Department of Pediatrics, David Geffen School of Medicine, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
⁵ Division of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA Medical Center, Los Angeles, California, USA.
⁶ Department of Ophthalmology, David Geffen School of Medicine, UCLA Medical Center, Los Angeles, California, USA.
⁷ Department of Radiological Sciences, University of California Los Angeles, Los Angeles, California, USA.
⁸ Department of Orthopedics, University of California Los Angeles, Los Angeles, California, USA.
⁹ Division of Pediatric Physical Medicine and Rehabilitation, University of California Los Angeles, Los Angeles, California, USA.
¹⁰ Department of Neurosurgery, David Geffen School of Medicine, UCLA Medical Center, Los Angeles, California, USA.
¹¹ Division of Clinical Genetics, Department of Human Genetics, David Geffen School of Medicine, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
¹² The UCLA Children's Discovery and Innovation Institute, Los Angeles, California, USA.

PMID: 39442533
DOI: 10.1002/epi4.13079

Abstract

Recent genetic studies have revealed that hemimegalencephaly (HME) is a multi-system disorder associated with germline or mosaic variants within the PI3K-mTOR-GATOR1 signaling pathways. Patients with HME typically develop drug-resistant epilepsy necessitating extensive evaluation, hemispherectomy, and long-term management. We describe the role of a multidisciplinary team (MDT) for the diagnosis and management of recent patients with HME at UCLA who underwent hemispherectomy. Genetic evaluation identified nine patients with the following variants: NPRL3 x2 germline, PIK3CA mosaicism x4, MTOR mosaicism x1, AKT3 mosaicism x1, unknown x1. Each patient's MDT comprised 4-9 specialties. One child with a MTOR variant had persistent epilepsy after hemispherectomy, but addition of everolimus resulted in an 80% decrease in seizure frequency. Another child with hemihypertrophy and PIK3CA mosaic variant was offered targeted PIK3CA inhibitor treatment, alpelisib, for overgrowth. A third child with germline NPRL3 variant inherited from their unaffected mother resulted in a sibling being diagnosed with the variant who later developed seizures secondary to focal cortical dysplasia. The implementation of a MDT offers essential guidance for families affected by HME, encompassing prognostication, surveillance, and therapeutic strategies. Identifying the etiology of HME can facilitate the development of targeted treatments and enable timely genetic counseling. PLAIN LANGUAGE SUMMARY: Hemimegalencephaly (HME) is a complex brain disorder caused by genetic changes. It often leads to severe epilepsy that doesn't respond to standard treatments and frequently requires surgery. In this case series, nine patients with HME were identified and found to have genetic mutations in key growth-regulating genes. A multidisciplinary team model was developed to facilitate patients' care. For example, one patient's seizures improved with surgery, another with a new targeted medication, and another received treatment for symptoms of overgrowth. This team approach provides comprehensive care for patients and can lead to efficient care coordination and implementation of novel therapies.

Keywords: MTOR; epilepsy; genetics; hemimegalencephaly (HME); multidisciplinary.

Grants and funding

K23NS128318/NH/NIH HHS/United States