UC San Diego

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 patients 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 doesnt 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 patients 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.