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Treatment of Refractory Epilepsy With MEK Inhibitor in Patients With RASopathy.
D'Onofrio, Gianluca; Delrue, Marie-Ange; Lortie, Anne; Marquis, Christopher; Striano, Pasquale; Jaworski, Magdalena; Andelfinger, Gregor; Perreault, Sebastien.
Afiliação
  • D'Onofrio G; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Division of Pediatric Neurology, Department of Neurosciences, CHU Sainte-Justine, Montreal, QC, Canada.
  • Delrue MA; Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
  • Lortie A; Division of Pediatric Neurology, Department of Neurosciences, CHU Sainte-Justine, Montreal, QC, Canada.
  • Marquis C; Department of Pharmacy, CHU Sainte-Justine, Montreal, QC, Canada.
  • Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "Giannina Gaslini", Genoa, Italy.
  • Jaworski M; Department of Pediatrics, Developmental Pediatrics Division, CHU Sainte-Justine.
  • Andelfinger G; Division of Cardiology, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada.
  • Perreault S; Division of Pediatric Neurology, Department of Neurosciences, CHU Sainte-Justine, Montreal, QC, Canada. Electronic address: s.perreault@umontreal.ca.
Pediatr Neurol ; 148: 148-151, 2023 Nov.
Article em En | MEDLINE | ID: mdl-37722300
ABSTRACT

BACKGROUND:

Several specific syndromes within the RASopathies spectrum lead to an increased risk of seizures up to developing refractory epileptic encephalopathy. Management remains symptomatic.

METHODS:

Here we report two patients treated with trametinib, a MEK1-2 inhibitor, as a precision strategy for drug-resistant epilepsy. Patient 1 is a six-year-old girl with cardiofaciocutaneous syndrome (BRAF p.F595L, germline mutation), and Patient 2 is a 14-month-old boy with Schimmelpenning syndrome (KRAS p.G12D, postzygotic somatic mutation). Trametinib was initiated at a dosage of 0.025 mg/kg/day.

RESULTS:

Patient 1 had multiple seizures per day, multifocal motor to bilateral tonic-clonic. Electroencephalography (EEG) showed a dramatic reduction in EEG discharges three months after trametinib onset, while a marked clinical improvement occurred after about five months, at the same dosage, and the girl is currently seizure-free for more than six months. Patient 2 had left cerebral hemiatrophy leading to right focal motor seizures, multiple per week to multiple per day, since the age of three months. On trametinib, he experienced an early benefit, remaining seizure-free for more than three months. However, after six months we observed recurrence of seizures. After 22 months of treatment, trametinib was discontinued because of a suspected drug-induced inflammatory colitis. After discontinuation, we observed a significant clinical and EEG "rebound effect."

CONCLUSIONS:

We provide proof of concept that MEK inhibition is a promising approach for the treatment of patients with refractory epilepsy with selected germline and mosaic RASopathies. Future trials are encouraged to better investigate their potentials and limitations.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Pediatr Neurol Assunto da revista: NEUROLOGIA / PEDIATRIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Pediatr Neurol Assunto da revista: NEUROLOGIA / PEDIATRIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá