Targeted therapy prevents rare neurodevelopmental disorder seizures

By Peter Sergo, medwireNews Reporter

Rapamycin treatment reduces seizure frequency and improves receptive language in patients with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), or Pretzel syndrome, a study finds.

The rare neurodevelopmental disorder, characterized by infantile-onset epilepsy, neurocognitive delay, and craniofacial dysmorphism affects a distinct Mennonite population, known as the Old Order. It is caused by a homozygous deletion in the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1).

The researchers, led by Peter Crino (University of Pennsylvania, Philadelphia, USA) initially showed that rapamycin-induced mTORC1 inhibition could prevent disrupted pathfinding caused by STRADA depletion in migrating mouse neural progenitor cells in vitro.

"As a strategy to initiate therapeutic discovery for the rare disorder PMSE, we used these preclinical signaling and functional assay data as a translational rationale to treat five PMSE patients with the mTOR inhibitor sirolimus," explain the research team in Science Translational Medicine.

Crino and colleagues treated five Mennonite children who were homozygous for the LYK5/STRADA deletion with rapamycin from infancy and followed them during their course of treatment. Patients began rapamycin therapy at a mean age of 4.8 months with the aim of maintaining a blood concentration between 5 and 15 ng/mL.

The children had a mean age of 3 years (0.7 to 4.7 years) at follow up; the youngest remained seizure-free at 8 months of age, while over the last 12 months of follow up only one seizure occurred in one child.

Notably, a patient who was 3 years and 6 months of age and experienced 180 seizures during his worst year was without a single seizure for the past 12 months when treated with rapamycin.

The study patients were also able to take just one or two antiepileptic drugs rather than four or five that PMSE patients would otherwise typically take without rapamycin treatment.

No deaths or severe adverse events that would have required stopping rapamycin treatment occurred within the cohort.

When compared with historical Mennonite PMSE patients who did not receive rapamycin treatment, the treatment cohort exhibited greater provisional development in receptive language and social domains. However, there was no clear treatment effect with regard to expressive language, gross motor function, or adaptive learning.

Crino and colleagues say their findings suggest that mTORC1 inhibition could be an effective treatment for PMSE, as well as other mTOR-associated neurodevelopmental disorders.

"The direct therapeutic implications of our results apply to a small number of patients. However, there is a clear clinical mandate for the development of targeted therapies to treat rare and devastating neurological diseases," conclude the authors.

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