Precision therapy for a new disorder of AMPA receptor recycling due to mutations in .

TitlePrecision therapy for a new disorder of AMPA receptor recycling due to mutations in .
Publication TypeJournal Article
Year of Publication2017
AuthorsAhrens-Nicklas RC, Umanah GKE, Sondheimer N, Deardorff MA, Wilkens AB, Conlin LK, Santani AB, Nesbitt A, Juulsola J, Ma E, Dawson TM, Dawson VL, Marsh ED
JournalNeurol Genet
Volume3
Issue1
Paginatione130
Date Published2017 Feb
ISSN2376-7839
Abstract

OBJECTIVE: encodes Thorase, a mediator of α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptor recycling; in this work, we characterized the phenotype resulting from mutations and developed a targeted therapy in both mice and humans.

METHODS: Using exome sequencing, we identified a novel mutation (p.E276X) as the etiology of a devastating neurologic disorder characterized by hypertonia, seizures, and death in a consanguineous family. We postulated that pathogenesis was a result of excessive AMPA receptor activity and designed a targeted therapeutic approach using perampanel, an AMPA-receptor antagonist.

RESULTS: Perampanel therapy in knockout mice reversed behavioral defects, normalized brain MRI abnormalities, prevented seizures, and prolonged survival. The patients treated with perampanel showed improvement in hypertonicity and resolution of seizures.

CONCLUSIONS: This work demonstrates that identification of novel monogenic neurologic disorders and observation of response to targeted therapeutics can provide important insights into human nervous system functioning.

DOI10.1212/NXG.0000000000000130
Alternate JournalNeurol Genet
PubMed ID28180185
PubMed Central IDPMC5289017
Grant ListR01 NS082761 / NS / NINDS NIH HHS / United States
R37 NS067525 / NS / NINDS NIH HHS / United States

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