摘要：SummaryLafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in eitherEPM2A,encoding the glycogen phosphatase laforin, orEPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed manyEPM2Avariants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutationsin vitrousing complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identifiedEPM2Amutations, providing clinicians and researchers genetic information to guide treatment of LD patients.Graphical abstractDisplay OmittedHighlights•Lafora disease (LD) patients present with varying clinical progression•LD missense mutations differentially affect laforin function•An empiricalin vitropipeline is used to classify laforin missense mutations•Patient progression can be predicted based on mutation classDisease; Biochemistry; Structural biology; Biophysics
