Personalized Diagnosis for Lafora Disease, a Fatal Epilepsy

Abstract

Lafora disease (LD) is a fatal, genetic disorder characterized by progressive neurodegeneration, myoclonus (i.e. uncontrolled muscle spasms), and epilepsy. LD patients present with seizures in adolescence that become increasingly severe and frequent, suffer rapid cognitive decline, and typically die within ten years of onset. Abnormal carbohydrate deposits known as Lafora bodies are found in the brains of LD patients and have been shown to drive disease progression.Approximately 50% of LD cases are caused by mutations in the Epilepsy progressive myoclonus 2A (EPM2A) gene that encodes a protein called laforin. Laforin is the only protein in humans that can release phosphate from carbohydrates. In LD patients, mutations in laforin lead to excess phosphate and abnormal branching in cellular carbohydrate stores, causing carbohydrate accumulation and toxicity. There are >50 different laforin mutations that have been described in LD patients, and some patients have milder forms of the disease. We have shown that not all laforin mutations are the same and that many mutations may have milder effects on protein function. Our biochemical analysis of disease mutations would allow us to predict disease outcome based on a patient's individual genetics.Recently an unusual case of late‐onset LD was described in a patient who lived to the age of 59. This patient contained a novel laforin mutation, where a specific amino acid at position 321 was changed from a phenylalanine to a cysteine (F321C). The objective of this study was to determine the effect of the F321C mutation on laforin function. We generated and purified recombinant laforin F321C, tested its biochemical effects using activity, binding, and stability assays, and found that this mutation and a previously described LD patient mutation, F321S, only mildly alter the function of laforin, providing a biochemical explanation for the very mild clinical phenotype. Our studies also establish a biochemical avenue for rapid, personalized diagnoses of LD patients, enabling doctors to predict patient progression and design treatment schemes that are specific to patients.Support or Funding InformationThis study was supported by NIH Grants F31NS093892 (M.K.B), R01NS070899 and P01NS097197 (M.S.G.), and NSF Grant IIA‐1355438 (M.S.G.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.