Poster Title

Personalized Diagnosis for Lafora Disease, a Fatal Epilepsy

Presenter Information

Jeremiah WayneFollow

Grade Level at Time of Presentation

Junior

Institution

University of Kentucky

KY House District #

11

KY Senate District #

4

Department

Department of Biochemistry

Abstract

Personalized Diagnosis for Lafora Disease, a Fatal Epilepsy

Jeremiah Wayne

Dr. Matthew Gentry

Molecular and Cellular Biochemistry

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 the 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 hypothesized 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). Using the 3-dimensional structure of laforin and a series of biochemical tools, we found that this mutation and a previously described LD patient mutation, F321S, uniquely 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.

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Personalized Diagnosis for Lafora Disease, a Fatal Epilepsy

Personalized Diagnosis for Lafora Disease, a Fatal Epilepsy

Jeremiah Wayne

Dr. Matthew Gentry

Molecular and Cellular Biochemistry

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 the 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 hypothesized 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). Using the 3-dimensional structure of laforin and a series of biochemical tools, we found that this mutation and a previously described LD patient mutation, F321S, uniquely 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.