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Published on: May 18, 2010
Structural and Functional Brain Abnormalities in Mouse Models of Lafora Disease
Daniel F Burgos1,2, Lorena Cussó3,4,5,6, Gentzane Sánchez-Elexpuru1,2,7
1Laboratory of Neurology, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain.
Abstract:
Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a mice revealed abnormal glucose uptake, although no alterations in Epm2b mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.
Insights
Neuroimaging studies reveal brain abnormalities in mouse models of Lafora disease. These findings in Epm2a and Epm2b mice offer insights into epilepsy mechanisms and potential biomarkers.
Area of Science:
- Neuroscience
- Genetics
- Medical Imaging
Background:
- Lafora disease is a fatal genetic epilepsy caused by mutations in EPM2A (laforin) and EPM2B (malin) genes.
- Patient neuroimaging shows brain atrophy, altered glucose metabolism, and metabolite changes, primarily in the frontal cortex, basal ganglia, and cerebellum.
- Laforin- and malin-deficient mice mimic human Lafora disease features, including cognitive, motor, and epileptic deficits.
Purpose of the Study:
- To characterize the neuroimaging features of two Lafora disease mouse models.
- To compare imaging findings between Epm2a and Epmb mouse models and relate them to human patient data.
- To explore the utility of these models for understanding disease mechanisms and developing biomarkers.
Main Methods:
- Magnetic Resonance Imaging (MRI) for volumetric analysis of brain structures.
- Positron Emission Tomography (PET) to assess glucose uptake in specific brain regions.
- Magnetic Resonance Spectroscopy (MRS) to analyze brain metabolite concentrations.
Main Results:
- MRI revealed altered brain volumes in the cerebral cortex, hippocampus, basal ganglia, and cerebellum in both mouse models.
- PET scans showed abnormal glucose metabolism in the cerebral cortex, hippocampus, and cerebellum of Epm2a mice, but not Epm2b mice.
- MRS detected significant changes in brain metabolites, such as N-acetylaspartate (NAA), consistent with human patient findings.
Conclusions:
- Lafora disease mouse models exhibit distinct neuroimaging abnormalities mirroring human pathology.
- These models provide valuable insights into the pathophysiology of Lafora disease.
- Neuroimaging findings in these animal models may aid in developing diagnostic and therapeutic biomarkers for Lafora disease.
