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Phenotypes Associated with This Genotype
Genotype
MGI:3054886
Allelic
Composition
Epm2atm1Kzy/Epm2atm1Kzy
Genetic
Background
involves: 129P2/OlaHsd * C57BL/6J
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Epm2atm1Kzy mutation (1 available); any Epm2a mutation (6 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
behavior/neurological
• at 4 months, homozygotes exhibit a deficit in retention in the passive avoidance task
• mutants exhibit an increase in water intake
• mutants exhibit an increase in food intake compared to controls
• at 4 months, homozygotes display an increased magnitude of acoustic startle reflex in response to a stimulus of standard intensity
• at 9 months, homozygotes are ataxic
• at 9 months, homozygotes display impaired balance
• at 9 months, homozygotes display impaired coordination
• at 9 months, homozygotes display a significantly reduced grip strength relative to wild-type
• at 9 months, homozygotes develop spontaneous myoclonic seizures (~80% penetrance)
• at this age, homozygotes exhibit ear and head spasms and shoulder jerks or minor shaking of the torso
• each episode lasts for a few seconds and comprises of 1-2 jerks
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
• homozygotes do NOT develop grand mal tonic-clonic seizures up until 1 year of age

muscle
• at 9 months, homozygotes develop spontaneous myoclonic seizures (~80% penetrance)
• at this age, homozygotes exhibit ear and head spasms and shoulder jerks or minor shaking of the torso
• each episode lasts for a few seconds and comprises of 1-2 jerks
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
• homozygotes do NOT develop grand mal tonic-clonic seizures up until 1 year of age
• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions
• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes
• at 9 months, homozygotes display reduced neuromuscular strength and endurance force in the dynamometer relative to wild-type

nervous system
• at 9 months, homozygotes develop spontaneous myoclonic seizures (~80% penetrance)
• at this age, homozygotes exhibit ear and head spasms and shoulder jerks or minor shaking of the torso
• each episode lasts for a few seconds and comprises of 1-2 jerks
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
• homozygotes do NOT develop grand mal tonic-clonic seizures up until 1 year of age
• in neurons, mitochondrial, endoplasmic reticulum and Golgi apparatus swelling with lysis of cell membranes results in cell death
• neuronal cell death and Lafora inclusion bodies precede the behavioral deficits, ataxia, and myoclonic epileptiform activity
• at 2 months, hippocampal pyramidal and granular cells, and cerebral cortical pyramidal cells exhibit signs of degeneration, such as dark mitochondria, enlarged cisterni of endoplasmic reticulum, and a collapsed Golgi apparatus
• at 2 months, cerebellar Purkinje cells show signs of degeneration, including a shrunken cytoplasm with enlarged cisterni, abnormally dense mitochondria, lipofuscin granules and an invaginated nucleus
• at 2 months, homozygotes display a few small PAS+ inclusions (Lafora bodies) within neurons throughout the brain (J:76688)
• by 4 months, prominent PAS+ granules are noted in the hippocampus, cerebellum, cerebral cortex, thalamus and brain stem (J:76688)
• in these brain regions, Lafora inclusion bodies are positive for ubiquitin and advanced glycation end-products (AGEP) (J:76688)
• by 9 months, large Lafora inclusions in the neuronal cytoplasm often displace the nucleus and other organelles (J:76688)
• at 9 months, Lafora bodies are also detected in mutant muscle and liver tissues; however, such bodies are not detectable at 4 months, and fail to react with anti-ubiquitin or anti-AGEP antibodies (J:76688)
• mutants treated with insulin exhibit periodic acid-Schiff-positive inclusions in cardiomyocytes, characteristic of polyglucosan depositions or Lafora bodies (J:173769)
• at 2 months, myelinated axons display a disrupted myelin sheath, a watery axoplasm and a central dark body with a granular and a dense component; swollen mitochondria lacking recognizable cristae are obseved
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes

adipose tissue
• mutants exhibit higher adiposity

cardiovascular system
• mutants treated with insulin exhibit periodic acid-Schiff-positive inclusions in cardiomyocytes, characteristic of polyglucosan depositions or Lafora bodies
• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions

growth/size/body
• mutants exhibit higher adiposity
• mutants fed a regular chow diet exhibit an increase in body weight starting at 9 weeks of age

homeostasis/metabolism
• mutants exhibit lower basal levels of blood glucose, with a much larger difference when mice are fasted for 12 hours, however, plasma insulin levels and liver glycogen levels are no different from controls
• increase in plasma cholesterol levels, in both the fed state and after 12 hours of starvation
• increase in plasma levels of non-sterified fatty acids
• increase in plasma triglyceride levels, in both the fed state and after 12 hours of starvation
• mutants exhibit an increase in diurnal energy expenditure; this increase in energy expenditure is not explained by an increase in total spontaneous locomotor activity, which is similar to controls, although diurnal and nocturnal distribution of the ambulation is different
• increase in the enzymes, fatty acid synthase and acetyl-CoA carboxylase
• respiratory exchange rate indicates that during the nocturnal period, mutants and controls use a similar carbohydrate substrate, but during the diurnal phase, mutants show an increase in the respiratory quotient
• mutants exhibit a blunted response to a glucose tolerance test after a 12 hour fast that is not due to increased insulin levels, indicating enhanced glucose disposal
• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes
• in the insulin tolerance test, mutants exhibit an increased insulin response, showing a marked drop in glucose levels that do not reach basal levels even after 2 hours after insulin injection

liver/biliary system
• accumulation of lipid droplets in the liver

cellular
• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions
• in neurons, mitochondrial, endoplasmic reticulum and Golgi apparatus swelling with lysis of cell membranes results in cell death
• neuronal cell death and Lafora inclusion bodies precede the behavioral deficits, ataxia, and myoclonic epileptiform activity

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
Lafora disease DOID:3534 OMIM:254780
J:76688 , J:173769


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last database update
05/14/2019
MGI 6.14
The Jackson Laboratory