Phenotypes Associated with This Genotype

Genotype
MGI:3054886

• Allelic Composition: Epm2a^tm1Kzy/Epm2a^tm1Kzy
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

abnormal passive avoidance behavior ( J:76688 )

• at 4 months, homozygotes exhibit a deficit in retention in the passive avoidance task

increased fluid intake ( J:173769 )

• mutants exhibit an increase in water intake

polyphagia ( J:173769 )

• mutants exhibit an increase in food intake compared to controls

increased startle reflex ( J:76688 )

• at 4 months, homozygotes display an increased magnitude of acoustic startle reflex in response to a stimulus of standard intensity

ataxia ( J:76688 )

• at 9 months, homozygotes are ataxic

impaired balance ( J:76688 )

• at 9 months, homozygotes display impaired balance

impaired coordination ( J:76688 )

• at 9 months, homozygotes display impaired coordination

decreased grip strength ( J:76688 )

• at 9 months, homozygotes display a significantly reduced grip strength relative to wild-type

myoclonus ( J:76688 )

• 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

myoclonus ( J:76688 )

• 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

increased cardiac muscle glycogen level ( J:173769 )

• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes

increased cardiac muscle cell glucose uptake ( J:173769 )

• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions

muscle weakness ( J:76688 )

• at 9 months, homozygotes display reduced neuromuscular strength and endurance force in the dynamometer relative to wild-type

nervous system

myoclonus ( J:76688 )

• 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

increased neuron apoptosis ( J:76688 )

• 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

hippocampal neuron degeneration ( J:76688 )

• 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

Purkinje cell degeneration ( J:76688 )

• 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

Lafora bodies ( J:76688 , J:173769 )

• 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)

axon degeneration ( J:76688 )

• 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

abnormal brain wave pattern ( J:76688 )

• 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

increased body fat mass ( J:173769 )

• mutants exhibit higher adiposity

cardiovascular system

increased cardiac muscle glycogen level ( J:173769 )

• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes

abnormal heart morphology ( J:173769 )

• mutants treated with insulin exhibit periodic acid-Schiff-positive inclusions in cardiomyocytes, characteristic of polyglucosan depositions or Lafora bodies

increased cardiac muscle cell glucose uptake ( J:173769 )

• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions

growth/size/body

increased body fat mass ( J:173769 )

• mutants exhibit higher adiposity

increased body weight ( J:173769 )

• mutants fed a regular chow diet exhibit an increase in body weight starting at 9 weeks of age

homeostasis/metabolism

increased cardiac muscle glycogen level ( J:173769 )

• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes

hypoglycemia ( J:173769 )

• 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

increased circulating ketone body level ( J:173769 )

increased circulating cholesterol level ( J:173769 )

• increase in plasma cholesterol levels, in both the fed state and after 12 hours of starvation

increased circulating free fatty acids level ( J:173769 )

• increase in plasma levels of non-sterified fatty acids

increased circulating triglyceride level ( J:173769 )

• increase in plasma triglyceride levels, in both the fed state and after 12 hours of starvation

increased energy expenditure ( J:173769 )

• 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

abnormal enzyme/coenzyme level ( J:173769 )

• increase in the enzymes, fatty acid synthase and acetyl-CoA carboxylase

increased oxygen consumption ( J:173769 )

increased respiratory quotient ( J:173769 )

• 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

improved glucose tolerance ( J:173769 )

• 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

increased insulin sensitivity ( J:173769 )

• 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

increased liver cholesterol level ( J:173769 )

increased liver triglyceride level ( J:173769 )

liver/biliary system

increased liver cholesterol level ( J:173769 )

increased liver triglyceride level ( J:173769 )

hepatic steatosis ( J:173769 )

• accumulation of lipid droplets in the liver

cellular

increased cardiac muscle cell glucose uptake ( J:173769 )

• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions

increased neuron apoptosis ( J:76688 )

• 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