Phenotypes Associated with This Genotype

Genotype
MGI:2183898

• Allelic Composition: Psap^tm2Suz/Psap^tm2Suz
• Genetic Background: involves: 129S/SvEv * C57BL/6J

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

mortality/aging

premature death ( J:73188 , J:78223 , J:198242 )

• median lifespan of males and virgin females is ~122 days; with pregnancy, females show extended lifespan and improved neurological symptoms (J:73188)

• females experiencing 1 pregnancy have median lifespan of ~158 days, while females experiencing 2 or more consecutive pregnancies live an average of 195 days (J:73188)

• mice only survive up to 5 months; median life span is 122 days (J:78223)

• average lifespan 85 days (J:198242)

nervous system

seizures ( J:78223 )

• some mutants show generalized seizures at ~3 months

CNS inflammation ( J:78223 )

• infiltration of macrophages containing periodic Schiff-positive (PAS) materials (i.e. galactosylceramide) is seen before 1 month of age; by 2 months, macrophage infiltration becomes more conspicuous

abnormal nervous system morphology ( J:73188 , J:78223 )

• males and virgin females at 136 days show greatly thickened peripheral nerves, while pregnant females have nerves that are supple and thin, similar to wild-type mice (J:73188)

• peripheral nerves are abnormally thick (J:78223)

• peripheral nervous system involvement globoid cell leukodystrophy (GLD) pathology is very significant with demyelination and infiltration by globoid-like cells (macrophages containing galactosylceramide) (J:78223)

microgliosis ( J:198242 )

• restricted to selected myelin enriched regions, including the corpus callosum below the cortex, white matter of the cerebellum and the brain stem

abnormal brain white matter morphology ( J:78223 )

• macrophages are widespread in entire white matter, including corpus callosum, internal capsule, pencil fibers in the striatum and brain stem fiber tracts

abnormal brainstem morphology ( J:78223 )

• demyelination is seen in white matter fiber tracts

abnormal cerebellum morphology ( J:78223 )

• demyelination is seen

abnormal Schwann cell morphology ( J:78223 )

• Schwann cells also display needle-shaped inclusions similar to those seen in infiltrating macrophages

• myelin droplets in paranodal Schwann cell cytoplasm is observed in some animals

neurogenic bladder ( J:78223 )

• neurogenic bladder is commonly seen in mutants

abnormal myelin sheath morphology ( J:73188 )

• when mutants are transplanted with pellet releasing estradiol continuously to simulate pregnancy, at 90 days after pellet placement, mutants are indistinguishable from wild-type controls and show no neuropathology like untreated males and virgin females

neuronal intranuclear inclusions ( J:78223 )

• mice show intranuclear inclusions, frequently found in reticular formation, anterior horn, hippocampal CA3 region and cerebellar cortex

abnormal ventral spinal root morphology ( J:78223 )

• anterior spinal root and root exit zone are severely affected by GLD pathology

abnormal spinal cord morphology ( J:78223 )

• demyelination is seen

increased spinal cord size ( J:78223 )

• at ~4-5 months (terminal stage of GLD disease), spinal cord is grossly enlarged with severe demyelination with numerous multinucleated macrophages (globoid-like cells) especially in gracile tract

demyelination ( J:73188 , J:78223 )

• males and virgin females show extensive demyelination with numerous infiltration periodic acid Schiff (PAS)-positive macrophages (globoid cells) but pregnant females and females that had experienced pregnancies had well-preserved myelin sheaths with much less macrophage infiltration in the CNS (J:73188)

• progressive demyelination with macrophage infiltration is observed before 1 month of age in white matter of brain stem fiber tracts, cerebellum, and spinal cord (J:78223)

behavior/neurological

abnormal habituation ( J:198242 )

abnormal involuntary movement ( J:78223 )

• twitching becomes obvious in period just preceding death

impaired coordination ( J:198242 )

• at 8 and 12 weeks, mice exhibit increased foot slips on a 5 mm squared round beam compared with wild-type mice

• at 12 weeks, exhibit increased foot slips on a 11 mm squared round beam compared with wild-type mice

• at 12 week, mice exhibit increased latency to cross the tested beams compared with wild-type mice

• age-dependent increase in foot slips on 12 and 17 mm squared round beams

• mice exhibit more foot slips on a round beam compared with Psap^tm4.1Ggb homozygotes

abnormal gait ( J:73188 , J:78223 )

• male and virgin female mutants show severe gait disturbances at 136 days of age, but female mutants that had experienced pregnancy retained much better motor function, although their walking pattern is flat-footed with a wider base and shorter strides than wild-type mice (J:73188)

short stride length ( J:73188 )

• in females that had been pregnant

decreased locomotor activity ( J:78223 , J:198242 )

• at ~2.5 months, affected mice can be distinguished by reduced activity (J:78223)

• in the periphery at 12 weeks (J:198242)

hyperactivity ( J:78223 , J:198242 )

• some mutants display hyperactivity at ~3 months (J:78223)

• in the central regions at 8 and 12 weeks (J:198242)

hindlimb paralysis ( J:78223 )

• hindlimb paralysis progresses slowly

seizures ( J:78223 )

• some mutants show generalized seizures at ~3 months

muscle

abnormal intestinal peristalsis ( J:78223 )

• ileus is commonly seen

muscular atrophy ( J:78223 )

• hindlimb muscles show severe atrophy, with muscle being replaced with fat at terminal stage

muscle weakness ( J:78223 )

• at ~2.5 months, affected mice can be distinguished by hindlimb weakness

immune system

abnormal macrophage morphology ( J:78223 )

• macrophages are large and multinucleated, clustered around blood vessels, PAS-positive, and contain needle-shaped inclusions

microgliosis ( J:198242 )

• restricted to selected myelin enriched regions, including the corpus callosum below the cortex, white matter of the cerebellum and the brain stem

CNS inflammation ( J:78223 )

• infiltration of macrophages containing periodic Schiff-positive (PAS) materials (i.e. galactosylceramide) is seen before 1 month of age; by 2 months, macrophage infiltration becomes more conspicuous

renal/urinary system

neurogenic bladder ( J:78223 )

• neurogenic bladder is commonly seen in mutants

digestive/alimentary system

abnormal intestinal peristalsis ( J:78223 )

• ileus is commonly seen

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:120657 )

N • similar to wild-type testes, seminolipid level increases rapidly by 12 days, then increases gradually by 17 days; level remains constant from day 17 until terminal stage in mutants

enhanced autophagy ( J:198242 )

• increased autophagy in the brain

abnormal lipid level ( J:73188 , J:78223 , J:120657 )

• brain psychosine levels in mutants are ~2-fold higher than in controls throughout the disease term; levels in pregnant mutants are not different from affected littermate males or virgin females, despite improved neurological symptoms (J:73188)

• mice show a slight increase in brain galactosylceramide and monogalactosyl diglyceride at 30 days compared to wild-type (J:78223)

• 30-day old mice have a significantly higher level of galactosylceramide in the kidney compared to wild-type controls, and levels of 1-alkyl,2-acyl, galactosylglycerol (seminolipid) in testis are increased (J:78223)

• brain levels of psychosine (galactosylsphingosine) are ~2-fold higher than in controls at 2 and 4 months of age (~60 pmol/mg vs ~32 pmol/mg) (J:78223)

• galactosylalkylacylglycerol (GalEAG) levels in the testis continuously increase to 70 days with levels being ~10-fold greater than normal controls (J:120657)

abnormal enzyme/coenzyme activity ( J:78223 )

• galactosylceramidase (GALC) activities in brains of mutants is ~half the level in brains of wild-type

hematopoietic system

abnormal macrophage morphology ( J:78223 )

• macrophages are large and multinucleated, clustered around blood vessels, PAS-positive, and contain needle-shaped inclusions

microgliosis ( J:198242 )

• restricted to selected myelin enriched regions, including the corpus callosum below the cortex, white matter of the cerebellum and the brain stem

cellular

enhanced autophagy ( J:198242 )

• increased autophagy in the brain

liver/biliary system

abnormal liver morphology ( J:198242 )

• engorged storage macrophages in the liver

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Krabbe disease		DOID:10587	OMIM:245200	J:78223