Phenotypes associated with this allele

• Allele Symbol: Galc^twi
• Allele Name: twitcher
• Allele ID: MGI:1856218
• Summary: 13 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Galc^twi/Galc^twi	B6.CE-Galc^twi/J	MGI:3581125
hm2	Galc^twi/Galc^twi	involves: 129P2/OlaHsd * C57BL/6J * CE/J	MGI:4452614
hm3	Galc^twi/Galc^twi	involves: C57BL/6J * CAST/EiJ * CE/J	MGI:4452478
hm4	Galc^twi/Galc^twi	involves: C57BL/6J * CE/J	MGI:4361523
hm5	Galc^twi/Galc^twi	involves: CE/J	MGI:4452257
ht6	Galc^twi/Galc^twi-3J	involves: C57BL/6J * CE/J	MGI:5285218
cx7	Galc^twi/Galc^twi Ptgdr^tm1Sna/Ptgdr^tm1Sna	B6.Cg-Galc^twi Ptgdr^tm1Sna	MGI:3624280
cx8	Galc^twi/Galc^twi Hpgds^tm1Urad/Hpgds^tm1Urad	B6.Cg-Hpgds^tm1Urad Galc^twi	MGI:3624279
cx9	Galc^twi/Galc^twi Glb1^tm1Adz/Glb1^tm1Adz	involves: 129P2/OlaHsd * C57BL/6J * CE/J	MGI:4452612
cx10	Galc^twi/Galc^twi Glb1^tm1Adz/Glb1^+	involves: 129P2/OlaHsd * C57BL/6J * CE/J	MGI:4452613
cx11	Galc^twi/Galc^twi Il6^tm1Kopf/Il6^tm1Kopf	involves: 129S2/SvPas * C57BL/6J * CE/J	MGI:4452118
cx12	Galc^twi/Galc^twi Il6^+/?	involves: 129S2/SvPas * C57BL/6J * CE/J	MGI:4452147
cx13	Csf1^op/Csf1^op Galc^twi/Galc^twi	involves: C3HeB/Fe * C57BL/6J * CE/J	MGI:5003115

Genotype
MGI:3581125

hm1

• Allelic Composition: Galc^twi/Galc^twi
• Genetic Background: B6.CE-Galc^twi/J

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

mortality/aging

premature death ( J:108359 , J:126892 , J:170081 )

• Background Sensitivity: lifespan of mutants is 45.5 days; death is result of peripheral and cranial nerve palsy (J:108359)

• Background Sensitivity: the average lifespan of homozygotes in this study is 37 days (J:126892)

• median survival is 51 days (J:170081)

homeostasis/metabolism

decreased circulating insulin-like growth factor I level ( J:165361 )

• IGF-1 plasma levels are reduced by 37.6%

abnormal lipid level ( J:165361 )

• galactosylsphingosine accumulation, with 14 fold higher levels than in wild-type, in the long bones

abnormal sphingomyelin level ( J:165361 )

• increase in total sphingomyelin in femurs, and in most of the sphingomyelin and ceramide containing saturated-unsaturated fatty acids

abnormal enzyme/coenzyme activity ( J:108359 )

• levels of Ptgds2 activity are 3-fold higher in the cerebrum and 5-fold higher in the cerebellum of mutants compared to wild-type

behavior/neurological

impaired righting response ( J:108359 )

• mutants have poorer righting response compared to wild-type or Ptgds2/Galc double mutants

tremors ( J:108359 , J:126892 )

• mutants barely stagger with strong intentional tremor (J:108359)

• Background Sensitivity: mean age of onset 21 days (J:126892)

ataxia ( J:108359 )

abnormal gait ( J:126892 )

• Background Sensitivity: wobbly gait appears at approximately 28-30 days of age

paresis ( J:170081 )

• moribund mice develop spastic paresis

paraparesis ( J:126892 )

nervous system

abnormal microglial cell morphology ( J:108359 )

• microglia in mutant brains have increased levels of Ptgds2 protein and have irregular thick processes in the region of demyelination

abnormal brain morphology ( J:126892 )

• Background Sensitivity: lectin-positive macrophages are found in the cerebellum, pons, and medulla more severely on this genetic background than when outcrossed to CAST/EiJ

increased oligodendrocyte progenitor number ( J:170081 )

• mutants exhibit an increase in oligodendrocyte progenitor cell (OPC) population compared to wild-type

abnormal forebrain morphology ( J:170081 )

• levels of psychosine are increased in the forebrain while levels of free sphingosine are lower compared to wild-type mice

abnormal hindbrain morphology ( J:126892 )

• dramatically increased concentration of psychosine in the pons/medulla which is not impacted by genetic background

abnormal astrocyte morphology ( J:108359 , J:126892 )

• there are hypertrophied astrocytes with large soma and thick-branched processes in mutant brains (J:108359)

• Background Sensitivity: increased GFAP staining astrocytes are found in the cerebellar granular layer and pons (J:126892)

astrocytosis ( J:170081 )

• white matter exhibits similar reactive astrocytosis as double Galc^twi Csf1^op mice

abnormal oligodendrocyte morphology ( J:170081 )

• oligodendrocyte progenitor cells become hypertrophic and have short and stout processes instead of well branched fine processes as in wild-type mice

decreased oligodendrocyte number ( J:170081 )

• mutants exhibit a moderate decrease in oligodendrocytes

abnormal sciatic nerve morphology ( J:126892 )

• sciatic nerves are swollen and demyelination and myelin debris is found in moribund homozygotes

demyelination ( J:108359 , J:126892 , J:170081 )

• 39 day-old mutant brains exhibit demyelination; demyelination appears to be restricted to the CNS (J:108359)

• Background Sensitivity: extensive demyelination is found in the cerebellar white matter at the moribund stage on this genetic background (J:126892)

• myelin degeneration in the white matter, with a preferential loss of myelin in large diameter axons (J:170081)

• sciatic nerves are severely demyelinated (J:170081)

• however, development (wrapping) of myelin from P15 to P30 is not affected (J:170081)

hematopoietic system

abnormal microglial cell morphology ( J:108359 )

• microglia in mutant brains have increased levels of Ptgds2 protein and have irregular thick processes in the region of demyelination

abnormal osteoclast physiology ( J:165361 )

• enhanced osteoclast activity

immune system

abnormal microglial cell morphology ( J:108359 )

• microglia in mutant brains have increased levels of Ptgds2 protein and have irregular thick processes in the region of demyelination

abnormal osteoclast physiology ( J:165361 )

• enhanced osteoclast activity

growth/size/body

decreased body weight ( J:165361 )

• body weight is reduced starting at P20

weight loss ( J:170081 )

• mutants start to lose weight after P35

limbs/digits/tail

decreased femur size ( J:165361 )

• femurs are smaller

decreased femur weight ( J:165361 )

• femurs weigh 27% less than wild-type at 32-33 days of age

skeleton

decreased femur size ( J:165361 )

• femurs are smaller

decreased femur weight ( J:165361 )

• femurs weigh 27% less than wild-type at 32-33 days of age

abnormal long bone metaphysis morphology ( J:165361 )

• metaphyseal region of femurs show structural differences, with reduced trabecular bone mainly in the secondary spongiosa

decreased bone mineral density ( J:165361 )

• mice exhibit features of osteopenia

decreased compact bone thickness ( J:165361 )

• decrease in cortical bone thickness in femurs

decreased bone trabecula number ( J:165361 )

• decrease in the number of trabeculae in femurs

abnormal skeleton development ( J:165361 )

• growth of long bones is retarded

abnormal bone remodeling ( J:165361 )

• reduction of bone deposition in the metaphyseal and epiphyseal region of femurs, but no differences in mineral apposition rate

abnormal osteoclast physiology ( J:165361 )

• enhanced osteoclast activity

muscle

muscle twitch ( J:170081 )

• mutants develop fine twitching in the neck around P20

cellular

increased oligodendrocyte progenitor number ( J:170081 )

• mutants exhibit an increase in oligodendrocyte progenitor cell (OPC) population compared to wild-type

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Krabbe disease		DOID:10587	OMIM:245200	J:6390 , J:6423 , J:165361 , J:170081

Genotype
MGI:4452614

hm2

• Allelic Composition: Galc^twi/Galc^twi
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * CE/J

mortality/aging

premature death ( J:63197 )

• Background Sensitivity: average lifespan 48 days of age with nearly all dead before 58 days of age

Genotype
MGI:4452478

hm3

• Allelic Composition: Galc^twi/Galc^twi
• Genetic Background: involves: C57BL/6J * CAST/EiJ * CE/J

mortality/aging

premature death ( J:126892 )

• Background Sensitivity: average lifespan is 61.4 days on this mixed genetic background, longer than on the congenic C57BL/6J background, and there is much wider variation in the life span of individuals, which ranges from 45 to 77 days

behavior/neurological

tremors ( J:126892 )

• Background Sensitivity: mean age of tremor onset is 24 days which is delayed when compared with homozygotes on a congenic C57BL/6J background, which have a mean age of onset of 21 days

abnormal gait ( J:126892 )

• Background Sensitivity: wobbly gait does not develop until 30 days of age or beyond which is delayed compared with the congenic C57BL/6J background on which a wobbly gait appears at approximately 28-30 days of age

paraparesis ( J:126892 )

• Background Sensitivity: the longer lived homozygotes display more severe wasting of the hindlimbs when at moribund conditions than do those on a C57BL/6J congenic background

nervous system

abnormal brain morphology ( J:126892 )

• lectin-positive macrophages are found in the cerebellum, pons, and medulla in the moribund stage, although to a lesser degree than in homozygotes on a C57BL/6J congenic background

abnormal hindbrain morphology ( J:126892 )

• on both this mixed genetic background and on the congenic C57BL/6J background the concentration of psychosine in the pons/medulla is dramatically higher than normal and the level of increase is not impacted by genetic background

abnormal medulla oblongata morphology ( J:126892 )

abnormal pons morphology ( J:126892 )

abnormal astrocyte morphology ( J:126892 )

• Background Sensitivity: increased GFAP staining astrocytes are found in the cerebellar granular layer to a greater degree on this mixed genetic background than homozygotes on the congenic C57BL/6J background, and increased GFAP staining of astrocytes is found in the pons but to a lesser degree on this mixed genetic background than in homozygotes on the congenic C57BL/6J background

abnormal sciatic nerve morphology ( J:126892 )

• Background Sensitivity: sciatic nerves from longer-lived homozygotes on this mixed genetic background show a greater degree of swelling than those on the congenic C57BL/6J background, loss of discrete fasicules, increased cellularity of lipid-filled cells, and demyelination

axonal spheroids ( J:126892 )

• Background Sensitivity: found in the axonal plexus of the granular layer and the cerebellar white matter, but generally not seen in the moribund homozygotes on the C57BL/6J congenic background which die at an earlier age

demyelination ( J:126892 )

• Background Sensitivity: focal areas of demyelination are found in the cerebellar white matter at the moribund stage, but this is less severe than the extensive demyelination of the cerebellar white matter found in homozygotes on a C57BL/6J congenic background at the moribund stage

Genotype
MGI:4361523

hm4

• Allelic Composition: Galc^twi/Galc^twi
• Genetic Background: involves: C57BL/6J * CE/J

mortality/aging

premature death ( J:6390 )

• affected mice live only about 3 months

behavior/neurological

tremors ( J:6390 )

growth/size/body

cachexia ( J:6390 )

hematopoietic system

abnormal macrophage morphology ( J:6390 )

• multinucleated macrophages contain a variety of abnormal inclusions

immune system

abnormal macrophage morphology ( J:6390 )

• multinucleated macrophages contain a variety of abnormal inclusions

muscle

progressive muscle weakness ( J:6390 )

nervous system

abnormal myelin sheath morphology ( J:6390 )

• degeneration in both central and peripheral nervous systems

Genotype
MGI:4452257

hm5

• Allelic Composition: Galc^twi/Galc^twi
• Genetic Background: involves: CE/J

behavior/neurological

tremors ( J:13867 )

• clinically evident between 15 and 20 days of age, beginning as a fine tremor

• involves the whole body

impaired limb coordination ( J:13867 )

• particularly the hindlimbs

hindlimb paralysis ( J:13867 )

• evident by terminal stages of the disease

immune system

CNS inflammation ( J:78223 )

• mice show greater macrophage infiltration than Psap^tm1Suz mice

nervous system

abnormal brain white matter morphology ( J:13867 )

• demonstrated by light and electron microscopic investigations

abnormal oligodendrocyte morphology ( J:57215 )

• at 15 days of age the only difference found in the cerebral cortex and corpus callosum is rare cells with focal swelling of the cell soma, but by 20 days of age the oligodendrocytes, identified as expressing glutathione S-transferase pi, display irregular, often polygonal swelling of the cell soma, with or without unstained vacuoles, and with thicker processes and some focal swelling, and after 25 days of age the oligodendrocyte cellular processes and soma become progressively shrunken with only markedly shrunken soma, which lack identifiable processes

decreased oligodendrocyte number ( J:57215 )

• there is gradual decrease in oligodendrocyte number after 35 days of age and very few remain in the cortical layers at 45 days of age

abnormal spinal cord white matter morphology ( J:13867 )

• demonstrated by light and electron microscopic investigations

axon degeneration ( J:13867 )

• some degeneration is evident by light and electron microscopic investigations

peripheral nervous system degeneration ( J:13867 )

• both motor and sensory nerves are involved

abnormal nervous system physiology ( J:7115 )

• this mutation is the first spontaneous model for endoneurial edema and increased endoneurial fluid pressure

abnormal glial cell apoptosis ( J:57215 )

• at 40 days of age 10% of oligodendrocytes stain TUNEL positive and there is a correspondence between TUNEL staining and stage of demyelination with the oligodendrocytes with cytoplasmic swelling or thick cellular processes still negative for TUNEL stain and oligodendrocytes with thin or shrunken processes and relatively small soma positive for TUNEL stain

CNS inflammation ( J:78223 )

• mice show greater macrophage infiltration than Psap^tm1Suz mice

demyelination ( J:13867 , J:78223 )

• mice show more severe demyelination than do homozygous Psap^tm1Suz mice (J:78223)

growth/size/body

decreased body size ( J:13867 )

• mutant mice are smaller than normal siblings especially noticeable between 15 and 20 days of age

cellular

abnormal glial cell apoptosis ( J:57215 )

• at 40 days of age 10% of oligodendrocytes stain TUNEL positive and there is a correspondence between TUNEL staining and stage of demyelination with the oligodendrocytes with cytoplasmic swelling or thick cellular processes still negative for TUNEL stain and oligodendrocytes with thin or shrunken processes and relatively small soma positive for TUNEL stain

homeostasis/metabolism

edema ( J:7115 )

• endoneurial edema contributing to increased endoneurial fluid pressure

abnormal lipid level ( J:78223 )

• 45-day old mice have a much greater accumulation of galactosylceramide in kidney is greater than in 4-month old Psap-deficient mice

• at 40 days, brain levels of psychosine (galactosylsphingosine) are much higher than in wild-type controls or Psap-deficient mice (223 pmol/mg vs 60 or 32 pmol/mg)

abnormal protein level ( J:7311 )

• 50 times the normal amount of galactosylceramide is found in the kidneys of homozygous mice at 42 days of age with less significant increases in liver and lung

• no abnormal increases of galactosylceramide or sulfatide are noted in the spinal cord or sciatic nerve at any age

renal/urinary system

renal/urinary system phenotype ( J:7313 )

N • light microscopy reveals no abnormalities in kidneys of 5 to 45 day old homozygous mice

abnormal kidney morphology ( J:7313 )

• light microscopy reveals no abnormalities in kidneys of 5 to 45 day old homozygous mice

• ultrastructural analysis shows increasing amounts of epithelial cell inclusions as mutant mice age

abnormal kidney development ( J:7313 )

• cytoplasmic inclusions are found in the thin limbs of the loop of Henle in developing papillae of 5 day old mice

abnormal kidney epithelium morphology ( J:7313 )

• ultrastructural analysis reveals an increasing amount of cytoplasmic inclusions as mice age

• inclusions are restricted to the thin limbs of the loop of Henle but occasionally are seen in the lumen of thta structure

abnormal kidney physiology ( J:7311 )

• demonstrated by the occurrence of cytoplsmic inclusions in kidney tissue

Genotype
MGI:5285218

ht6

• Allelic Composition: Galc^twi/Galc^twi-3J
• Genetic Background: involves: C57BL/6J * CE/J

behavior/neurological

tremors ( J:30778 )

growth/size/body

decreased body size ( J:30778 )

Genotype
MGI:3624280

cx7

• Allelic Composition: Galc^twi/Galc^twi; Ptgdr^tm1Sna/Ptgdr^tm1Sna
• Genetic Background: B6.Cg-Galc^twi Ptgdr^tm1Sna

mortality/aging

premature death ( J:108359 )

• lifespan of mutants is 46.2 days

behavior/neurological

ataxia ( J:108359 )

• milder than in Galc^twi single mutants

nervous system

abnormal astrocyte morphology ( J:108359 )

• astrocyte processes are much thinner than in Galc^twi single mutants

Genotype
MGI:3624279

cx8

• Allelic Composition: Galc^twi/Galc^twi; Hpgds^tm1Urad/Hpgds^tm1Urad
• Genetic Background: B6.Cg-Hpgds^tm1Urad Galc^twi

mortality/aging

premature death ( J:108359 )

• lifespan of mutants is 47.3 days

cellular

decreased apoptosis ( J:108359 )

• fewer apoptotic oligodendrocytes are detected in double mutants compared to Galc^twi single mutants

behavior/neurological

ataxia ( J:108359 )

• milder than in Galc^twi single mutants

nervous system

abnormal astrocyte morphology ( J:108359 )

• astrocyte processes are much thinner than in Galc^twi single mutants

Genotype
MGI:4452612

cx9

• Allelic Composition: Galc^twi/Galc^twi; Glb1^tm1Adz/Glb1^tm1Adz
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * CE/J

mortality/aging

premature death ( J:63197 )

• average lifespan is 74.3 days with some surviving up to 94 days, a significant extension of longevity compared with mice homozygous for twitcher only

hematopoietic system

enlarged spleen ( J:63197 )

• macrophage infiltration in the lymph follicles of the spleen at 94 days of age

abnormal macrophage physiology ( J:63197 )

immune system

enlarged spleen ( J:63197 )

• macrophage infiltration in the lymph follicles of the spleen at 94 days of age

abnormal macrophage physiology ( J:63197 )

liver/biliary system

abnormal liver morphology ( J:63197 )

• at 94 days of age macrophage-filled sinusoids compress the hapatocytes and the hepatic architecture is disrupted

enlarged liver ( J:63197 )

renal/urinary system

abnormal renal glomerular capsule morphology ( J:63197 )

• finely vacuolated cells, which stain PAS-negative, are found within the Bowman capsule in the glomeruli

abnormal renal tubule epithelium morphology ( J:63197 )

• renal tubular epithelium is diffusely vacuolated

nervous system

demyelination ( J:63197 )

• unlike mice homozygous for only the twitcher mutation, the central nervous system shows normal myelination with rare infiltration of globoid cells at 35-40 days of age but progressively more common at 77 and 94 days of age and the sciatic nerve pathology at 94 days of age is similar to that of 35 to 40 day old twitcher controls

• although the central nervous system maintains myelination, the peripheral nervous system shows distinct demyelination

homeostasis/metabolism

abnormal lipid level ( J:63197 )

• massive lactosylceramide accumulation in brain, kidney, and liver due to a block in lactosylceramide degradation, a reduction to 50-60% of normal levles of galactosylceramide in the kidney and brain, and drastic reduction of brain psychosine levels

growth/size/body

enlarged liver ( J:63197 )

enlarged spleen ( J:63197 )

• macrophage infiltration in the lymph follicles of the spleen at 94 days of age

Genotype
MGI:4452613

cx10

• Allelic Composition: Galc^twi/Galc^twi; Glb1^tm1Adz/Glb1⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * CE/J

mortality/aging

premature death ( J:63197 )

• average lifespan is 37.7 days and nearly all die before 46 days of age

behavior/neurological

induced hyperactivity ( J:63197 )

• between 30 and 35 days of age mice are extremely hyper-responsive in response to touching the cage or lifting the lid

seizures ( J:63197 )

• between 30 and 35 days of age the hyper-reactivity can include generalized seizures

nervous system

seizures ( J:63197 )

• between 30 and 35 days of age the hyper-reactivity can include generalized seizures

neurodegeneration ( J:63197 )

• at 27 days of age many dying neurons with deeply eosinophilic cytoplasm and pyknotic nuclei are present diffusely in the cerebral cortex where activated astrocytes and microglia/macrophages are found

• neuronal degeneration of the hippocampus is most pronounced in CA3 and the subiculum and scattered necrotic cells are also found in the hypothalamus, amygdala, caudate/putamen and lateral septal nuclei

• cerebral cortex and to a lesser extent the white matter have activated astrocytes and microglia/macrophages with many dying cells present

demyelination ( J:63197 )

immune system

immune system phenotype ( J:63197 )

N • spleen is free of pathology

liver/biliary system

liver/biliary system phenotype ( J:63197 )

N • liver is free of pathology

homeostasis/metabolism

abnormal lipid level ( J:63197 )

• at 30 and 40 days of age psychosine is significantly elevated in the brain

Genotype
MGI:4452118

cx11

• Allelic Composition: Galc^twi/Galc^twi; Il6^tm1Kopf/Il6^tm1Kopf
• Genetic Background: involves: 129S2/SvPas * C57BL/6J * CE/J

behavior/neurological

tremors ( J:56656 )

• the average onset of twitching is earlier in double homozygotes than mice homozygous only for twitcher (22.2 days of age versus 25.9 days of age respectively), although lifespan, body weight and frequency of twitching do not differ significantly

nervous system

abnormal blood-brain barrier function ( J:56656 )

• leakage of the blood-brain barrier is detected in the cerebrum, hindbrain, and cervical spinal cord as detected by horseradish peroxidase tail vein injection, and immunoglobulin and albumin immunohistochemistry

• lipopolysaccharide injection greatly enhances the blood-brain barrier disruption leading to death

abnormal cerebellum white matter morphology ( J:56656 )

• the deep cerebellar white matter shows a significant increase in periodic acid-Schiff staining cells and a trend toward increased lectin-positive cells relative to mice homozygous only for twitcher

gliosis ( J:56656 )

• more exaggerated gliosis is found around some vessels and pial surfaces in the double mutants than in mice homozygous only for twitcher

cardiovascular system

abnormal blood-brain barrier function ( J:56656 )

• leakage of the blood-brain barrier is detected in the cerebrum, hindbrain, and cervical spinal cord as detected by horseradish peroxidase tail vein injection, and immunoglobulin and albumin immunohistochemistry

• lipopolysaccharide injection greatly enhances the blood-brain barrier disruption leading to death

homeostasis/metabolism

abnormal tumor necrosis factor level ( J:56656 )

• hindbrain has TNF levels elevated above that found in mice homozygous only for twitcher and mice homozygous only for twitcher have significantly elevated TNF levels in hindbrain

immune system

abnormal tumor necrosis factor level ( J:56656 )

• hindbrain has TNF levels elevated above that found in mice homozygous only for twitcher and mice homozygous only for twitcher have significantly elevated TNF levels in hindbrain

Genotype
MGI:4452147

cx12

• Allelic Composition: Galc^twi/Galc^twi; Il6⁺/?
• Genetic Background: involves: 129S2/SvPas * C57BL/6J * CE/J

mortality/aging

premature death ( J:56656 )

• Background Sensitivity: average lifespan is 39.29 days

cardiovascular system

abnormal blood-brain barrier function ( J:56656 )

• modest disruption of the blood-brain barrier detected by immunohistochemical detection of IgG or albumin

• lipopolysaccharide injection results in increased blood-brain barrier disruption and further shortens lifespan

homeostasis/metabolism

abnormal tumor necrosis factor level ( J:56656 )

• hindbrain has elevated TNF levels (9.38 pg/mg versus 6.54 pg/mg)

immune system

abnormal tumor necrosis factor level ( J:56656 )

• hindbrain has elevated TNF levels (9.38 pg/mg versus 6.54 pg/mg)

nervous system

abnormal blood-brain barrier function ( J:56656 )

• modest disruption of the blood-brain barrier detected by immunohistochemical detection of IgG or albumin

• lipopolysaccharide injection results in increased blood-brain barrier disruption and further shortens lifespan

abnormal cerebellum white matter morphology ( J:56656 )

• the deep cerebellar white matter has periodic acid-Schiff staining globoid cells and lectin-positive macrophages

gliosis ( J:56656 )

• severe gliosis in both gray and white matter regions

demyelination ( J:56656 )

• most severe in the hindbrain/cervical spinal cord

behavior/neurological

tremors ( J:56656 )

• the average onset of twitching is 25.85 days

Genotype
MGI:5003115

cx13

• Allelic Composition: Csf1^op/Csf1^op; Galc^twi/Galc^twi
• Genetic Background: involves: C3HeB/Fe * C57BL/6J * CE/J

mortality/aging

premature death ( J:170081 )

• mutants have a shorter lifespan than single homozygous Galc^twi mice, with a more exacerbated neurological phenotype

behavior/neurological

tremors ( J:170081 )

• mutants develop fine twitching in the neck around P18, 2-3 days earlier than Galc^twi mice, and shortly after develop a coarse tremor that gradually spreads from the neck to the trunk

hindlimb paralysis ( J:170081 )

• moribund mice are paralyzed in the hindlimbs

craniofacial

absent incisors ( J:170081 )

domed cranium ( J:170081 )

growth/size/body

absent incisors ( J:170081 )

decreased body size ( J:170081 )

• smaller than either single mutant

weight loss ( J:170081 )

• mutants start to lose weight between P29 and P33

immune system

impaired macrophage chemotaxis ( J:170081 )

• macrophage infiltration in the CNS white matter observed in Galc^twi mice is almost completely blocked: although degenerated myelin is observed in the white matter parenchyma, PAS stain is rarely seen, indicating that PAS+ macrophages, or globoid cells are not observed in demyelinated lesions and that there is an absence of myelin phagocytosis by macrophages

nervous system

decreased oligodendrocyte progenitor number ( J:170081 )

• white matter exhibits similar reactive astrocytosis as single Galc^twi mice, however double mutants have a smaller oligodendrocyte progenitor cell (OPC) population

abnormal forebrain morphology ( J:170081 )

• levels of psychosine are increased in the forebrain compared to wild-type mice, however levels are lower than in single Galc^twi mice, indicating that levels of psychosine do not correlate with the severity of disease

• mutants have lower levels of free sphingosine compared to wild-type mice, and levels are lower in double mutants than in single Galc^twi mice

abnormal oligodendrocyte morphology ( J:170081 )

• oligodendrocyte progenitor cells become hypertrophic and have short and stout processes instead of well branched fine processes as in wild-type mice

decreased oligodendrocyte number ( J:170081 )

• mutants exhibit fewer oligodendrocytes than wild-type or single Galc^twi mice

abnormal oligodendrocyte physiology ( J:170081 )

• recruitment of oligodendrocyte progenitor cells in response to demyelination is compromised

demyelination ( J:170081 )

• mutants exhibit a more severe demyelinating pathology than single homozygous Galc^twi mice due to inhibition of remyelination and a delay in myelin development, rather than enhanced demyelination

• myelin degeneration is seen in the white matter, with significantly more nonmyelinated axons at P45 in mutants than single Galc^twi mice and a preferential loss of myelin in large diameter axons

• sciatic nerves are severely demyelinated

• however, development (wrapping) of myelin from P15 to P30 is not affected

skeleton

absent incisors ( J:170081 )

domed cranium ( J:170081 )

cellular

decreased oligodendrocyte progenitor number ( J:170081 )

• white matter exhibits similar reactive astrocytosis as single Galc^twi mice, however double mutants have a smaller oligodendrocyte progenitor cell (OPC) population

impaired macrophage chemotaxis ( J:170081 )

• macrophage infiltration in the CNS white matter observed in Galc^twi mice is almost completely blocked: although degenerated myelin is observed in the white matter parenchyma, PAS stain is rarely seen, indicating that PAS+ macrophages, or globoid cells are not observed in demyelinated lesions and that there is an absence of myelin phagocytosis by macrophages

hematopoietic system

impaired macrophage chemotaxis ( J:170081 )

• macrophage infiltration in the CNS white matter observed in Galc^twi mice is almost completely blocked: although degenerated myelin is observed in the white matter parenchyma, PAS stain is rarely seen, indicating that PAS+ macrophages, or globoid cells are not observed in demyelinated lesions and that there is an absence of myelin phagocytosis by macrophages