Analysis Tools
nervous system
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• activation of microglia starts at 1 year and by 2 years the white matter is crowded with epitheloid microglia
• activation of microglia tends to occur earlier and is more severe in the cerebellum than in the telencephalic hemispheres
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• at 11 months of age, sulfatide is abnormally stored within the brain white matter (corpus callosum, hippocampal fimbria, internal capsule, and optic nerve)
• sulfatide storage is displayed as (i) numerous fine granules arranged immediately adjacent to myelinated nerve fibers and (ii) as clusters of larger granules within swollen cells interspersed within the white matter
• lamellar deposits, herringbone patterns, and tuffstone-like materials are detected in astrocytes, oligodendrocytes, microglial, and Schwann cells
• by 2 years of age, sulfatide accumulation is also noted in the white matter of the cerebellum
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• by 2 years of age, morphological alterations of Purkinje cells and Bergmann glia are observed in the molecular layer of the cerebellum
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• at 1 year of age, significant astrogliosis is noted in brain white matter tracts, including the corpus callosum and optic nerve
(J:37978)
• the number of astocytes is significantly increased while enlarged, sometimes epitheloid somata and broader cell processes are observed
(J:37978)
• the extent of astrogliosis remains unaltered when mutant brains are compared at 1 and 2 years of age
(J:37978)
• at 10-12 months, homozygygotes display significant astrogliosis in the white matter
(J:52310)
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• abnormal sulfatide storage is detected in Schwann cells of the peripheral nerves, but without any signs of demyelination
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• at 1 year of age, neurons exibiting abnormal sulfatide storage with no obvious cellular damage include several nuclei of the brainstem, diencephalon, spinal chord, and cerebellum
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• at 10-12 months, the antler-like shape of the normal Purkinje cell dendritic tree is missing, whereas the somata of Purkinje cells are of normal morphology and number, and no storage of sulfatide is found
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• Purkinje cells of the cerebellar cortex exhibit crippled dendritic trees with narrower profiles and irregular swellings; however, no sulfatide storage is detected in these cells
(J:37978)
• by 2 years of age, fewer Purkinje cells are found, and the number of radial extensions of cerebellar Bergmann glia into the molecular layer of the cerebellum is significantly decreased
(J:52310)
• many of the Purkinje cells are lost from the cerebellar cortex in 2 year old mutant mice
(J:59770)
• Purkinje cell function (prolonged inhibition of simple spike frequency) is also impaired in these 2 year old mutants
(J:59770)
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• at 11 months of age, axon cross-sectional area of myelinated fibers in the optic nerve and the corpus callosum is significantly reduced
(J:37978)
• at 10-12 months, homozygotes display a 30% reduction in axonal diameter, as shown in axons of the optic nerve
(J:52310)
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• at 8 and 11 months of age, the number of acoustic ganglion cells and their corresponding myelinated nerve fibers are markedly reduced
(J:37978)
• the remaining ganglion cells are surrounded by Schwann cells containing accumulated storage material
(J:37978)
• at 6 months of age, the number of acoustic ganglion cells appears normal, but the neurons and surrounding Schwann cells display significant sulfatide storage
(J:37978)
• at 6-12 months of age, homozygotes display neurodegeneration of the acoustic ganglion; however, only sulfatide storage is noted until 6 months
(J:52310)
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• at 6 months of age, abnormal sulfatide storage is noted in the vestibular ganglion but without reduction of neurons and nerve fibers
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• although axon cross-sectional area of myelinated fibers in the optic nerve and the corpus callosum is reduced, mutant mice do not display evidence of widespread demyelination up to 2 years of age
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demyelination
(
J:52310
)
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• between the age of 6 and 12 months, homozygotes display an almost complete demyelination of the acoustic nerve
• however, up to the age of 20 months, no demyelination is detectable in the central or peripheral nervous system, explaining the surprisingly mild phenotype and long lifespan seen in mice
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behavior/neurological
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• at 12-14 months of age, mutant females perform significantly worse than wild-type mice in the Morris water maze test
• in contrast, no differences are noted between mutant and wild-type mice in the passive avoidance learning test
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• at 2 years of age, mutant females develop a low frequency head tremor, not visible when animals are at rest
(J:37978)
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• 2 year old mutants have an atactic and faltering gait
(J:59770)
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• at 8 months of age, some males display mild ataxia
(J:178538)
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• at 12-14 months of age, only 4 or 5 out of 10 female homozygotes are able to stay on the rotarod for 2 min
(J:37978)
• general motor and open field activity are normal at 12-14 months of age
(J:37978)
• at 10-12 months, homozygotes fall off a rotating rod more frequently than wild-type mice
(J:52310)
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• at 12-14 months of age, swimming speed is significantly reduced in female mutants compared to wild-type mice
(J:37978)
• by 2 years of age, homozygotes are unable to swim
(J:52310)
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abnormal gait
(
J:52310
)
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• at 12-14 months of age, the hind limb paw print distance is significantly smaller in mutant females compared to wild-type mice
(J:37978)
• other paw measures such as print length and toe spread are normal
(J:37978)
• at 10-12 months, the distance between two paw prints is ~1 cm shorter than normal
(J:52310)
• maximal distance between paw prints on the same side is shorter in 1 year old mutants compared to wild-type mice
(J:59770)
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reproductive system
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• sulfogalactosylglycerolipid (SGG) levels are normal at 5 months but significantly decreased in primary spermatocytes and condensing elongated spermatids at 8 months of age
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• a drastic increase in the number of apoptotic germ cells is observed in the seminiferous tubules at 8 months, but not at 5 months, of age
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• whole testes show significantly increased levels of sulfogalactosylglycerolipid (also known as SGG or seminolipid) at both 5 and 8 months of age
• C18:0/C16:0 SGG (m/z 823) and C18:1/C16:0 SGG (m/z 821), as well as C16:0 SGC (palmitoylsulfatide, m/z 778) are uniquely present in the testes, in addition to 3 other SGG species that are normally present in wild-type testes
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• seminiferous tubule epithelium area is significantly decreased at 8 months of age
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• at 8 months of age, Sertoli cells show accumulation of intracellular sulfogalactosylglycerolipid (SGG) and abnormal morphology such as dislocalization of the nucleus and smaller sizes with fewer cellular processes
• some Sertoli cells have numerous lysosomes with irregular shapes and heterogeneous content or enlarged spherical structures; lipid droplets are abundant esp. at stages I-VII of the spermatogenic cycle
• in some tubules, lysosomes of Sertoli cells are quite large, more or less spherical and numerous, indicating a lysosomal storage disorder
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• testis weight is only 60% of that in wild-type controls at 8 months of age
• however, testis weight is normal at 5 months of age
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• at 8 months of age, spermatogenesis is reduced with high rates of apoptotic germ cells, disorganization of germ cell layers, and smaller profile areas of seminiferous tubules
• sulfogalactosylglycerolipid (SGG) levels are normal at 5 months but decreased to 50% of wild-type levels in epididymal and vas deferens sperm at 8 months of age
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• numbers of epididymal and vas deferens sperm are only 50% of wild-type controls at 8 months of age
• however, sperm counts are normal at 5 months of age
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• a high number of spermatozoa with abnormal morphology are observed at 8 months of age
• even in the swim-up suspension, ~30-40% of motile sperm show abnormal morphology
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• at 8 months of age, some sperm exhibit 180 degrees folding of the tails
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• abnormal sperm heads are often observed at 8 months of age
• several elongated spermatid heads are disoriented, lying horizontal instead of vertically to the basement membrane
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• several elongated spermatid heads are disoriented, lying horizontal instead of vertically to the basement membrane
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• Sertoli cell phagocytic function is impaired at 8 months of age
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• immature round germ cells are found in the lumen of the epididymis at 8 months of age
• however, epididymis weights and the epididymal epithelium appear normal
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• male fertility is significantly reduced after 5 months of age
• however, rate of vaginal plug formation is normal
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• ability of epididymal and vas deferens sperm to fertilize eggs in vitro is severely reduced at 8 months, but not at 5 months, of age
• near-zero in vitro fertilizing ability is accompanied by a 50% decrease in sperm sulfogalactosylglycerolipid (SGG) levels
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• in vitro sperm-zona pellucida binding ability is significantly reduced at 8 months, but not at 5 months, of age
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homeostasis/metabolism
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• homozygotes are unable to degrade sulphatide and store the lipid intralysosomally
(J:37978)
• at 6-11 months of age, sulfatide, a sphingolipid, is abnormally stored in the kidneys (most prominently in Henle's loop, distal tubules and collecting ducts), gall bladder, epithelia of the bile duct and the lung, and in the white matter of the brain
(J:37978)
• sulfatide accumulation in the brain is increased in 2-year-old mutant mice compared to 1-year-olds
(J:37978)
• no evidence of storage is found in hepatocytes, adrenal glands, thyroid, skeletal muscle, lymphatic organs, urinary bladder epithelia, and gastric mucosa
(J:37978)
• at 10-12 months, sulfatide storage in the brain is found in oligodendrocytes, astrocytes and certain types of neurons
(J:52310)
• surprisingly, most homozygotes transplanted with bone marrow exhibit sustained expression of arylsulfatase A from a retroviral construct up to 5 months but fail to show a reduction of sulfatide storage in kidney, liver or brain
(J:52310)
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hearing/vestibular/ear
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• at 12-14 months of age, all female mutants lack brainstem auditory-evoked potentials
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hematopoietic system
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• activation of microglia starts at 1 year and by 2 years the white matter is crowded with epitheloid microglia
• activation of microglia tends to occur earlier and is more severe in the cerebellum than in the telencephalic hemispheres
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vision/eye
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• at 8 months of age, some males display ocular problems
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cellular
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• sulfogalactosylglycerolipid (SGG) levels are normal at 5 months but significantly decreased in primary spermatocytes and condensing elongated spermatids at 8 months of age
|
|
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• numbers of epididymal and vas deferens sperm are only 50% of wild-type controls at 8 months of age
• however, sperm counts are normal at 5 months of age
|
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• a high number of spermatozoa with abnormal morphology are observed at 8 months of age
• even in the swim-up suspension, ~30-40% of motile sperm show abnormal morphology
|
|
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• at 8 months of age, some sperm exhibit 180 degrees folding of the tails
|
|
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• abnormal sperm heads are often observed at 8 months of age
• several elongated spermatid heads are disoriented, lying horizontal instead of vertically to the basement membrane
|
|
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• several elongated spermatid heads are disoriented, lying horizontal instead of vertically to the basement membrane
|
|
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• Sertoli cells show sulfogalactosylglycerolipid (SGG) accumulation leading to lysosomal swelling and other cellular abnormalities typical of a lysosomal storage disorder at 8 months of age
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• a drastic increase in the number of apoptotic germ cells is observed in the seminiferous tubules at 8 months, but not at 5 months, of age
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endocrine/exocrine glands
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• whole testes show significantly increased levels of sulfogalactosylglycerolipid (also known as SGG or seminolipid) at both 5 and 8 months of age
• C18:0/C16:0 SGG (m/z 823) and C18:1/C16:0 SGG (m/z 821), as well as C16:0 SGC (palmitoylsulfatide, m/z 778) are uniquely present in the testes, in addition to 3 other SGG species that are normally present in wild-type testes
|
|
|
• seminiferous tubule epithelium area is significantly decreased at 8 months of age
|
|
|
• at 8 months of age, Sertoli cells show accumulation of intracellular sulfogalactosylglycerolipid (SGG) and abnormal morphology such as dislocalization of the nucleus and smaller sizes with fewer cellular processes
• some Sertoli cells have numerous lysosomes with irregular shapes and heterogeneous content or enlarged spherical structures; lipid droplets are abundant esp. at stages I-VII of the spermatogenic cycle
• in some tubules, lysosomes of Sertoli cells are quite large, more or less spherical and numerous, indicating a lysosomal storage disorder
|
|
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• testis weight is only 60% of that in wild-type controls at 8 months of age
• however, testis weight is normal at 5 months of age
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immune system
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• activation of microglia starts at 1 year and by 2 years the white matter is crowded with epitheloid microglia
• activation of microglia tends to occur earlier and is more severe in the cerebellum than in the telencephalic hemispheres
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| metachromatic leukodystrophy | DOID:10581 |
OMIM:249900 OMIM:250100 |
J:37978 , J:52310 | |
