Analysis Tools
mortality/aging
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• mice die at approximately 7-13 weeks of age
• neonatal treatment with a single injection of human ACDase-encoding lentivector extends survival, with 7 out of 9 LV/ACDase-treated mice surviving beyond 11 weeks and up to 16.5 weeks (median survival = 91 days) whereas all LV/enGFP (control)-treated mice die by 11 weeks (median survival = 70 days)
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growth/size/body
weight loss
(
J:232306
)
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• after 4 weeks of age, mice display continuous and progressive weight loss
• neonatal treatment of mice with LV/ACDase restores growth until 5 weeks of age; after that, LV/ACDase-treated mice start to lose weight at a rate similar to the LV/enGFP-treated group, although body weights remain significantly higher than those in mice treated with control LV/enGFP
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• mice start exhibiting postnatal growth retardation as early as 3 weeks of age and reach maximum weight at 4 weeks
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• remarkably enlarged spleen
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• spleen weight to body weight ratio is significantly increased
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homeostasis/metabolism
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• significantly increased serum monocyte chemoattractant protein-1 (MCP-1) levels at 7-9 weeks of age
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• significantly increased serum IL-12 (p40) levels at 7-9 weeks of age
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• mild pulmonary alveolar edema
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• dramatically increased total ceramide levels in all tested organs (spleen, brain, heart, liver, lungs, and kidneys) at 8 weeks of age
• neonatal treatment of mice with LV/ACDase results in a striking reduction of ceramide levels in spleen and liver
• whereas both total ceramide and ceramide/DAG ratios are reduced in the spleen and liver in LV/ACDase-treated mice, brain ceramide levels remain high
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• intact mouse embryonic fibroblasts (MEFs) derived from homozygous mutant embryos are deficient in acid ceramidase (ACDase) activity, as evident by accumulation of lysosomal ceramide; however, degradation of sphingomyelin is normal
• ACDase activity is significantly reduced in lysates from all tested organs (liver, heart, spleen, thymus, and brains) at 7-10 weeks of age
• spleen, thymus, and liver exhibit the most severe reduction of ACDase activity
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hematopoietic system
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• remarkably enlarged thymus
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• remarkably enlarged spleen
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• spleen weight to body weight ratio is significantly increased
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• significantly increased erythrocyte cell number at 7-10 weeks of age
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• significantly increased hemoglobin levels at 7-10 weeks of age
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• dramatically increased total WBC count at 7-10 weeks of age
• neonatal treatment with LV/ACDase reduces total leukocyte counts to relatively normal levels
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• moderate-to-marked histiocytic infiltrates are noted in the liver, spleen, and thymus at 7-10 weeks of age, with expansion and disruption of the parenchyma
• similar histiocytic infiltrates are noted in the bone marrow, lymph nodes, skin, spinal cord, and sciatic nerve, but not in sections of kidneys, testes, or skeletal muscles
• in the sciatic nerve, random multifocal histiocytic aggregates are seen intercalating between axons, with disruption of myelin and accumulation of cellular debris; in the spinal cord, similar changes are noted with disruption of neuronal tracts
• infiltrating histiocytes show abundant pale, foamy-to-finely granular, eosinophilic cytoplasms with displaced nuclei
• histiocytic infiltrates are accompanied by mild-to-moderate neutrophilic infiltrates
• neonatal treatment of mice with LV/ACDase reduces macrophage infiltrations in the liver and spleen and, to a lesser extent, in brain; however, infiltrations are still noted in the spinal cord, sciatic nerve, thymus, lymph nodes, bone marrow, lung, and skin
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• significantly increased levels of eosinophils at 7-10 weeks of age
• neonatal treatment with LV/ACDase results in significantly reduced eosinophil counts
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• significantly increased levels of neutrophils at 7-10 weeks of age
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• significantly increased levels of monocytes at 7-10 weeks of age
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pale spleen
(
J:232306
)
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• spleen is firm and pale
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immune system
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• remarkably enlarged thymus
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• remarkably enlarged spleen
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• spleen weight to body weight ratio is significantly increased
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• dramatically increased total WBC count at 7-10 weeks of age
• neonatal treatment with LV/ACDase reduces total leukocyte counts to relatively normal levels
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• moderate-to-marked histiocytic infiltrates are noted in the liver, spleen, and thymus at 7-10 weeks of age, with expansion and disruption of the parenchyma
• similar histiocytic infiltrates are noted in the bone marrow, lymph nodes, skin, spinal cord, and sciatic nerve, but not in sections of kidneys, testes, or skeletal muscles
• in the sciatic nerve, random multifocal histiocytic aggregates are seen intercalating between axons, with disruption of myelin and accumulation of cellular debris; in the spinal cord, similar changes are noted with disruption of neuronal tracts
• infiltrating histiocytes show abundant pale, foamy-to-finely granular, eosinophilic cytoplasms with displaced nuclei
• histiocytic infiltrates are accompanied by mild-to-moderate neutrophilic infiltrates
• neonatal treatment of mice with LV/ACDase reduces macrophage infiltrations in the liver and spleen and, to a lesser extent, in brain; however, infiltrations are still noted in the spinal cord, sciatic nerve, thymus, lymph nodes, bone marrow, lung, and skin
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• significantly increased levels of eosinophils at 7-10 weeks of age
• neonatal treatment with LV/ACDase results in significantly reduced eosinophil counts
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• significantly increased levels of neutrophils at 7-10 weeks of age
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• significantly increased levels of monocytes at 7-10 weeks of age
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pale spleen
(
J:232306
)
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• spleen is firm and pale
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• significantly increased serum monocyte chemoattractant protein-1 (MCP-1) levels at 7-9 weeks of age
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• significantly increased serum IL-12 (p40) levels at 7-9 weeks of age
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• remarkably enlarged axillary, cervical, and inguinal lymph nodes
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• significantly increased levels of MCP-1 protein in liver, brain, spleen, and thymus lysates at 9 weeks of age
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cellular
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• moderate-to-marked histiocytic infiltrates are noted in the liver, spleen, and thymus at 7-10 weeks of age, with expansion and disruption of the parenchyma
• similar histiocytic infiltrates are noted in the bone marrow, lymph nodes, skin, spinal cord, and sciatic nerve, but not in sections of kidneys, testes, or skeletal muscles
• in the sciatic nerve, random multifocal histiocytic aggregates are seen intercalating between axons, with disruption of myelin and accumulation of cellular debris; in the spinal cord, similar changes are noted with disruption of neuronal tracts
• infiltrating histiocytes show abundant pale, foamy-to-finely granular, eosinophilic cytoplasms with displaced nuclei
• histiocytic infiltrates are accompanied by mild-to-moderate neutrophilic infiltrates
• neonatal treatment of mice with LV/ACDase reduces macrophage infiltrations in the liver and spleen and, to a lesser extent, in brain; however, infiltrations are still noted in the spinal cord, sciatic nerve, thymus, lymph nodes, bone marrow, lung, and skin
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• curvilinear tubular structures (Farber bodies) are noted within the lysosomal compartments of cells in hepatic and peripheral nerve sections
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nervous system
hydrocephaly
(
J:232306
)
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• massive hydrocephaly detected in 5 out of 7 mice at 10 weeks of age
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• dilated ventricles at 10 weeks of age
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skeleton
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• shorter epiphyseal growth plates in femurs at 7 weeks of age
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• reduced endochondral ossification in femurs at 7 weeks of age
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respiratory system
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• scattered foamy alveolar macrophages and mild increases in neutrophils within alveolar septae
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• mild pulmonary alveolar edema
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behavior/neurological
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• mice show a weak forelimb grasp that worsens with advancing age
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liver/biliary system
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• patchy single-cell necrosis to random multifocal areas of acute hepatocellular necrosis
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reproductive system
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• trend towards lower ovarian follicle numbers, especially at the antral stage
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small ovary
(
J:232306
)
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• ovaries are smaller than normal at 9 weeks of age
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• penile prolapse is observed in males
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endocrine/exocrine glands
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• remarkably enlarged thymus
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• trend towards lower ovarian follicle numbers, especially at the antral stage
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small ovary
(
J:232306
)
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• ovaries are smaller than normal at 9 weeks of age
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renal/urinary system
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• penile prolapse is observed in males
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adipose tissue
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• ovaries are covered with less fat relative to wild-type ovaries
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Farber lipogranulomatosis | DOID:0050464 |
OMIM:228000 |
J:232306 | |
