Phenotypes Associated with This Genotype

Genotype
MGI:5800675

• Allelic Composition: Asah1^tm1Medin/Asah1^tm1Medin
• Genetic Background: involves: 129S6/SvEvTac * CD-1

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

mortality/aging

premature death ( J:232306 )

• 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)

growth/size/body

weight loss ( J:232306 )

• 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

cachexia ( J:232306 )

• generalized wasting of body tissues and organs ("dystrophy")

postnatal growth retardation ( J:232306 )

• mice start exhibiting postnatal growth retardation as early as 3 weeks of age and reach maximum weight at 4 weeks

enlarged spleen ( J:232306 )

• remarkably enlarged spleen

increased spleen weight ( J:232306 )

• spleen weight to body weight ratio is significantly increased

homeostasis/metabolism

abnormal circulating chemokine level ( J:232306 )

• significantly increased serum monocyte chemoattractant protein-1 (MCP-1) levels at 7-9 weeks of age

increased circulating interleukin-12b level ( J:232306 )

• significantly increased serum IL-12 (p40) levels at 7-9 weeks of age

pulmonary alveolar edema ( J:232306 )

• mild pulmonary alveolar edema

abnormal ceramide level ( J:232306 )

• 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

abnormal enzyme/coenzyme activity ( J:232306 )

• 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

hematopoietic system

enlarged thymus ( J:232306 )

• remarkably enlarged thymus

enlarged spleen ( J:232306 )

• remarkably enlarged spleen

increased spleen weight ( J:232306 )

• spleen weight to body weight ratio is significantly increased

increased erythrocyte cell number ( J:232306 )

• significantly increased erythrocyte cell number at 7-10 weeks of age

increased hemoglobin content ( J:232306 )

• significantly increased hemoglobin levels at 7-10 weeks of age

increased leukocyte cell number ( J:232306 )

• dramatically increased total WBC count at 7-10 weeks of age

• neonatal treatment with LV/ACDase reduces total leukocyte counts to relatively normal levels

increased macrophage derived foam cell number ( J:232306 )

• 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

increased eosinophil cell number ( J:232306 )

• significantly increased levels of eosinophils at 7-10 weeks of age

• neonatal treatment with LV/ACDase results in significantly reduced eosinophil counts

increased neutrophil cell number ( J:232306 )

• significantly increased levels of neutrophils at 7-10 weeks of age

increased monocyte cell number ( J:232306 )

• significantly increased levels of monocytes at 7-10 weeks of age

pale spleen ( J:232306 )

• spleen is firm and pale

immune system

enlarged thymus ( J:232306 )

• remarkably enlarged thymus

enlarged spleen ( J:232306 )

• remarkably enlarged spleen

increased spleen weight ( J:232306 )

• spleen weight to body weight ratio is significantly increased

increased leukocyte cell number ( J:232306 )

• dramatically increased total WBC count at 7-10 weeks of age

• neonatal treatment with LV/ACDase reduces total leukocyte counts to relatively normal levels

increased macrophage derived foam cell number ( J:232306 )

• 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

increased eosinophil cell number ( J:232306 )

• significantly increased levels of eosinophils at 7-10 weeks of age

• neonatal treatment with LV/ACDase results in significantly reduced eosinophil counts

increased neutrophil cell number ( J:232306 )

• significantly increased levels of neutrophils at 7-10 weeks of age

increased monocyte cell number ( J:232306 )

• significantly increased levels of monocytes at 7-10 weeks of age

pale spleen ( J:232306 )

• spleen is firm and pale

abnormal circulating chemokine level ( J:232306 )

• significantly increased serum monocyte chemoattractant protein-1 (MCP-1) levels at 7-9 weeks of age

increased circulating interleukin-12b level ( J:232306 )

• significantly increased serum IL-12 (p40) levels at 7-9 weeks of age

enlarged lymph nodes ( J:232306 )

• remarkably enlarged axillary, cervical, and inguinal lymph nodes

abnormal chemokine secretion ( J:232306 )

• significantly increased levels of MCP-1 protein in liver, brain, spleen, and thymus lysates at 9 weeks of age

cellular

increased macrophage derived foam cell number ( J:232306 )

• 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

abnormal lysosome morphology ( J:232306 )

• curvilinear tubular structures (Farber bodies) are noted within the lysosomal compartments of cells in hepatic and peripheral nerve sections

hepatic necrosis ( J:232306 )

• patchy single-cell necrosis to random multifocal areas of acute hepatocellular necrosis

nervous system

hydrocephaly ( J:232306 )

• massive hydrocephaly detected in 5 out of 7 mice at 10 weeks of age

dilated brain ventricle ( J:232306 )

• dilated ventricles at 10 weeks of age

skeleton

decreased long bone epiphyseal plate size ( J:232306 )

• shorter epiphyseal growth plates in femurs at 7 weeks of age

abnormal endochondral bone ossification ( J:232306 )

• reduced endochondral ossification in femurs at 7 weeks of age

respiratory system

abnormal pulmonary alveolus morphology ( J:232306 )

• scattered foamy alveolar macrophages and mild increases in neutrophils within alveolar septae

pulmonary alveolar edema ( J:232306 )

• mild pulmonary alveolar edema

behavior/neurological

lethargy ( J:232306 )

limb grasping ( J:232306 )

• mice show a weak forelimb grasp that worsens with advancing age

liver/biliary system

hepatic necrosis ( J:232306 )

• patchy single-cell necrosis to random multifocal areas of acute hepatocellular necrosis

reproductive system

decreased tertiary ovarian follicle number ( J:232306 )

♀ • trend towards lower ovarian follicle numbers, especially at the antral stage

small ovary ( J:232306 )

♀ • ovaries are smaller than normal at 9 weeks of age

penis prolapse ( J:232306 )

♂ • penile prolapse is observed in males

endocrine/exocrine glands

enlarged thymus ( J:232306 )

• remarkably enlarged thymus

decreased tertiary ovarian follicle number ( J:232306 )

♀ • trend towards lower ovarian follicle numbers, especially at the antral stage

small ovary ( J:232306 )

♀ • ovaries are smaller than normal at 9 weeks of age

renal/urinary system

penis prolapse ( J:232306 )

♂ • penile prolapse is observed in males

adipose tissue

decreased gonadal fat pad weight ( J:232306 )

♀ • ovaries are covered with less fat relative to wild-type ovaries

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Farber lipogranulomatosis		DOID:0050464	OMIM:228000	J:232306