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Clinical, pathological, and biochemical studies on an infantile case of sulfatide/GM1 activator protein deficiency
D A Wenger1, G DeGala, C Williams
1Department of Medicine, Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, PA 19107.
Abstract:
A 28-month-old black male died with severe complications of mental and motor deterioration, seizures, and aspiration. Autopsy demonstrated moderate liver enlargement, normal spleen and kidneys, small testes, and a grossly normal brain. Further examination showed irregular macrogyrae with evidence of a storage or sclerotic process. Thin layer chromatography of the lipids in formalin-fixed tissue demonstrated elevated levels of ceramide trihexoside and possibly sulfatides in liver and a decrease in the ratio of galactosylceramide to sulfatide in brain. Examination of the gangliosides in formalin-fixed brain indicated a slight increase in the percentage of GM1 ganglioside and a clear elevation in GM2 and GM3 gangliosides. Cultured skin fibroblasts had a normal activity for a large number of lysosomal enzymes including arylsulfatase A and galactocerebrosidase. When the cells were loaded with [14C]sulfatide only about 12% of the sulfatide was metabolized after 3 days. Extracts of the cells were subjected to SDS-PAGE and immunoblotting with antisphingolipid activator protein-1 (SAP-1) rabbit antiserum, and no cross-reacting material was detected confirming the diagnosis of metachromatic leukodystrophy caused by SAP-1 deficiency. This patient was clinically more severe than the other patients described previously with this deficiency. Further studies are underway to define the nature of the mutation in this patient.
Insights
Metachromatic leukodystrophy due to sphingolipid activator protein-1 (SAP-1) deficiency is a severe neurological disorder. This case highlights a particularly severe presentation, confirming SAP-1 deficiency as the cause.
Area of Science:
- Biochemistry
- Neurology
- Genetics
Background:
- Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder affecting the nervous system.
- Sphingolipid activator proteins (SAPs) are crucial for the enzymatic breakdown of specific lipids.
- Deficiency in SAP-1 impairs the metabolism of sulfatides, leading to MLD.
Observation:
- Autopsy revealed neurological deterioration, liver enlargement, and brain abnormalities suggestive of a storage process.
- Biochemical analysis showed elevated ceramide trihexoside and sulfatides in the liver, and altered ganglioside profiles in the brain.
- Fibroblast studies indicated impaired sulfatide metabolism and absence of SAP-1 protein.
Findings:
- The patient presented with severe clinical manifestations of MLD, including developmental regression, seizures, and aspiration.
- Lipid analysis confirmed abnormal accumulation of specific sphingolipids.
- Absence of detectable SAP-1 protein in fibroblasts confirmed the diagnosis of MLD caused by SAP-1 deficiency.
Implications:
- This case represents a severe, previously undescribed clinical phenotype of SAP-1 deficiency.
- Understanding the molecular basis of SAP-1 deficiency is crucial for potential therapeutic strategies.
- Further research into the specific mutation is needed to elucidate the full spectrum of this rare genetic disorder.