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A new type of peroxisomal disorder with variable expression in liver and fibroblasts
Insights
This study details a rare peroxisome biogenesis disorder with mosaicism in liver cells, presenting neurodegenerative symptoms. Tissue-specific expression highlights the complexity of diagnosing peroxisomal disorders.
Area of Science:
- Cell Biology
- Biochemistry
- Genetics
Background:
- Peroxisomal disorders are a group of genetic diseases affecting peroxisome function.
- These disorders can lead to severe neurodevelopmental deficits and metabolic abnormalities.
Observation:
- Two siblings presented with neurodegenerative symptoms and elevated very long chain fatty acids, pipecolic acid, and phytanic acid.
- Liver biopsies revealed a mosaic pattern of peroxisome deficiency, with ~90% of hepatocytes lacking peroxisomes.
- The remaining hepatocytes contained normal peroxisomes with catalase activity and key enzymes, while cultured fibroblasts showed normal peroxisomal function.
Findings:
- The study identified a peroxisome biogenesis defect with significant tissue-specific and intra-tissue heterogeneity.
- This mosaicism in peroxisome distribution within the liver is a key characteristic of this disorder.
- Discordant findings between liver tissue and cultured fibroblasts underscore the complexity of peroxisomal disease manifestation.
Implications:
- Understanding this heterogeneity is crucial for accurate diagnosis of peroxisomal disorders.
- Prenatal diagnosis strategies may need to account for variable tissue expression.
- This research contributes to the understanding of peroxisome assembly and its clinical consequences.
Abstract:
We describe two siblings, presently 5 and 9 years of age, who had neurodegenerative symptoms after the first year of life. Although they lacked clinical characteristics of a peroxisomal disorder, they had elevated levels of plasma very long chain fatty acids, pipecolic and phytanic acids, and abnormal bile acid intermediates, which suggested a generalized peroxisome deficiency disorder. Immunocytochemical study and electron microscopy of the liver disclosed absence of peroxisomes in approximately 90% of hepatocytes. However, the remaining 10% of the hepatocytes had numerous normal-looking peroxisomes containing catalase activity and catalase antigen. Alanine glyoxylate aminotransferase and the peroxisomal beta-oxidation enzymes acyl-coenzyme A oxidase and 3-ketoacyl coenzyme A thiolase were also present in the organelles. Both cell types were grouped in clusters. In contrast to most of the liver cells, fibroblasts cultured from skin biopsy specimens had normal peroxisomal functions. Thus this defect in peroxisome biogenesis is characterized by variable expression in different tissues (liver vs fibroblasts), as well as within individual cells in the same tissue (liver mosaicism). Awareness of the heterogeneity in tissue expression of peroxisomal disorders could be of critical importance in prenatal diagnosis.