Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice
- Toshio Ohshima*,†,
- Raphael Schiffmann†,
- Gary J. Murray†,
- Jeffrey Kopp‡,
- Jane M. Quirk†,
- Stefanie Stahl†,
- Chi-Chao Chan§,
- Patricia Zerfas¶,
- Jung-Hwa Tao-Cheng¶,
- J. M. Ward‖,
- Roscoe O. Brady†, and
- Ashok B. Kulkarni*,**
- *Functional Genomics Unit, National Institute of Dental and Craniofacial Research, †Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke; ‡Kidney Disease Section, National Institute of Digestive Diseases and Kidney; and §Laboratory of Immunology, National Eye Institute, and ¶Electron Microscopy Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; and ‖Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, National Institutes of Health, Frederick, MD 21702
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Contributed by Roscoe O. Brady
Abstract
Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.
Footnotes
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↵ ** To whom reprint requests should be addressed at Building 30, Room 529, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892-4326. e-mail: ak40m{at}nih.gov.
- ABBREVIATIONS:
- α-Gal A,
- α-galactosidase A;
- BM,
- bone marrow;
- BMT,
- bone marrow transplantation;
- EM,
- electron microscopy;
- Gb3,
- globotriaosylceramide
- Copyright © 1999, The National Academy of Sciences
