Accumulation of glycosphingolipids in spinal and sympathetic ganglia of a symptomatic heterozygote of Fabry's disease

Hozumi, Isao; Nishizawa, Masatoyo; Ariga, Toshio; Inoue, Yoshiya; Ohnishi, Yoshifusa; Yokoyama, Akihiro; Shibata, Akira; Miyatake, Tadashi

doi:10.1016/0022-510x(89)90113-5

Cited by 28 publications

(14 citation statements)

References 16 publications

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“…However, Gb3 in liver from ␣-Gal A Ϫ͞0 mice was approximately 30-fold elevated in liver and 4-to 6-fold elevated in kidney. In a study of a single patient with Fabry disease, the highest concentration of Gb3 was found in the kidneys, followed by heart and liver (14). Interestingly, the concentration of Gb3 in liver and kidney of ␣-Gal A Ϫ͞0 mice was approximately the same in contrast to the patient samples reported in which the concentration in kidney is 35 times higher than in liver.…”

Section: Resultsmentioning

confidence: 64%

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Ohshima

Schiffmann

Murray

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Fabry disease is an X-linked metabolic disorder caused by a deficiency of ␣-galactosidase A (␣-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with ␣-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 ␣-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 ␣-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 ␣-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.

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Section: Resultsmentioning

confidence: 64%

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Ohshima

Schiffmann

Murray

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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“…The average reduction in Gb 3 in the liver after a single enzyme dose was approximately 30%. Because approximately 10% of the total Gb 3 in the body is deposited in the liver (18,19) one can estimate that a single dose of ␣-gal A catabolized 3% of the total body burden of Gb 3 . The rapid turnover of the plasma Gb 3 fraction likely explains the lack of significant reduction in plasma Gb 3 after a single ␣-gal A infusion (it should be noted that the enzyme is nearly inactive at the pH of plasma).…”

Section: Discussionmentioning

confidence: 99%

Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease

Schiffmann

Murray

Treco

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

334

221

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Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme ␣-galactosidase A (␣-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb 3; also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified ␣-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered ␣-gal A, (ii) to assess the pharmacokinetics of i.v.-administered ␣-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. ␣-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified ␣-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of ␣-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of ␣-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb 3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.

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“…This assumption is based on the fact that about 10% of the total Gb3 in the body is deposited in the liver (31,32). In addition, the three-target cell types in liver play a central role in the Gb3 synthesis and turnover (33).…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice

Jung

Han

Limaye

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

130

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Accumulation of glycosphingolipids in spinal and sympathetic ganglia of a symptomatic heterozygote of Fabry's disease

Cited by 28 publications

References 16 publications

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease

Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice

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