Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement

Schiffmann, Raphael; Rapkiewicz, Amy; Abu‐Asab, Mones; Ries, Markus; Askari, Hasan; Tsokos, Maria; Quezado, Martha

doi:10.1007/s00428-005-0089-x

Cited by 89 publications

(90 citation statements)

References 20 publications

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“…This finding is supported by our observation that only vascular endothelial cells were cleared of lipid deposits in a patient who was treated for 2.5 years with the other enzyme preparation (agalsidase beta) [26,27]. It would therefore be important to further study the mechanism of uptake of agalsidase alfa into various cell types and tissues.…”

Section: Discussionsupporting

confidence: 56%

Cellular and tissue distribution of intravenously administered agalsidase alfa

Murray

Anver

Kennedy

et al. 2007

Molecular Genetics and Metabolism

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Abstractα-Galactosidase A is the lysosomal hydrolase that is deficient in patients with Fabry disease. Intravenous infusion of agalsidase alfa, a preparation of α-galactosidase A, is used for enzyme replacement therapy (ERT) in patients with Fabry disease. Although ERT appears to show some beneficial effects, most patients show only a modest response. We investigated using immunohistochemistry the relative tissue and cellular distribution of agalsidase alfa after a single intravenous injection in a mouse knockout model of Fabry disease. Specific immunostaining for agalsidase alfa was found only in liver, kidney, heart, testes, adrenal gland, spleen and bone marrow. There was no difference in distribution of the infused enzyme distribution among tissues sampled 4, 24, and 48 hours post-injection. The intracellular localization of immunopositivity varied considerably between organs with vascular endothelium being the most commonly positive site. α-Galactosidase A specific activity in tissue homogenates matched the relative extent of agalsidase alfa immunostaining distribution in the same organs. We conclude that intravenously injected agalsidase alfa has a very heterogeneous systemic distribution using an immunostaining technique.

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Section: Discussionsupporting

confidence: 56%

Cellular and tissue distribution of intravenously administered agalsidase alfa

Murray

Anver

Kennedy

et al. 2007

Molecular Genetics and Metabolism

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“…Clinically, the disease presents as a vascular disease, with development of cerebral white matter lesions (WMLs), cardiac hypertrophy, and kidney disease. Premature coronary artery and cerebral artery disease were found in one cohort 5 but was not confirmed in other studies. 6,7 A proportion of female carriers with α-galactosidase A deficiency also develop disease, albeit with a more protracted course.…”

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confidence: 71%

“…In Fabry disease patients, lysoGb3 levels in plasma were measured with a newly developed method based on tandem mass spectrometry with isotope-labeled lysoGb3 (5,6,7,8,9,13C5-lysoGb3) as an internal standard.…”

Section: Laboratory Assessmentsmentioning

confidence: 99%

Vascular Aspects of Fabry Disease in Relation to Clinical Manifestations and Elevations in Plasma Globotriaosylsphingosine

et al. 2012

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Abstract-Fabry disease is an X-linked hereditary lysosomal storage disorder attributed to a deficiency of α-galactosidaseA leading to increased plasma levels of globotriaosylsphingosine (lysoGb3 01).In women and atypical patients these vascular parameters were comparable with controls. Pulse wave velocity was not different; advanced glycation end products were only slightly increased in atypical patients. In classically affected women, a small increase in lysoGb3 was associated with an increase in IMT independent of age.In the classically affected men, all with increased IMT and high levels of plasma lysoGb3, lysoGb3 levels did not add to a higher IMT, suggestive of a ceiling effect. For FMD, elevated lysoGb3 levels (>7 nmol/L) contributed to a 2.9% lower FMD independent of age and sex (P=0.02). Increased carotid IMT and decreased brachial FMD occur in classic Fabry disease, which is associated with plasma lysoGb3 level independent of age and sex. These observations still exist despite enzyme replacement therapy. (Hypertension. 2012;60:998-1005.)

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“…Eng et al (2001b) reported that microvascular endothelial deposits of globotriaosylceramide were remarkably decreased by ERT with agalsidase beta but that no significant difference was observed in regard to improvement in neuropathy between Fabry patients treated with agalsidase beta and those treated with a placebo. Schiffmann et al (2006) reported the autopsy results for a 47-year-old man who was on ERT for more than 2 years before he died. They revealed that repeated infusions with agalsidase beta over a prolonged period did not appreciably remove storage material from tissues, including dorsal root ganglia, other than vascular endothelial cells.…”

Section: Human Fibroblastsmentioning

confidence: 99%

Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase

et al. 2007

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Peripheral neuropathy is one of the important manifestations of Fabry disease. Enzyme replacement therapy with presently available recombinant a-galactosidases does not always improve the Fabry neuropathy. But the reason has not been determined yet. We established a Schwann cell line from Fabry mice, characterized it, and then examined the uptake of a-galactosidase by cells and its effect on the degradation of accumulated substrate. The cells exhibited a distinct Schwann cell morphology and biochemical phenotype (a-Galactosidase activity was deficient, and numerous cytoplasmic inclusion bodies were present in the cells). A recombinant a-galactosidase added to the culture medium was incorporated into the cultured Fabry Schwann cells dose dependently. But the increase in cell-associated enzyme activity was less than that in the cases of human and mouse Fabry fibroblasts. The administration of a high dose of the enzyme improved the pathological changes in cells, although a low dose of it did not. Cellular uptake of the enzyme was strongly inhibited in the presence of mannose 6-phosphate. This suggests that the enzyme is incorporated via cation-independent mannose 6-phosphate receptors in Schwann cells. The low expression of cation-independent mannose 6-phosphate receptors in Schwann cells must be one of the reasons their uptake of the present enzymes was low. The administration of a high dose of the enzyme or the development of an enzyme containing many mannose 6-phosphate residues is required to improve Fabry neuropathy.Keywords Fabry disease Á Schwann cell Á a-Galactosidase Á Globotriaosylceramide Á Enzyme replacement therapy Á Cation-independent mannose 6-phosphate receptor

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Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement

Cited by 89 publications

References 20 publications

Cellular and tissue distribution of intravenously administered agalsidase alfa

Cellular and tissue distribution of intravenously administered agalsidase alfa

Vascular Aspects of Fabry Disease in Relation to Clinical Manifestations and Elevations in Plasma Globotriaosylsphingosine

Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase

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