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BRIEF COMMUNICATIONS: Gheona Altarescu, David F. Moore, and Raphael Schiffmann Effect of genetic modifiers on cerebral lesions in Fabry disease Neurology 2005; 64: 2148-2150 [Abstract] [Full text] [PDF]

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Effect of genetic modifiers on cerebral lesions in Fabry disease

Dimitri M. Hemelsoet, Anna Vantilborgh and Jan L. De Bleecker   (10 October 2005)

Reply from the Authors

Raphael Schiffmann, David F. Moore, Gheona Altarescu   (10 October 2005)

Effect of genetic modifiers on cerebral lesions in Fabry disease 10 October 2005
Dimitri M. Hemelsoet, Gent University Hospital, Department of Neurology De Pintelaan 185, B-9000 Gent, Belgium, Anna Vantilborgh and Jan L. De Bleecker Send Correspondence to journal: Re: Effect of genetic modifiers on cerebral lesions in Fabry disease dimitri.hemelsoet{at}ugent.be Dimitri M. Hemelsoet, et al.	We read the article by Altarescu et al with great interest.[1] They showed that factor V Leiden (FVL) and protein Z polyporphisms were significantly associated with cerebral lesions in Fabry disease. It is unclear whether it is only the heterozygous, and not the homozygous carrier state that appears to be associated with the occurrence of vascular lesions. It is possible that the patient numbers were too small and the incidence of the homozygous carriers was too low to show a significant difference. The authors do not provide any pathophysiological consideration regarding the relationship between a procoagulant state and Fabry disease. We think that there might be a pathophysiological link between FVL with increased activated protein C (APC) resistance and the accumulation of glycosphingolipids in Fabry disease. Sphingolipids are important components of cell membranes and tend to be clustered together with cholesterol in microdomains, called lipid rafts.[2] Lipid rafts have to cluster together to engage in specialized membrane function.[3] The ordered lipid environment might directly affect raft function and in lipid storage diseases involving raft lipids, the accumulation of one raft lipid class would slowly lead to trapping of other raft lipids in late endosomes.[2] Lipoproteins and membrane surfaces accelerate the proteolytic inactivation of factor Va by APC demonstrating the crucial role of glycosphingolipids in the blood coagulation system.[4] Neutral glycosphingolipids (e.g. globotriaosylceramide (Gb3Cer)) can enhance anticoagulant activity of APC.[4] It is possible that neutral glycosphingolipids may help form microdomains where they could enhance the binding of APC to a subset of microdomains, called “antithrombotic” microdomains because they could bind APC to interact with protein S and to enhance factor Va inactivation.[5] We think that accumulation of Gb3Cer in patients with Fabry disease may influence the formation and function of the ‘antithrombotic’ lipid rafts, and by doing so alter the glycosphingolipid-dependent inactivation of factor Va by activated protein C. In patients with Fabry disease and FVL this would lead to an increased poor anticoagulant response to APC and an increased procoagulant state (compared to patients with FVL and without Fabry disease) leading to cerebral white matter lesions and stroke. This mechanism is speculative and is based on partial results yet we think this hypothesis merits further experimental assessment. References 1. Altarescu G, Moore DF, Schiffmann R. Effect of genetic modifiers on cerebral lesions in Fabry disease. Neurology 2005;64:2148-215 2. Brown DA, London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 1998;14:111-136 3. Rajendran L, Simons K. Lipid rafts and membrane dynamics. J Cell Sci 2005;118:1099-1102 4. Deguchi H, Fernandez JA, Pabinger I, Heit JA, Griffin JH. Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway. Blood 2001;97:1907-1914 5. Deguchi H, Fernandez JA, Griffin JH. Neutral glycosphingolipid- dependent inactivation of coagulation factor Va by activated protein C and protein S. J Biol Chem 2002;277:8861-8865 Disclosure: The authors report no conflicts of interest.
Reply from the Authors 10 October 2005
Raphael Schiffmann, NIH Bldg. 10, Rm. 3D03, 9000 Rockville Pike, Bethesda, MD 20892-1260, David F. Moore, Gheona Altarescu Send Correspondence to journal: Re: Reply from the Authors rs4e{at}nih.gov Raphael Schiffmann, et al.	We thank Hemelsoet et al for their comments regarding our paper. [1] The most likely explanation for the increased risk of stroke being found mainly in heterozygotes for polymorphisms for factor V Leiden and protein Z is that there were very few if any homozygotes in our patient population. We agree with the speculation of Hemelsoet et al that globotriaosylceramide (Gb3) interferes with the function of rafts. We recently proposed that hypothesis. [6] We would like to emphasize that it has not yet been demonstrated that Gb3 is indeed an offending metabolite. In addition, the mechanism for stroke in Fabry is likely to be complex and multi-faceted. We, and others, previously describe the following abnormalities in Fabry disease: a prothrombotic state, endothelium-dependent vascular hyper-reactivity, cerebral hyper-perfusion associated with brain MRI lesions, abnormal regulation of cerebrovascular tone, and strong evidence for increased production of reactive oxygen species. [6-10] These and other unclear mechanisms, all modulated by other genetic factors, lead to a marked increased risk of stroke in Fabry disease. We hope that renewed interest in Fabry disease as a risk factor for stroke will lead to better understanding and treatment of this rare disorder and stroke in the general population. References 6. Moore DF, Ye F, Brennan M-L et al. Ascorbate decreases Fabry cerebral hyperpefusion suggesting a reactive oxygen species abnormality. J Magnet Res Imaging 2004;20:674-683. 7. Moore DF, Scott LJC, Gladwin MT, et al. Regional cerebral hyper-perfusion and nitric oxide dysregulation in Fabry disease: Reversal by enzyme replacement therapy. Circulation 2001;104:1506-12. 8. Moore DF, Altarescu G Barker WC, Patronas NJ Herscovitch P, Schiffmann R. White matter lesions (Leukoaraiosis) in Fabry disease occur in ‘prior’ selectively hypometabolic and hyperperfused brain regions. Brain Res Bull 2003;62:231-240. 9. Bodary PF, Shen Y, Vargas FB, et al. Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency. Circulation 2005;111:629-632. Epub January 24, 2005. 10. Hilz MJ, Kolodny EH, Brys M, Stemper B, Haendl T, Marthol H. Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease. J Neurol 2004;251:564-570. Disclosure: The authors report no conflicts of interest.