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Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease

Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease

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GROLEZ, Guillaume, Sayah MEGUIG, Caroline MOREAU, Bernard SABLONNIERE, Isabelle STRUBI-VUIKLHAUME, G. RYCKEWAERT, Patrice JISSENDI, L. HOPES, Marcel LEIST, Dominik PÖLTL, 2014. Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease. In: Movement Disorders. Wiley. 29(Suppl 1), pp. S241. ISSN 0885-3185. eISSN 1531-8257. Available under: doi: 10.1002/mds.25914

@article{Grolez2014Modif-52646, title={Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease}, year={2014}, doi={10.1002/mds.25914}, number={Suppl 1}, volume={29}, issn={0885-3185}, journal={Movement Disorders}, author={Grolez, Guillaume and Meguig, Sayah and Moreau, Caroline and Sablonniere, Bernard and Strubi-Vuiklhaume, Isabelle and Ryckewaert, G. and Jissendi, Patrice and Hopes, L. and Leist, Marcel and Pöltl, Dominik}, note={Poster Presentation Article Number: Meeting Abstract 652} }

2021-02-01T08:43:19Z terms-of-use Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease Sablonniere, Bernard 2021-02-01T08:43:19Z Hopes, L. Meguig, Sayah Moreau, Caroline Strubi-Vuiklhaume, Isabelle Meguig, Sayah Pöltl, Dominik Ryckewaert, G. Ryckewaert, G. Hopes, L. Leist, Marcel Pöltl, Dominik Leist, Marcel Grolez, Guillaume eng Grolez, Guillaume Sablonniere, Bernard Jissendi, Patrice Moreau, Caroline Strubi-Vuiklhaume, Isabelle Objective: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Our aim was to evaluate the interaction between iron chelation response on clinical, biological and MRI parameters and the variable ferroxidase activity in relation with the ceruloplasmin polymorphism D544E.<br /><br />Background: In PD, excess iron is detected primarily in the substantia nigra (SN), where dopaminergic neurons are exposed to high levels of Reactive oxygen species (ROS). Excess labile iron can further worsen neuronal functions and triggered apoptosis by Fenton reaction. By oxidation of toxic ferrous (Fe2+) iron into ferric (Fe3+) iron, ceruloplasmin allows iron transportation between blood and cells. Ceruloplasmin metabolism disturbances, notably through lower ferroxidase activity of AT polymorphism, may increase brain iron overload.<br /><br />Methods: A pilot, double blind, placebo‐controlled randomized clinical trial with a 6‐month delayed‐start paradigm, was set in 40 early‐stage patients on stabilized dopamine regimens with deferiprone (oral administration of 30mg/kg/day). The effect of deferiprone was analyzed according to the ceruloplasmine genotypes (AT versus AA), on motor UPDRS, MRI R2* (T2*=1/R2*) sequences (indirect assessment of iron overload) and the plasmatic ceruloplasmin, iron serum, transferrin and ferritin levels.<br /><br />Results: Early‐start patients (n = 19) compared to delayed start patients (n = 18) (37/40 completed) responded significantly earlier and sustainably to treatment in both SN iron deposits (R2* MRI) and motor UPDRS (p < 0.03 and p < 0.04, respectively). After 12 months of deferiprone, the AT group (n=5) had a greater clinical improvement, an increase in ceruloplasmin levels and a reduction of R2* value as compared with AA group (n=32).<br /><br />Conclusions: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. The benefit appeared higher in patients carrying the AT polymorphism, suggesting that patients with lower ceruloplasmin activity may be at higher risk of iron metabolism dysfunction and may require stronger iron chelation. These results warrant confirmation with multicenter study on a larger population and longer time. Jissendi, Patrice 2014

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