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

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2014
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Grolez, Guillaume
Meguig, Sayah
Moreau, Caroline
Sablonniere, Bernard
Strubi-Vuiklhaume, Isabelle
Ryckewaert, G.
Jissendi, Patrice
Hopes, L.
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Introduction: In Parkinson’s disease (PD), excess iron is detected primarily in the substantia nigra (SN), where dopaminergic neurons are exposed to high levels of reactive oxygen species. Excess labile iron can enhance neuronal death by Fenton reaction. By oxidation of iron, ceruloplasmin allows iron transportation between blood and cells. Ceruloplasmin metabolism disturbances may increase brain iron overload. Our aim was to evaluate the interaction between iron chelation response on clinical, biological and MRI parameters and the ferroxidase activity in relation with the ceruloplasmin polymorphism D544E.

Methods: A pilot, double blind, placebo-controlled randomized clinical trial with a 6-month delayed-start paradigm, was set in 40 patients on stabilized dopamine regimens with deferiprone. Effects of deferiprone were analyzed according to the ceruloplasmine genotypes, on motor UPDRS, MRI R2* sequences (indirect assessment of iron overload) and blood iron metabolism.

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 . The AT group (n=5) had a greater clinical improvement, an greater increase in ceruloplasmin levels and a greater reduction of R2* value as compared with AA group (n=32).

Conclusions: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a therapeutic modality for all PD patients but with a higher benefit in patients carrying the AT polymorphism. Lower ceruloplasmin activity may be at higher risk of iron metabolism dysfunction and may require stronger iron chelation.

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ISO 690GROLEZ, 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: European Journal of Neurology. Wiley. 2014, 21(Suppl 1), pp. 444. ISSN 1351-5101. eISSN 1468-1331. Available under: doi: 10.1111/ene.12497
BibTex
@article{Grolez2014Modif-52647,
  year={2014},
  doi={10.1111/ene.12497},
  title={Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease},
  number={Suppl 1},
  volume={21},
  issn={1351-5101},
  journal={European Journal of Neurology},
  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: PP1186}
}
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    <dcterms:abstract xml:lang="eng">Introduction: In Parkinson’s disease (PD), excess iron is detected primarily in the substantia nigra (SN), where dopaminergic neurons are exposed to high levels of reactive oxygen species. Excess labile iron can enhance neuronal death by Fenton reaction. By oxidation of iron, ceruloplasmin allows iron transportation between blood and cells. Ceruloplasmin metabolism disturbances may increase brain iron overload. Our aim was to evaluate the interaction between iron chelation response on clinical, biological and MRI parameters and the ferroxidase activity in relation with the ceruloplasmin polymorphism D544E.&lt;br /&gt;&lt;br /&gt;Methods: A pilot, double blind, placebo-controlled randomized clinical trial with a 6-month delayed-start paradigm, was set in 40 patients on stabilized dopamine regimens with deferiprone. Effects of deferiprone were analyzed according to the ceruloplasmine genotypes, on motor UPDRS, MRI R2* sequences (indirect assessment of iron overload) and blood iron metabolism.&lt;br /&gt;&lt;br /&gt;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 . The AT group (n=5) had a greater clinical improvement, an greater increase in ceruloplasmin levels and a greater reduction of R2* value as compared with AA group (n=32).&lt;br /&gt;&lt;br /&gt;Conclusions: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a therapeutic modality for all PD patients but with a higher benefit in patients carrying the AT polymorphism. Lower ceruloplasmin activity may be at higher risk of iron metabolism dysfunction and may require stronger iron chelation.</dcterms:abstract>
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