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Background
The oxidative damage associated with extrahepatic siderosis is generally attributed to excessive generation of reactive oxygen species following a rise in labile cell iron. The latter generally attains toxic levels as a result of imbalances between iron ingress, use, storage and egress. Cell iron egress and thereby cell iron accumulation appear to be modulated by ceruloplasmin (CP), a copper ferroxidase that facilitates the incorporation of plasma iron (II) into circulating apotransferrin. Ceruloplasmin's key role is illustrated by an extreme example: that of aceruloplasminemia, which affects both systemic and brain iron metabolism. Low CP-ferroxidase activity has also been identified in the substantia nigra (SN) and the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD), and particularly in individuals bearing the AT genotype of the rs707753 CP gene variant (corresponding to a D544E protein change). A screening of ceruloplasmin gene sequences variations allowed to identify five new missense variations and an already known variation (rs707753), which was not previously identified in PD. Of these six missenses variations, D544E polymorphism was the most frequent and the only one to be significantly associated with PD and iron overload measured in SN by transcranial ultrasound. Although a growing body of evidence suggests that PD is associated with oxidative damage via iron accumulation in the SN, CP's putative involvement in iron accumulation and disease progression remains subject to debate. One way of addressing this issue involves comparing the ability of moderate iron chelation treatment to reducing both SN iron levels and United Parkinson's Disease Rating Scale (UPDRS) scores in PD patients according to the level of ceruloplasmin activity. The underlying rationale is that PD patients with lower CP activity might retain more cell iron and thus respond more favorably to iron chelation therapy.
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