Association between sex, systemic iron variation and probability of Parkinson's disease.

OBJECTIVE: Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD. MATERIALS AND METHODS: In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins. RESULTS: The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation. CONCLUSIONS: This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex.

A case of a mild Wolfram Syndrome with concomitant ATP7B mutation.

BACKGROUND: Wolfram Syndrome 1 (WS1) has been characterized on the basis of mutation in the WFS1 gene encoding a calcium storage wolframin endoplasmatic reticulum transmembrane glycoprotein. PATIENTS AND METHODS: We observed a WS 10-years old female subject, with Type 1 diabetes-mellitus (DM), that had compound heterozygous WSF1 mutations but without other symptoms generally observed in WS subjects, such as optic atrophy or neurodegeneration. RESULTS: Decreased copper, ceruloplasmin, and transferrin levels, pointing to a copper deficiency, were associated with a new c.18703A>G mutation in the ATP7B gene, while lower calcium levels were associated with WSF1 mutations. An omega-3 fatty acids therapy was administrated to the subject in the attempt to ameliorate diabetes symptoms, restored copper deficiency, and normal calcium levels. CONCLUSIONS: This specific case report provides new insights into the potential interplay of ATP7B mutation in shaping a milder WS clinical picture.

Non-ceruloplasmin bound copper and ATP7B gene variants in Alzheimer's disease.

ATP7B, a protein mainly expressed in the hepatocytes, is a copper chaperone that loads the metal into the serum copper-protein ceruloplasmin during its synthesis and also escorts superfluous copper into the bile, by a sophisticated trafficking mechanism. Impaired function of this ATPase is associated with a well-known inborn error of copper metabolism, Wilson's disease (WD). Several mutations of ATP7B are known, involving different regions of the protein, thus resulting in a plethora of phenotypes in WD patients. It is a consolidated notion that copper dysmetabolism occurs in Alzheimer's disease (AD) as well. Besides the molecular mechanisms relating copper to the protein hallmarks of this disease and neurodegeneration, more recently the observation that a free-copper in the serum, not bound to ceruloplasmin (non-Cp-Cu), characterizes AD patients, prompted our research to identify possible genetic defects of the ATP7B gene in AD patients. Four specific single nucleotide polymorphisms and a WD rare mutation have a statistical association with AD. They contribute to characterize a copper subtype of AD. Additional facets of this AD phenotype, typified by higher levels of non-Cp-Cu, are presented and discussed in the framework of copper failure as an accelerator risk factor of neurological disorders with different aetiology.

Effects of hemochromatosis and transferrin gene mutations on peripheral iron dyshomeostasis in mild cognitive impairment and Alzheimer's and Parkinson's diseases.

Deregulation of iron metabolism has been observed in patients with neurodegenerative diseases. We have carried out a molecular analysis investigating the interaction between iron specific gene variants [transferrin (TF, P589S), hemochromatosis (HFE) C282Y and (H63D)], iron biochemical variables [iron, Tf, ceruloplasmin (Cp), Cp:Tf ratio and % of Tf saturation (% Tf-sat)] and apolipoprotein E (APOE) gene variants in 139 Alzheimer's disease (AD), 27 Mild Cognitive Impairment (MCI), 78 Parkinson's disease (PD) patients and 139 healthy controls to investigate mechanisms of iron regulation or toxicity. No difference in genetic variant distributions between patients and controls was found in our Italian sample, but the stratification for the APOEε4 allele revealed that among the APOEε4 carriers was higher the frequency of those carriers of at least a mutated TF P589S allele. Decreased Tf in both AD and MCI and increased Cp:Tf ratio in AD vs. controls were detected. A multinomial logistic regression model revealed that increased iron and Cp:Tf ratio and being man instead of woman increased the risk of having PD, that increased values of Cp:Tf ratio corresponded to a 4-fold increase of the relative risk of having MCI, while higher Cp levels were protective for PD and MCI. Our study has some limitations: the small size of the samples, one ethnic group considered, the rarity of some alleles which prevent the statistical power of some genetic analysis. Even though they need confirmation in larger cohorts, our data suggest the hypothesis that deregulation of iron metabolism, in addition to other factors, has some effect on the PD disease risk.

Inflammation and iron metabolism in adult patients with epilepsy: does a link exist?

PURPOSE: Inflammation has been shown to play a key role in epilepsy, and may also affect both the iron status and metabolism. Consequently, a relationship between iron metabolism and neuronal excitability and seizures could be expected. METHODS: We aimed at characterizing in 37 adult patients affected by focal epilepsy during the interictal period serum inflammatory cytokines, such as interleukin 6 (IL-6), IL-6 soluble receptor (IL6-sR), interleukin 1 (IL-1), IL-1 receptor-antagonist (IL-1RA), tumor necrosis factor-α (TNF-α), and markers of iron status and metabolism: hemoglobin concentration (Hgb), mean corpuscular volume (MCV), hematocrit (Hct) red blood cell (RBC) count, serum iron and copper concentrations, ceruloplasmin (iCp), the ceruloplasmin enzymatic activity (eCp), the specific ceruloplasmin activity (eCp/iCp), total ferroxidase activity, transferrin (Tf), serum ferritin (SF), Tf saturation (Sat-Tf), and ratio of ceruloplasmin to transferrin (Cp/Tf). We investigated the correlations between these biological markers as well their relationship with patients' clinical features. A group of 43 healthy subjects had the same serologic measurements to serve as controls. RESULTS: Our findings showed in the group of patients with epilepsy an increase of IL-6 (p=0.026) and a decrease of TNF-α (p=0.002) with respect to healthy subjects. For the first time, we also detected significant changes in iron metabolism as an increase of Cp/Tf (p=0.011) and a decrease of Tf (p=0.031), possibly driven by cytokine modifications and consistent with inflammation as acute phase and antioxidant activity markers. Accordingly, TNF-α positively correlated with Tf (p=0.005). Finally, a significant positive correlation between seizures frequency and eCp (p=0.046) and inversely with Hgb (p=0.038) and Hct (p=0.041), and an inverse correlation between TNF-α and the duration of epilepsy (p=0.021) was detected. CONCLUSIONS: Our findings demonstrate a relevant relationship between epilepsy and systemic inflammation, with a consistent link between seizures, inflammatory cytokines (IL-6 and TNF-α) and iron regulation and metabolism, as acute phase and antioxidant markers.