5-Aminolevulinic acid (ALA) seems to be responsible for the neuropsychiatric manifestations of acute intermittent porphyria (AIP). Our aim was to study the effect of ALA on the different metabolic pathways in the mouse brain to enhance our knowledge about the action of this heme precursor on the central nervous system. Heme metabolism, the cholinergic system, the defense enzyme system, and nitric oxide metabolism were evaluated in the encephalon of CF-1 mice receiving a single (40 mg/kg body mass) or multiple doses of ALA (40 mg/kg, every 48 h for 14 days). We subsequently found ALA accumulation in the encephalon of the mice. ALA also altered the brain cholinergic system. After one dose of ALA, a decrease in superoxide dismutase activity and a reduction in glutathione levels were detected, whereas malondialdehyde levels and catalase activity were increased. Heme oxygenase was also increased as an antioxidant response to protect the encephalon against injury. All nitric oxide synthase isoforms were induced by ALA, these changes were more significant for the inducible isoform in glial cells. In conclusion, ALA affected several metabolic pathways in mouse encephalon. Data indicate that a rapid response to oxidative stress was developed; however, with long-term intoxication, the redox balance was probably restored, thereby minimizing oxidative damage.

Haemophilia A (HA) (OMIM #306700), an X-linked recessive disorder characterized by reduced activity of coagulation factor VIII (FVIII:C), is caused by deleterious mutations in the F8. HA can be treated by administration of the deficient FVIII. However, about 20%-30% of severe HA patients (biochemically defined as FVIII:C < 1 IU/dL) developed FVIII neutralizing antibodies (inhibitors) making replacement therapy ineffective. Inhibitors result in higher therapy costs and decreased quality-of-life and life expectancy of patients with haemophilia. From the Public Health System perspective, Argentina currently compiles 96 HA patients with clinically identified inhibitors out of a total 2220 [1]. This reduced figure (96/2220) is a successful result of undergoing an extended prophylaxis covering more than 65% of patients, in which therapeutic FVIII is not administered under risk conditions, and immune-tolerance induction treatment for inhibitor eradication.As a typical complex trait (multifactorial) an operative classification of inhibitor development in haemophilia focuses on two main groups of risk factors: modifiable (environmental factors) and non-modifiable (genetic factors, often involving several genes with different relative weight predisposing to the phenotype). Among the former, environmental risk factors include treatment-related factors and immune-system challenges. Among the latter, in HA, the causative F8 genotype has been established as the main factor conditioning inhibitor development (in Argentina [2], and worldwide, reviewed in [3]), but it also counts a group of secondary risk factors, weaker than the F8 genotype, such as family history of inhibitors, ethnicity, human lymphocyte antigen haplotype and polymorphisms linked to immune-system genes, such as

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