Possible Implication of GSTP1 and NQO1 Polymorphisms on Natalizumab Response in Multiple Sclerosis.

Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphism of genes encoding detoxification enzymes, such as NQO1 and GSTP1 could influence susceptibility to MS. The monoclonal antibody natalizumab is an effective treatment in MS. Natalizumab's efficacy in MS patients with regard to NQO1 and GSTP1 genetic polymorphisms is investigated. 130 patients with definite MS according to the Mc Donald's criteria treated monthly with natalizumab were included in the study. MS patients were classified with regard to their clinical subtype, gender and clinical outcome after Natalizumab administration. GSTP1 and NQO1 genotyping was performed using Real-Time PCR and PCR-RFLP assays. Among our cohort of MS patients, 88.5% responded and 11.5% manifested clinical deterioration after natalizumab treatment. Statistical analysis revealed a significantly increased frequency of double NQO1 and GSTP1 mutant polymorphisms in non responders compared to the responders. Therefore, patients who carry the wild type genotype or only one polymorphism for either NQO1 or GSTP1 gene have possibly a better clinical outcome after the natalizumab therapy. Our findings indicate that antioxidant efficiency might reflect a better clinical outcome after natalizumab administration. Hence, oxidative stress reduction might be another mechanism through which natalizumab exerts its protective effect.

Combined GSTP1 and NQO1 germline polymorphisms in the susceptibility to Multiple Sclerosis.

Germline polymorphisms of detoxification genes could influence susceptibility to Multiple Sclerosis (MS). Glutathione-S-transferases (GSTs) and NAD(P)H: quinone oxidoreductase 1 (NQO1) are detoxifying enzymes involved in biotransformation of metabolites preventing cells from oxidative damage. In order to evaluate the possible contribution of the A313G GSTP1 inactivating polymorphism, alone and in combination with the C609T NQO1 genetic variant in MS susceptibility, we performed a case-control study consisting of 254 MS patients and 370 healthy donors. Genotypes were investigated using a new Real-Time PCR and PCR-RFLP assays. The GSTP1 polymorphism was evaluated in relation to patients' characteristics (clinical subtypes, age and gender) and the NQO1 gene status. GSTP1 genotype distribution was similar between cases and controls. Higher frequency of GSTP1 heterozygotes was observed in patients with relapsing remitting disease (RRMS) (p = 0.019), especially in those presenting a benign form (EDSS ≤ 2 after 10-15 years from the disease onset). Interestingly, genotype distribution analysis of combined GSTP1 and NQO1 polymorphisms revealed significantly higher frequency of GSTP1 heterozygous (A/G) and NQO1 variant genotypes (C/T and T/T) in patients as compared to the controls (p = 0.031). The increased incidence of combined GSTP1 and NQO1 variant genotypes in MS patients may suggest that defective function of detoxification enzymes might be an important determinant of susceptibility and clinical manifestation of the disease. Moreover, the results suggest a possible role for the GSTP1 heterozygous background in the development of RRMS.

The C609T inborn polymorphism in NAD(P)H:quinone oxidoreductase 1 is associated with susceptibility to multiple sclerosis and affects the risk of development of the primary progressive form of the disease.

Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphisms of genes encoding detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), could influence susceptibility to MS. To test this hypothesis we performed a case-control study in which we compared the distribution of NQO1 genotypes between 231 MS patients and 380 controls, using both PCR-RFLP and real-time PCR assays. Correlations with MS clinical subtype classification and gender were also evaluated. A significantly higher frequency of the homozygous (T/T) and heterozygous (C/T) NQO1 C(609)T variant genotypes was observed among MS patients compared to controls (P=0.01), with MS patients showing a 1.5-fold increased risk of carrying at least one variant T allele (P=0.009). Interestingly, patients belonging to the primary progressive subgroup exhibited a significantly higher incidence of the heterozygous C/T variant genotype, compared to the other forms of MS (P=0.019). There was no correlation of the NQO1 polymorphism with gender. These results provide the first evidence for a pathogenetic role for the NQO1 C(609)T polymorphism in MS susceptibility and suggest a possible role for the NQO1 genetic background in the development of primary progressive MS.

On the calculation of transcallosal conduction time using transcranial magnetic stimulation.

Transcallosal conduction time (TCT), based on the results of transcranial magnetic stimulation studies, is currently calculated as a function of the ipsilateral silent period (iSP) and of the motor evoked potential (MEP) obtained from a target muscle (TCTcurrent = iSP latency - MEP latency). We argue that this measure overestimates TCT and may lead to a bias in statistical group comparisons. We propose an alternative measure, TCTproposed, which we defined as TCTproposed = iSP latency - cSP latency, where cSP is the contralateral silent period. We report our results on the comparison of the two measures in twenty healthy individuals and provide a theoretical basis for TCTproposed.

A novel CADASIL-causing mutation in a stroke patient.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an uncommon autosomal dominant genetic disease due to mutations in the Notch3 gene on chromosome 19. The major clinical characteristics of CADASIL are migraine, recurrent ischaemic strokes and dementia. CASE REPORT: We describe the case of a 58-year old man who presented with a minor stroke that occurred in the absence of significant vascular risk factors. His family history included stroke, dementia and early death. An MRI brain scan demonstrated hyperintensities in the white matter on FLAIR images with prominent involvement of the area of the external capsule bilaterally. Based on the family history and the MRI findings, CADASIL was suspected. Mutational analysis of the Notch3 gene disclosed a novel mutation substituting cysteine for glycine at codon 251 in exon 5, confirming the diagnosis of CADASIL. CONCLUSION: This case suggests that CADASIL should be suspected in patients with stroke that arises in the absence of known vascular risk factors, especially if there are typical MRI findings. A strong family history of stroke and dementia are also supportive.