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Increasing evidence links dysregulation of NR2B-containing N-methyl- d-aspartate receptor remodelling and trafficking to Alzheimer's disease (AD). This theme offers the possibility that the GRIN2B gene, encoding this selective NR2B subunit, represents a potential molecular modulating factor for this disease. Based on this hypothesis, we carried out a mutation scanning of exons and flanking regions of GRIN2B in a well-characterized cohort of AD patients, recruited from Southern Italy. A 'de novo' p.K1293R mutation, affecting a highly conserved residue of the protein in the C-terminal domain, was observed for the first time in a woman with familial AD, as the only genetic alteration of relevance. Moreover, an association study between the other detected sequence variants and AD was performed. In particular, the study was focused on five identified single nucleotide polymorphisms: rs7301328, rs1805482, rs3026160, rs1806191 and rs1806201, highlighting a significant contribution from the GRIN2B rs1806201 T allele towards disease susceptibility [adjusted odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.40-2.63, p < 0.001, after correction for sex, age, and APOE ε4 genotype]. This was confirmed by haplotype analysis that identified a specific haplotype, carrying the rs1806201 T allele (CCCTC), over-represented in patients versus controls (adjusted OR = 6.03; p < 0.0001). Although the pathogenic role of the GRIN2B-K1293R mutation in AD is not clear, our data advocate that genetic variability in the GRIN2B gene, involved in synaptic functioning, might provide valuable insights into disease pathogenesis, continuing to attract significant attention in biomedical research on its genetic and functional role. [ABSTRACT FROM AUTHOR]

Background Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-e4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer's Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons. Objective To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS. Methods Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms. Results Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the ε4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable. Conclusion The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment. [ABSTRACT FROM AUTHOR]

Although multiple sclerosis (MS) is considered to be an inflammatory demyelinating disease, increasing evidence indicates that it is also an axonal pathology; indeed, studies of experimental allergic encephalitis showed that several neuronal proteins such as synapsins take part in the pathogenesis of the axonal dysfunction. Synapsins are a family of abundant neuron-specific phosphoproteins with crucial roles in synaptogenesis and neuronal plasticity. Distinct genes encode the three different isolated proteins (I, II and III); of interest, the gene of synapsin III (SYN3) is located in the chromosome 22q12-q13, a locus close to one of the candidate susceptibility regions (22q13.1) for MS. In the present study we selected two polymorphisms (g.–631C > G and g.–196A > G) within the SYN3 5’-promoter region because of the protein’s role and genetic location; we analysed the allele and genotype distributions of these polymorphisms in a selected MS population of southern Italy. An inverse association between MS and the g-631C > G polymorphism was found; indeed, the two polymorphisms were in almost complete linkage disequilibrium and the haplotype analysis showed that the C631/A196 haplotype seemed to confer a significant protection against MS. [ABSTRACT FROM AUTHOR]

Objective:. To investigate the association between apolipoprotein E (APOE) polymorphisms and the progression of MS. Methods:. We investigated 428 subjects affected by clinically defined MS, with a disease duration of at least three years. We collected data concerning the age at onset of MS, clinical type, disease duration and disability according to the expanded disability status scale (EDSS). We also calculated the progression index (PI) to evaluate disease progression. APOE genotyping and the –491 A/T polymorphism of the APOE promoter were determined. Results:. No association was observed between the APOE ε4 allele and clinical characteristics of our study population. We also investigated the –491 A/T APOE promoter polymorphism in 236 MS subjects and did not find any association between the –491 A/T polymorphism and the selected clinical variables. Conclusions:. In our population the APOE ε4 allele and the –491 A/T APOE promoter polymorphism are not associated with a more rapid course of MS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on phenotypic variation of dominant optic atrophy and deafness due to a novel OPA1 mutation that was published in previous issue.