Rita Cittadella

GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe epilepsy

Background: Dysfunction of γ-aminobutyric acid (GABA) (B) receptors has been implicated in the pathogenesis of temporal lobe epilepsy (TLE). Objective: To evaluate the genetic contribution of cloned human GABA(B) receptors to TLE. Methods: The authors genotyped 141 patients (78 women and 63 men; mean age = 49.1 ± 18.0 years) with nonlesional TLE and 372 age- and sex-matched normal individuals for the known polymorphism G1465A in the human GABA(B) receptor 1 [GABA(B[1])] gene. Results: There was a highly significant overrepresentation of the G1465A heterozygote in patients with TLE compared with controls. The A/G genotype was found in 17% of the 141 patients with TLE and in only 0.5% of the 372 controls (p < 0.0001). The authors also found that patients carrying the A allele had a significantly higher risk (p = 0.003, OR = 6.47, 95% CI = 2.02 to 20.76) of developing drug-resistant TLE. Furthermore, the age at onset of seizures tended to be lower in patients with A/G genotype, but the difference was not significant. Conclusions: The results of this study indicate that the GABA(B[1]) polymorphism (G1465A) confers a highly increased susceptibility to TLE. Moreover, it seems to influence the severity of this common epileptic disorder.

Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis

Abstract.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-ε4 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.

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

OBJECTIVE To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. BACKGROUND Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. METHODS A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. RESULTS The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. CONCLUSIONS Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.

APOE and risk of cognitive impairment in multiple sclerosis

Objectives‐ The APOE gene polymorphism and the −491 A/T polymorphism in its regulatory region have been associated with an increased risk for developing Alzheimers disease. We examined these polymorphisms in multiple sclerosis (MS) patients, to determine if a genetic predisposition may explain the risk for developing cognitive decline in MS. Material and methods‐ Eighty‐nine relapsing‐remitting and secondary progressive MS patients underwent to a full neuropsychological battery as well as to determination of APOE and −491 A/T polymorphisms. Genetic analysis was also performed in 107 population controls. Results‐ The APOE polymorphism was not associated with the risk of cognitive impairment in MS patients. The AA genotype of the −491 A/T polymorphism in the APOE regulatory region was more frequent in cognitively impaired than in cognitively preserved MS subjects. Conclusion‐ The AA homozygous state of the −491 AIT polymorphism of the APOE regulatory region is associated with cognitive impairment in patients with MS.

ApoE Epsilon4 allele and disease duration affect verbal learning in mild temporal lobe epilepsy

Summary:  Purpose: To clarify the possible role of other factors including the ApoE ɛ4 allele for memory decline in temporal lobe epilepsy (TLE).

Apolipoprotein E genotype does not influence the progression of multiple sclerosis

Abstract.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.

Apolipoprotein E Polymorphisms and the Risk of Nonlesional Temporal Lobe Epilepsy

Summary: Purpose: To evaluate whether the inheritance of the apolipoprotein E (ApoE) ε4 allele is a risk factor for nonlesional temporal lobe epilepsy (TLE), and to determine whether the newly described ‐491 A/T ApoE polymorphism may independently affect the risk of nonlesional TLE.

Investigating the role of brain‐derived neurotrophic factor in relapsing–remitting multiple sclerosis

Multiple sclerosis (MS) is a common, heterogeneous disorder of the central nervous system with a complex trait composed of both genetic and environmental factors. Recently, scientific interest has increased in defining factors that possibly contribute to brain functional plasticity; the results might be useful to assess the relationship between MS lesion burden and clinical events, as well as explaining the well‐known phenotypic heterogeneity of the disease. In this study, we explored the effect of the Val66Met brain‐derived neurotrophic factor (BDNF) functional polymorphism on cognitive performances and volumetric measurements obtained by magnetic resonance imaging of the brain in a selected population of relapsing–remitting MS (RRMS) patients, with relatively short disease duration and minimal clinical disability, compared to gender, age and educational‐level matched healthy subjects. We found that in the RRMS group, the BDNF Met‐allele was significantly associated with the lower volume of cerebral grey matter (GM) (P = 0.005). Furthermore, a significant (P = 0.013) interaction effect between ‘MS‐status’ and the BDNF genotype was found for GM volumes, with the result that patients carrying the BDNF Met‐allele showed a higher risk of developing global GM atrophy than the homozygous Val/Val. No BDNF‐related impact on global neuropsychological functions resulted in either RRMS patients or controls. Our data seem to be consistent with the reported influence of BDNF in neuronal plasticity, thus suggesting that the Met‐allele might have a negative prognostic effect on cortical morphometry in RRMS patients.

Prodynorphin Gene Promoter Polymorphism and Temporal Lobe Epilepsy

∗†Antonio Gambardella, †Ida Manna, ∗†Angelo Labate, ‡Rosanna Chifari, †Paolo Serra, †Antonella La Russa, §Emilio LePiane, †Rita Cittadella, †Virginia Andreoli, §Francesco Sasanelli, ∗†Mario Zappia, §Umberto Aguglia, and ∗†Aldo Quattrone ∗Institute of Neurology, School of Medicine, Catanzaro; †Institute of Neurological Sciences, National Research Council, Cosenza; ‡Clinic of Neurology, Hospital of Melegnano, Milan; and §Regional Epilepsy Centre, Hospital of Reggio Calabria, Italy

Genetic association of α2-macroglobulin polymorphisms with AD in southern Italy

The authors investigated the segregation of two polymorphisms of the &agr;2-macroglobulin gene (A2M-I/D and A2M-Ile1000Val) in patients with sporadic AD from southern Italy. The A2M-I and A2M-Val1000 alleles were more frequent in cases than in controls, and this effect was independent from the APOE-&egr;4 status as well as from the age at onset of AD. Moreover, subjects carrying the A2M genotype I/I-Val/Val had a threefold increase of risk for AD. These data support a population-based susceptibility for AD linked to A2M polymorphisms.