Ida Manna

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.

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.

Familial mesial temporal lobe epilepsy (FMTLE) : a clinical and genetic study of 15 Italian families.

AbstractIntroductionFamilial mesial temporal lobe epilepsy (FMTLE) is characterized by prominent psychic and autonomic seizures, often without hippocampal sclerosis (HS) or a previous history of febrile seizures (FS), and good prognosis. The genetics of this condition is largely unknown.We present the electroclinical and genetic findings of 15 MTLE Italian families.Patients and methodsFMTLE was defined when two or more first-degree relatives had epilepsy suggesting a mesial temporal lobe origin. The occurrence of seizures with auditory auras was considered an exclusion criterion. Patients underwent video-EEG recordings, 1.5-Tesla MRI particularly focused on hippocampal analysis, and neuropsychological evaluation. Genetic study included genotyping and linkage analysis of candidate loci at 4q, 18q, 1q, and 12q as well as screening for LGI1/Epitempin mutations.ResultsMost of the families showed an autosomal dominant inheritance pattern with incomplete penetrance. Fifty-four (32 F) affected individuals were investigated. Twenty-one (38.8 %) individuals experienced early FS. Forty-eight individuals fulfilled the criteria for MTLE. Epigastric/visceral sensation (72.9 %) was the most common type of aura, followed by psychic symptoms (35.4 %), and déjà vu (31.2 %). HS occurred in 13.8% of individuals, three of whom belonged to the same family. Prognosis of epilepsy was generally good. Genetic study failed to show LGI1/Epitempin mutations or significative linkage to the investigated loci.DiscussionFMTLE may be a more common than expected condition, clinically and genetically heterogeneous. Some of the reported families, grouped on the basis of a specific aura, may represent an interesting subgroup on whom to focus future linkage studies.

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 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.

A functional polymorphism in the SCN1A gene does not influence antiepileptic drug responsiveness in Italian patients with focal epilepsy

A splice site variation (c.603‐91G>A or rs3812718) in the SCN1A gene has been claimed to influence efficacy and dose requirements of carbamazepine and phenytoin. We investigated the relationship between c.603‐91G>A polymorphism and response to antiepileptic drugs (AEDs) in 482 patients with drug‐resistant and 401 patients with drug‐responsive focal epilepsy. Most commonly used AEDs were carbamazepine and oxcarbazepine. The distribution of c.603‐91G>A genotypes was similar among drug‐resistant and drug‐responsive subjects, both in the entire population and in the groups treated with carbamazepine or oxcarbazepine. There was no association between the c.603‐91G>A genotype and dosages of carbamazepine or oxcarbazepine. These findings rule out a major role of the SCN1A polymorphism as a determinant of AED response.

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.

Morphological correlates of MAO A VNTR polymorphism: New evidence from cortical thickness measurement

A functional variant in the mono-amine oxidase A (MAO A) gene has been shown to impact neural function related to cognitive and affective processing and increase risk for conduct disorders. However, whether MAO A could be a candidate gene for structural variation in the human brain remains to be clarified. This study is the first to investigate the effect of this genotype on brain morphology by measuring cortical thickness. We genotyped 59 healthy male subjects (36 carrying the MAO A High-activity allele and 23 the MAO A Low-activity allele) who underwent structural MRI at 3T. Models of the grey-white and pial surfaces were generated for each individuals cortices, and the distance between these two surfaces was used to compute cortical thickness within a priori regions of interest of the orbitofrontal and cingulate cortices. Surface-based analysis of the cortical mantle showed that the MAO A genotype was associated with structural differences in the orbitofrontal cortex bilaterally, where the MAO A High-activity group showed the highest cortical thickness value and the MAO A Low-activity group the lowest. Otherwise, no significant difference was detected within the cingulate cortex. Thus, we confirm the hypothesis that the MAO A genotype has a specific impact on human brain morphology. In particular, thickness measurement of the orbitofrontal cortex provides new evidence about the biological impact of the MAO A genotype on neural systems relevant to the pathophysiology of behavioural disorders.