Association study of the 2-bp deletion polymorphism in exon 6 of the CHRFAM7A gene with idiopathic generalized epilepsy.

There is evidence of linkage between the 15q13-q14 locus, containing the gene encoding the α7 subunit (CHRNA7) of the neuronal nicotinic acetylcholine receptor (nAChR) and its partially duplicated isoform (CHRFAM7A), and epilepsy. Additionally, a 2-bp deletion polymorphism (c.497-498delTG; rs67158670) in CHRFAM7A, resulting in a frame shift and truncation of the protein product, is associated with some neurological diseases. This study was designed to explore the possibility of an association of the c.497-498delTG polymorphism of CHRFAM7A with idiopathic generalized epilepsies (IGEs) in Polish children and young patients. The study included 197 IGE patients and 258 unrelated healthy individuals. The frequency of the CHRFAM7A c.497-498delTG polymorphism was determined in each group using heteroduplex analysis. An association between the c.497-498delTG polymorphism of CHRFAM7A and IGE was evidenced. It was demonstrated that the frequency of the CHRFAM7A 2-bp deletion carriers was significantly lower in the IGE patients than in the control group. The observed frequency of 2-bp deletion carriers was high in IGE subjects (64%), but significantly higher in control subjects (76%). Carriers of at least one copy of the -2 bp allele had halved their risk of IGE susceptibility (delTG/delTG and delTG/wild-type versus wild-type/wild-type: odds ratio=0.55; 95% confidence intervals=0.365-0.827; p=0.004). Moreover, it has been demonstrated that this polymorphic variant is associated with the c.524-12_524-11insGTT variation (rs10649395) in intron 7 of CHRFAM7A. Our study substantiates the involvement of the α7 subunit of nAChR in the pathophysiology of IGEs and indicates that the CHRFAM7A c.497-498TG deletion or a nearby polymorphism may play a role in the pathogenesis of IGE. Further work should concentrate on ascertaining the exact mechanism of this polymorphism's effect and its relationship with IGE.

MTHFR, MTR, and MTHFD1 gene polymorphisms compared to homocysteine and asymmetric dimethylarginine concentrations and their metabolites in epileptic patients treated with antiepileptic drugs.

PURPOSE: The purpose of the study was to determine the frequency of occurrence of polymorphisms of genes MTHFR (C677T), MTR (A2756G), and MTHFD1 (G1958A), as well as to analyze the concentration of homocysteine (Hcy), methionine (Met), asymmetric dimethylarginine (ADMA), and arginine (Arg) in epileptics treatment with antiepileptic drugs (AEDs), and controls. METHOD: The study included 65 epileptic patients treated with variable AEDs and 61 controls. The levels of Hcy and Met were determined by HPLC/EC, ADMA and Arg by HPLC with fluorescence detection. Polymorphisms of the studied genes were determined by PCR-RFLP. RESULTS: The study demonstrates that AEDs treatment in epileptics leads to increase in Hcy (p<0.05) and ADMA (p<0.01) concentrations. Greater increases in Hcy concentration during AEDs treatment appear to occur in individuals with the MTHFR CT (C677T) and MTHFD1 GG (G1958A) genotypes. Genetic conditions also appear to be related with changes in the ratios of Hcy, Met, Arg, and ADMA. It seems that in cases of AEDs treatment's effect on hyperhomocysteinemia, epileptic individuals appear to have a disturbed control of Hcy over ADMA. CONCLUSIONS: It is possible, that polymorphisms of genes related to Hcy-to-Met metabolism, in epileptics treated with AEDs may have an effect on the regulation of levels of risk factors of vascular diseases, Hcy and ADMA.

[Homocysteine and asymmetric dimethylarginine (ADMA) in epilepsy]. / Homocysteina i asymetryczna dimetyloarginina (ADMA) w padaczce.

Homocysteine (Hcy) is a thyol amino acid resulting from demethylation of methionine. It is metabolized through two pathways: remethylation and trassulfuration, which use as cofactors folate, vitamin B6 and vitamin B12. Hyperhomocysteinemia (hHcy) is a risk factor for cerebrovascular disease, dementia, inborn defects, impaired cognitive function. Several drugs may change metabolic pathways of Hcy, leading to an alteration of plasma Hcy levels. HHcy has been documented in epileptic patients after chronic treatment with antiepileptic drugs (carbamazepine, valproate). HHcy may lead to increase of the level of asymmetric dimethylarginine (ADMA). ADMA has been identified as a potential risk factor for cardiovascular disease and endothelial dysfunction. ADMA is a product of methylation of L-arginine and endogenous nitric oxide (NO) synthase inhibitor, and regulator of NO production. NO plays a role in the convulsant effect. Supplementation of B vitamins, folate and L-arginine is a strategy to reduce Hcy levels in patients with epilepsy treatment antiepileptic drugs.