Das Abhijit, Balan Shabeesh, Mathew Anila, Radhakrishnan Venkataraman, Banerjee Moinak, Radhakrishnan Kurupath
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.
Indian J Hum Genet. 2011 May;17 Suppl 1(Suppl 1):S41-7. doi: 10.4103/0971-6866.80358.
Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory epilepsy syndrome in adults, and hippocampal sclerosis (HS) is the most frequently encountered lesion in patients with MTLE. Premature accumulation of corpora amylacea (CoA), which plays an important role in the sequestration of toxic cellular metabolites, is found in the hippocampus of 50-60% of the patients who undergo surgery for medically refractory MTLE-HS. However, the etiopathogenesis and clinical importance of this phenomenon are still uncertain. The ABCB1 gene product P-glycoprotein (P-gp) plays a prominent role as an antiapoptotic factor in addition to its efflux transporter function. ABCB1 polymorphism has been found to be associated with downregulation of P-gp expression. We hypothesized that a similar polymorphism will be found in patients with CoA deposition, as the polymorphism predisposes the hippocampal neuronal and glial cells to seizure-induced excitotoxic damage and CoA formation ensues as a buffer response.
We compared five single nucleotide polymorphisms in the ABCB1 gene Ex06+139C/T (rs1202168), Ex 12 C1236T (rs1128503), Ex 17-76T/A (rs1922242), Ex 21 G2677T/A (rs2032582), Ex26 C3435T (rs1045642) among 46 MTLE-HS patients of south Indian ancestry with and without CoA accumulation.
We found that subjects carrying the Ex-76T/A polymorphism (TA genotype) had a five-times higher risk of developing CoA accumulation than subjects without this genotype (Odds ratio 5.0, 95% confidence intervals 1.34-18.55; P = 0.016).
We speculate that rs1922242 polymorphism results in the downregulation of P-gp function, which predisposes the hippocampal cells to seizure-induced apoptosis, and CoA gets accumulated as a buffer response.
内侧颞叶癫痫（MTLE）是成人中最常见的药物难治性癫痫综合征，海马硬化（HS）是MTLE患者中最常遇到的病变。50%-60%接受药物难治性MTLE-HS手术的患者海马中发现过早出现淀粉样体（CoA）积聚，其在隔离有毒细胞代谢物中起重要作用。然而，这种现象的病因发病机制和临床重要性仍不确定。ABCB1基因产物P-糖蛋白（P-gp）除了其外流转运蛋白功能外，还作为抗凋亡因子发挥重要作用。已发现ABCB1基因多态性与P-gp表达下调有关。我们推测CoA沉积患者中会发现类似的多态性，因为该多态性使海马神经元和神经胶质细胞易受癫痫发作诱导的兴奋性毒性损伤，随后CoA形成作为缓冲反应。
我们比较了46名具有南印度血统的MTLE-HS患者中ABCB1基因Ex06+139C/T（rs1202168）、Ex 12 C1236T（rs1128503）、Ex 17-76T/A（rs1922242）、Ex 21 G2677T/A（rs2032582）、Ex26 C3435T（rs1045642）的五个单核苷酸多态性，这些患者有或没有CoA积聚。
我们发现携带Ex-76T/A多态性（TA基因型）的受试者发生CoA积聚的风险比没有该基因型的受试者高五倍（优势比5.0，95%置信区间1.34-18.55；P = 0.016）。
我们推测rs1922242多态性导致P-gp功能下调，这使海马细胞易受癫痫发作诱导的凋亡，并且CoA作为缓冲反应而积聚。
