Musadiq Ahmad Bhat, Sameer Ahmad Guru, Rashid Mir, Ajaz Ahmad Waza, Mariyam Zuberi, Mamta Sumi, Shaam Bodeliwala, Amit Samadhiya, Vinod Puri and Alpana Saxena*
Introduction: Epilepsy is the most common heterogeneous neurological disorder affecting approximately 42 million people worldwide. Juvenile myoclonic epilepsy (JME) is a common form of idiopathic generalized epilepsy representing 5-10% of all epilepsy cases. Lennox-Gastaut syndrome (LGS) is one of the most severe epileptic encephalopathies of childhood onset, the cause of which may be symptomatic, i.e., secondary to an underlying brain disorder or cryptogenic, i.e., with no known cause. Sodium channels are integral membrane proteins which play a central role in neuronal membrane excitability and action potential generation. Alpha subunit of voltage gated sodium channels encoded by SCN1A, SCN2A and other genes is pivotal for neuronal signalling. It was planned to analyse the roles of SCN1A Thr1067Ala and SCN2A Arg19Lys polymorphisms in the pathophysiology and risk JME and LGS in the Indian population.
Methods: A total of 50 JME patients, 50 LGS Patients and 100 age and sex matched healthy volunteers were recruited in this study. The genotyping of SCN1A Thr1067Ala i.e., 3184 A>G (rs2298771) and SCN2A Arg19Lys i.e., 56 G>A (rs17183814) polymorphism was performed by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) analysis.
Results: The SCN1A Thr1067Ala polymorphism genotypic distribution in LGS was significantly different from the normal population (P=0.008), with mutant homozygous (GG) plus heterozygous (AG) genotypes’ percentage in LGS patients (16%) being lower than in healthy controls (24%). Frequency of the mutant ‘G’ allele of this SNP in LGS patients was 0.1, while it was 0.2 in control subjects (P=0.04). These observations which suggest a protective role of SCN1A Thr1067Ala polymorphism in LGS, were in sync with computation of an odds ratio of 0.21 (95% CI 0.07 to 0.66, p=0.005) for the GG genotype in LGS patients. Though no correlation of SCN1A Thr1067Ala SNP with the severity of disease phenotype in LGS viz. frequency/duration of seizures etc. was noted, a conflicting finding was the significant association of its mutant genotypes with an early age of onset of the syndrome (p=0.007). Contrary to the findings in SCN1A Thr1067Ala, in case of SCN2A Arg19Lys polymorphism, though a significantly different genotypic distribution was present in LGS, in comparison to normal population (p=0.03), the mutant homozygous (AA) and heterozygous (GA) combined percentage in LGS patients (16%) was greater than in healthy controls (11%). This was complemented by observation of an odds ratio of 4.24 (95% CI 1.15 to 15.55, p=0.029, in case of LGS patients with heterozygous (GA) genotype, indicative of an increased disease susceptibility. Unlike LGS, in JME patients no significant differences in genotypic/allelic frequencies of SCN1A Thr1067Ala and SCN2A Arg19Lys polymorphisms were noted and the associated odds ratios for mutant genotypes were also non-significant.
Conclusion: The SCN1A Thr1067Ala and SCN2A Arg19Lys polymorphisms may play contrary roles in the pathophysiology of LGS. Inheritance of SCN1A Thr1067Ala mutant allele decreases the susceptibility for LGS occurrence, and may hamper Na+ channels opening and neuronal excitability. On the other hand, the mutant allele of SCN2A Arg19Lys polymorphism confers an increased risk for development of LGS, consequent to a likely facilitatory effect on action potential generation and misfiring in neurons. Neither of these two SNPs appears to influence the pathogenesis/susceptibility to JME.