Mitochondrial D Loop Variants in Juvenile Myoclonic Epilepsy Patients: A Study from Asian Indians

Background: Mitochondrial mutations may exert unfavorable effect on neuron synapses which may lead to the loss of motor functions causing seizures. Mitochondrial displacement loop (D-loop) is the hotspot for mtDNA alterations which influence the generation of cellular reactive oxygen species (ROS). Lack of cellular energy (ATP) due to defective oxidative phosphorylation (OXPHOS) and ROS can cause somatic mutations in mtDNA. The concern of the present study is to understand the mitochondrial basis of the disease in our population by identifying the Novel mitochondrial mutations which in turn may facilitate the diagnosis of a section of Juvenile myoclonic epilepsy (JME) patient’s thereby better management of the condition. Most neurodegenerative diseases is abnormal folding and these changes in normal protein metabolism often lead to neuronal cell death and failure of the affected regions of the central nervous system. Abnormal protein accumulation may be attributed to dysfunctional mitochondria and damage by reactive oxygen species. No treatments have yet been found successful to rid a person of neurodegeneration completely. Methods: The two hypervariable segments (HV1 and HV2) of mtDNA D-Loop region were sequenced in 35 unrelated JME patient’s blood samples. The mtDNA samples were amplified by polymerase Chain Reaction (PCR), and then SNPs were detected by direct sequencing and comparing the sequencing results with the mtDNA Cambridge Reference Sequence. Result: We detected multiple mutations in D-loop region including Pyrimidine transitions 27%, 56%; Purine transitions 23%, 39% and Transversion 50%, 5% in HV1 and HV2 segments respectively. Overall we observed 64 mutations in different nucleotide positions in HV1 and HV2 segments of D-loop region and 18 mutations in HV2 segments in the JME patients. Conclusion: The study deal with the sequencing of HV1 and HV2 regions of mtDNA D- loop region in JME patients of Asian Indians. We found several novel mutations, suggesting these mutations may be involved in the pathogenesis of JME as many neurological disorders are associated with mitochondrial mutations and mitochondrial dysfunction. Further studies including normal healthy individuals from same ethnicity may help in identifying the role of these genetic variations in the pathogenesis of JME