The pathophysiology of migraine is also explained by a genetic component. Family and twin studies have estimated the heritability of migraine at 42% (Polderman et al. 2015). Studies carried out in the case of familial hemiplegic migraine (FHM) have made it possible to highlight several genes involved. MHF is a rare variety of migraine with autosomal dominant transmission which is essentially defined by motor auras causing muscle weakness that can go as far as paralysis (Ducros 2010). Thus, 3 autosomal dominant mutations have been identified:
The mutation of the CACNAIA gene encodes the alpha 1 subunit of the Cav 2.1 channel and leads to a gain of function of this channel. Widely expressed within the central nervous system, this channel enters into presynaptic neurotransmitter release mechanisms and postsynaptic neuronal excitability (Pietrobon and Brennan 2019).
The second mutation concerns the ATP1A2 gene which encodes the alpha 2 subunit of an astrocyte Na + /K + pump particularly involved in the regulation of glutamatergic excitatory synapses (Friedrich, Tavraz, and Junghans 2016). This mutation can lead to a loss of function of the pump or modify its affinity with K + . The hypothesis is that the mutation would cause a decrease in the glial reuptake of glutamate and K + in the synaptic cleft, which would have the consequence of increasing neuronal excitability (Ducros 2010).
Finally, the mutation of the SCN1A gene, encoding the alpha 1 subunit of the Nav 1.1 channel leads to a gain of function of the channel. It is expressed mainly by inhibitory interneurons, at the level of the initial segment of their axon. It plays a key role in the excitability of these neurons, and a loss of function of this channel is also correlated with epilepsy (Schutte et al. 2016). Gain of channel function in MHF is then associated with hyperexcitability of inhibitory interneurons.
The three mutations found in MHF involve ion channels, suggesting that migraine can be considered a channelopathy. To account for this hypothesis, genomic studies have revealed 38 loci associated with a higher risk of migraine (Gormley et al. 2016). However among them, only two loci were attached to a channel. Thus, the study concludes that migraine, apart from MHF, is not a channelopathy. Find out how to treat migraine naturally In this same study, several identified loci were related to vascular tissue, which confirms the important role of this component in the physiopathology of migraine. Based on these results, a study on single cell RNA sequencing data (Renthal 2018) showed that these mutations affected all cell types present in the brain (neurons, astrocytes, microglia, oligoendrocytes, endothelial cells ), and that 40% of the polymorphism of migraine-associated genes was specific for a cell subtype. Thus, it should be considered that all cell types (neuronal, glial or endothelial) can play a significant role in the pathophysiology of migraine (Renthal 2018). Ducros, A. 2010. “Genetics of migraine”. Pain and Analgesia 23(3): 133‑39. https://doi.org/10.1007/s11724-010-0210-z. Friedrich, Thomas, Neslihan N. Tavraz, and Cornelia Junghans. 2016. “ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease.” Frontiers in Physiology 7 (June). https://doi.org/10.3389/fphys.2016.00239. Gormley, Padhraig, Bendik S. Winsvold, Dale R. Nyholt, Mikko Kallela, Daniel I. Chasman, and Aarno Palotie. 2016. “Migraine genetics: from genome-wide association studies to translational insights”. Genome Medicine 8(1):86. https://doi.org/10.1186/s13073-016-0346-4. Pietrobon, Daniela, and KC Brennan. 2019. “Genetic mouse models of migraine.” The Journal of Headache and Pain 20 (1). https://doi.org/10.1186/s10194-019-1029-5. Polderman, Tinca JC, Beben Benyamin, Christiaan A. de Leeuw, Patrick F. Sullivan, Arjen van Bochoven, Peter M. Visscher, and Danielle Posthuma. 2015. “Meta-Analysis of the Heritability of Human Traits Based on Fifty Years of Twin Studies.” Nature Genetics 47(7): 702-9. https://doi.org/10.1038/ng.3285. Renthal, William. 2018. “Localization of Migraine Susceptibility Genes in Human Brain by Single-Cell RNA Sequencing.” Cephalalgia: An International Journal of Headache 38 (13): 1976-83. https://doi.org/10.1177/0333102418762476. Schutte, Soleil S., Ryan J. Schutte, Eden V. Barragan, and Diane K. O'Dowd. 2016. “Model Systems for Studying Cellular Mechanisms of SCN1A-Related Epilepsy”. Journal of Neurophysiology 115 (4): 1755-66. https://doi.org/10.1152/jn.00824.2015.
