The pathophysiology of migraine is also explained by a genetic component. Studies on families and twins have estimated the heritability of migraine at 42% (Polderman et al. 2015). Studies carried out in the case of familial hemiplegic migraine (FHM) have highlighted several genes involved. FHM is a rare variety of migraine with autosomal dominant transmission that is essentially defined by motor auras leading to muscle weakness that can lead to paralysis (Ducros 2010). Thus, 3 autosomal dominant mutations have been identified:
- The CACNAIA gene mutation encodes the alpha 1 subunit of the Cav 2.1 channel and results in a gain of function of this channel. Widely expressed in the central nervous system, this channel is involved in the presynaptic release of neurotransmitters and in postsynaptic neuronal excitability (Pietrobon and Brennan 2019).
- The second mutation concerns the ATP1A2 gene, which codes for the alpha 2 subunit of an astrocytic Na + /K + pump particularly involved in the regulation of glutamatergic excitatory synapses (Friedrich, Tavraz, and Junghans 2016). This mutation may result in a loss of function of the pump or modify its affinity with K + . The hypothesis is that the mutation would result in a decrease in glial reuptake of glutamate and K + in the synaptic cleft, which would result in increased neuronal excitability (Ducros 2010).
- Finally, the mutation of the SCN1A gene, coding the alpha 1 subunit of the Nav 1.1 channel, leads to a gain of function of the channel. It is mainly expressed 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). A gain of function of the channel 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 highlighted 38 loci associated with a higher risk of migraine (Gormley et al. 2016). However, among them, only two loci were linked to a channel. Thus, the study concludes that migraine, outside of MHF, is not a channelopathy. Discover how to
treat migraine naturally In this same study, several loci identified were linked to vascular tissues, which supports the important role of this component in the pathophysiology 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 genes associated with migraine was specific to 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.
