Advances in genetics of migraine

Abstract

BackgroundMigraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology.FindingsMigraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants.With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology.ConclusionsThe complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.

Diagnostic and therapeutic aspects of hemiplegic migraine

“…Clinical overlap among the three diseases has been reported. 30 However, EA2 mutations can be missense, truncating or cause aberrant splicing of CACNA1A, usually leading to loss-of-function and decreased Ca 2+ influx. On the other side, SCA6 mutations are usually small expansions of a polyglutamine in the C-terminal of the gene, which are responsible for accumulation of mutant Cav2.1 channels and selective degeneration of Purkinje cells.…”

“…On the other side, SCA6 mutations are usually small expansions of a polyglutamine in the C-terminal of the gene, which are responsible for accumulation of mutant Cav2.1 channels and selective degeneration of Purkinje cells. 30 ATP1A2 gene is localised on chromosome 1q23.2. It encodes the a2 subunit of the glial sodium-potassium ATPase pump.…”

The epidemiology of headaches among patients with epilepsy: a systematic review and meta-analysis

“…For instance, a review conducted to see the relationship between headache and epilepsy reported the comorbidity of headache and epilepsy as a result of common genetic mutations and clinical features [18,19], but the suggested link is not revealed conclusive evidence of a real causal association [20]. Further, studies also suggested that there are genetic relationships [19] as well as common underlying pathophysiological mechanisms including the imbalance between excitatory and inhibitory neurotransmitters in epilepsy and headache, especially for migraine [18,21]. Proposed theories for shared etiologies include ion channel dysfunction, glutamatergic mechanisms, and mitochondrial dysfunction [22,23].…”

The Use of Antioxidants in the Treatment of Migraine

“…Migraine is a multifactorial disorder with a complex of mechanisms engaged in its pathogenesis [1,14,15]. That is why there is no single treatment that would be effective in every migraineur.…”