GENERAL INTRODUCTION 15 1 however, show that patients with a more severe phenotype were more prone to have a causal mutation in one of the HM genes. Patients with a causal mutation in CACNA1A, ATP1A2, or SCN1A had a lower age-at-onset, more affected family members, and had attacks more frequently. Moreover, attacks were (i) brought about by mild head trauma, (ii) typically with extensive motor weakness, and (iii) with brainstem features, confusion, and brain oedema. Noteworthy, progressive ataxia and intellectual disability were only found in patients with a causal gene mutation.93 As no mutation was found in “milder” patients, it was proposed that such HM patients may have the more extreme phenotype in the migraine with aura continuum.91 Illustrative of this is a Finnish polygenic risk score study that showed that patients with HM, but without a high-penetrant disease-causing mutation in a known HM gene, carry an excess of genome-wide association studies (GWAS) variants associated with common migraine compared to patients suffering from the common migraine subtypes,94 suggesting indeed a spectrum ranging from common lowrisk variants to rare highly-penetrant mutations to contributing to the risk for migraine. Further support for this hypothesis are loss-of-function mutations in PRRT2, which do not cause HM on their own, but rather function as modifying genetic risk factors.95 Illustrating the complex genetic architecture of HM is a recent whole-genome sequencing (WGS) where patients with HM were more likely to accumulate frameshift indels in multiple genes that have a role in synaptic signalling in the central nervous system compared to common migraine patients.96 Genetic studies in common migraine Various twin and familial studies investigating the genetic and environmental susceptibility in migraine have shown that migraine is a multifactorial (complex) genetic disorder with a strong familial aggregation.14, 15 The heritability of migraine was estimated to range from 35% to 60%.97 Population-based studies have shown that the relative risk for a first-degree relative of a migraine patient is increased by 1.5- to 4-fold in comparison to a patient in the general population.14 The risk was highest for those patients with a higher pain score and frequency of attacks, an early age of disease onset, and a migraine with aura phenotype.14-16 Studies of twins identified a higher genetic load in migraine with aura compared with migraine without aura.98 Migraine frequency, being the number of migraine days per month, appears mainly to be associated with a genetic predisposition in males.16 A stronger family history of migraine is also associated with migraine with aura, a lower age-at-onset and more medication days.16 For decades, identifying gene variants involved in complex disorders, such as migraine, has proven challenging. Genetic studies in cluster headache Twin and family studies have shown the involvement of genetic factors in cluster headache.21 Notably, first-degree relatives have an increased relative risk between 5- and 18-fold, whereas second-degree relatives have a risk 1- to 3-fold higher than in the general population.99 Thus far, most genetic studies have interrogated a limited number of variants in genes linked to presumed pathways in cluster headache.100, 101 Variants in the HCRTR2 gene were predominantly studied.
RkJQdWJsaXNoZXIy MTk4NDMw