In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM),... Show moreIn this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related diseases such as Alternating hemiplegia of Chilhood, Early Seizures and Cerebral Edema after Trivial Head Trauma, epilepsy and episodic ataxia were investigated. The second monogenic migraine syndrome studied is Retinal Vasculopathy with Cerebral Leukodystrophy (later renamed CHARIOT), where common migraine is part of the clinical spectrum. The identification of TREX1 as the causal gene for RVCL is described. Investigation of the clinical spectrum showed retinal, cerebral and internal organ involvement, without an apparent genotype-phenotype correlation. Endothelial dysfunction of large arteries was shown in RVCL patients and is proposed as a possible disease mechanism. Lastly, migraine patients were identified in a Dutch genetic isolate and the relation with depression and atherosclerosis was assessed. For depression it was shown that shared genetic factors, at least partly, underlie the comorbidity with migraine, in particular migraine with aura. These studies improve our insight in genetic factors and pathofysiological mechanisms involved in migraine, which may ultimately contribute to better treatment options for migraine patients Show less
The research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic... Show moreThe research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic familial hemiplegic migraine or other monogenic disorders in which migraine can be prevalent. Functional consequences of these mutations and the clinical phenotypes associated with them were investigated. Common migraine with a complex genetic background was studied using a genome-wide association analysis in an isolated population and with a meta-analysis study. Furthermore, FHM1 mice were used to study expression profiles in brain tissues that are relevant for the induction of cortical spreading depression ___ underlying the migraine aura - (i.e., the occipital cortex) and cerebellar ataxia (i.e., the cerebellum). These studies will further our insight in the molecular pathophysiology of migraine. Show less
Migraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors.... Show moreMigraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors. Unraveling its molecular basis and deciphering pathways leading to migraine attacks will help identifying novel treatment targets. For this thesis different genetic approaches were applied. Families with hemiplegic migraine (FHM), a rare monogenic subtype of migraine, were studied. Three genes were identified, all involved in modulation of ion influxes across neuronal and glial cell membranes. We identified many mutations in these genes and performed assays in cellular models to understand their functional consequences. In addition, we investigated the role of these genes in sporadic hemiplegic migraine (SHM). Importantly, we expanded the clinical spectrum associated with FHM genes, and established the link between migraine and epilepsy. We also performed genetic studies in common migraine families using two different approaches; the first was an outbred linkage approach with MO families, the second a family-based association approach with severe MA patients from a genetic isolate. Our results supported that, most likely, the intrinsic genetic heterogeneity in migraine families seriously hampers the identification of migraine loci and ultimately migraine genes. Show less
