Cephalalgia. 2025 Oct;45(10):3331024251389241. doi: 10.1177/03331024251389241. Epub 2025 Oct 28.
ABSTRACT
BackgroundMigraine is a common neurological disorder with a strong genetic component, yet the precise mechanisms underlying its genetic susceptibility remain largely unknown. Genome-wide association studies (GWAS) have identified multiple risk loci, but monogenic forms of migraine, particularly Familial Hemiplegic Migraine (FHM), have provided deeper insights into the pathophysiology of migraine. Studying monogenic disorders that present migraine as a symptom could help identify novel therapeutic targets by uncovering shared molecular pathways.MethodsA narrative literature review was conducted using a stepwise approach in the PubMed database. Reviewers were divided into three groups, each focusing on different aspects of migraine genetics. The first group analyzed monogenic migraine syndromes, including FHM and related ion-channelopathies. The second group examined clinical manifestations and phenotypic spectrum of FHM-related genes. The third group expanded the search to other monogenic disorders associated with migraine, such as Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and Familial Advanced Sleep Phase Syndrome (FASPS). Additional searches were conducted using the Compendium of Causative Genes for Monogenic Disorders.ResultsThe review identified multiple monogenic disorders associated with migraine, revealing distinct but interconnected mechanisms. Ion-channel dysfunction (CACNA1A, SCN1A, ATP1A2), vascular impairment (NOTCH3, TREX1), mitochondrial dysfunction (MT-TL1), and circadian dysregulation (CSNK1D) emerged as critical contributors to migraine pathophysiology. These findings highlight the roles of neuronal excitability, cortical spreading depression, trigeminal sensitization, and neurovascular dysfunction in migraine.ConclusionsMonogenic migraine disorders offer valuable insights into migraine pathogenesis, emphasizing the importance of ion homeostasis, vascular function, and circadian regulation. Although genetic studies have not yet directly translated into new therapeutic targets, the study and knowledge of these rare conditions is pivotal for neurologists and migraine specialists, as it might improve diagnosis and care, and provide new insights into migraine pathophysiology that may ultimately inform future treatments.
PMID:41147997 | DOI:10.1177/03331024251389241
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