Identifying a gene expression signature of cluster headache in blood.

Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri-)orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Gene expression data were analysed by gene and by module of co-expressed genes with particular attention to previously implicated disease pathways including hypocretin dysregulation. Only moderate gene expression differences were identified and no associations were found with previously reported pathogenic mechanisms. At the level of functional gene sets, associations were observed for genes involved in several brain-related mechanisms such as GABA receptor function and voltage-gated channels. In addition, genes and modules of co-expressed genes showed a role for intracellular signalling cascades, mitochondria and inflammation. Although larger study samples may be required to identify the full range of involved pathways, these results indicate a role for mitochondria, intracellular signalling and inflammation in cluster headache.

Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies.

BACKGROUND: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls. METHODS: Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p < 5 × 10(-8); thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs. RESULTS: Significant heterogeneity of SNP effects (p het < 1.4 × 10(-3)) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups. CONCLUSIONS: Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

Familial hemiplegic migraine treated by sodium valproate and lamotrigine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura that includes motor auras. Prophylactic treatment of FHM often has marginal effects and involves a trial-and-error strategy based on therapeutic guidelines for non-hemiplegic migraine and on case reports in FHM. METHODS: We assessed the response to prophylactic medication in an FHM family and sequenced the FHM2 ATP1A2 gene in all available relatives. RESULTS: A novel p.Met731Val ATP1A2 mutation was identified. Attack frequency was reduced significantly with sodium valproate monotherapy (n = 1) and attacks ceased completely with a combination of sodium valproate and lamotrigine (n = 2). CONCLUSIONS: We report dramatic prophylactic effects of sodium valproate and lamotrigine in an FHM2 family, making these drugs worth considering in the treatment of other FHM patients.