Molecular genetics of cluster headache: a review

Introduction In the past, cluster headache (CH) was not thought to be an inherited disorder. Recent studies have suggested that genetic factors play a role in the disease [1]. Genetic epidemiological surveys have clearly shown that first-degree relatives of CH patients are more likely to have CH than the general population. In addition, CH has been reported in some concordant monozygotic twin pairs. Recently, we have reported in an Italian population a significant association between the HCRTR2 gene and the disease. This association was confirmed in a German study. The purpose of this review is to describe recent advances in the molecular genetics of CH. Methods We searched MEDLINE (1966–2004) and reference lists of retrieved articles. The search terms “cluster headache”, “genetics” and “molecular genetics” were used. Only original articles published in English were included. Results Several studies reported lack of association between different candidate genes and CH. Excluded genes were: CACNA1A, NOS, HFE, Clock and elusive amine receptors (TAR 1, TAR 3, TAR 4, TAR 5, PNR, GPR58) genes. We reported a significant association between the 1246 G>A polymorphism of the gene encoding for the hypocretin receptor 2 (HCRTR2) and CH [2]. Patients homozygous for the G allele, in comparison with the remaining genotypes, have a five-fold higher risk of developing the disease. This association was confirmed in a large sample of 226 patients with CH from Germany. Discussion At present, the type and the number of genes involved in cluster headache are still unclear. A significant association between the HCRTR2 gene and the disease was found. This gene, however, is not a major gene but rather a disease-modifying gene. These findings suggest that the hypocretin/orexin system may be involved in the pathogenesis of CH. Hypocretins influence a wide range of physiological and behavioural processes like appetite regulation, sleep-wake cycle, neuroendocrine and sympathetic functions. Moreover, recent findings suggested that hypocretins modulate pain threshold and nociceptive transmission. Additional studies are needed to elucidate the role of the HCRTR2 gene in the pathogenesis of CH and to search for major genes in this rare but severe headache disorder. References 1. Russell MB (2004) Epidemiology and genetics of cluster headache. Lancet Neurol 3:279–283 2. Rainero I, Gallone S, Valfre W et al (2004) A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 63:1286–1288