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Invited Speakers for Scientific Sessions

Migraine is a common, episodic, multifactorial, neurovascular disorder with high socio-economic and personal impact. Although much is known about the underlying mechanisms of the headache (activation of the trigeminal vascular system) and aura (CSD: cortical spreading depression), little is understood of how and why attacks begin. Both genetic and environmental non-genetic factors seem to set and modulate the trigger threshold for migraine attacks. Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine associated with hemiparesis during attacks. Genes for FHM are candidate genes for the common types of migraine and studying the functional consequences of FHM gene mutations may help to elucidate common pathways for triggering migraine attacks. FHM1 is caused by missense mutations in the CACNA1A gene on chromosome 19p13. The gene encodes the main α 1A subunit of neuronal P/Q type calcium channels that modulate the release of neurotransmitters including monoamines, acethylcholine, glutamate, and calcitonin gene-related peptide (CGRP). Different CACNA1A mutations have been associated with a wide spectrum of brain disorders. These range from pure episodic disorders without interictal abnormalities such as FHM, episodic ataxia type 2 and epilepsy, via combinations of these disorders, to severe progressive ataxia and excessive, mild head trauma-triggered, fatal cerebral oedema. Genetic studies support the involvement of the CACNA1A gene in the common types of migraine. Two transgenic knockin mice models, harbouring human FHM mutations (one associated with pure FHM, the other with FHM and fatal cerebral oedema), have recently been constructed. Intensive functional characterization is underway to unravel the in vivo consequences of these mutations. The first results point to an increased release of neurotransmitters and a reduced threshold for CSD. FHM2 is caused by mutations in the Na + , K + ATPase pump α 1 subunit gene ATP1A2 on chromosome 1q23. The gene is primarily expressed in glial cells. ATP1A2 mutations can also cause epilepsy and alternating hemiplegia of childhood (AHC). Transgenic knock-in mice models are underway. It is predicted that FHM2 mutations will result in reduced glial cell re-uptake of glutamate and K + from the synaptic cleft, leading to increased levels of glutamate and K + . This, in turn, should facilitate the initiation and propagation of CSD as was found for FHM1 mutations. Recently, missense mutations in the SCN1A gene on chromosome 2q24 were found to cause FHM3. This gene encodes the α 1 subunit of neuronal voltage-gated sodium (Na v 1.1) channels that are critical for the generation and propagation of action potentials in cortical neurons, and mutations of which have previously been associated with epilepsy. FHM3 mutations were found to induce a twoto four-fold accelerated recovery from fast neuronal inactivation and are thus predicted to allow for higher neuronal firing rates and enhanced neuronal excitability. This should also lead to a greater propensity to CSD, again pointing at a pivotal role for CSD in FHM and possibly also normal migraine. Several other loci and genes have been associated with migraine as well. These include loci on chromosome 1q, 3p21 (likely to harbour a neurovascular gene responsible for a combination of vascular retinopathy, Raynaud’s syndrome, and migraine), 4q21–24 (linked to migraine in patients from Finnish and Icelandic genetic isolates), 6p12–21, 11q24, 14q21–22, 15q11–13, Xq24–28 (in Australian families) and the Notch3 CADASIL gene (in migraine with white matter abnormalities). Other possibly involved migraine genes encode for a 5HT transporter and MTHF reductase, as well as for insuline, endothelin type A and dopamine D2 receptors. Unraveling the genetic basis of migraine and studying the functional consequences of the genes involved will improve our understanding of the mechanisms involved in the onset of migraine attacks and the interaction with migraine trigger factors. This may ultimately lead to specific, more effective and well-tolerated migraine prophylactic drugs. Because of the many clinical and pathophysiological similarities, other episodic disorders such as ataxia, epilepsy, AHC, and traumatriggered cerebral oedema may also profit from these exciting developments.