Michel Ferrari Guest Lecture
Migraine, from myths to hereditary brain disorder.
Professor Michel D. Ferrari, M.D., Ph.D.
Professor of Neurology, Department of Neurology
Chair Leiden Centre for Translational Neuroscience
Leiden University Medical Centre (LUMC),
Leiden, The Netherlands
Migraine is a common, disabling brain disorder, mainly characterised by often lifelong recurring attacks of 1-3 days of severe, throbbing headaches associated with nausea, vomiting, and phono-, photo- and osmophobia. In about one third of patients attacks may be preceded by or associated with neurological aura symptoms. Over 12% of the general population is suffering from, on average, two migraine attacks per month; 3-4% is even having more than one attack per week. According to the WHO, migraine is in the top 12 of most disabling diseases for patient and society. In 2001, the costs in the EC due to migraine were estimated to be an astonishing 30 billion Euro.
The mechanisms for the migraine aura, headache, and associated symptoms are reasonably well understood. Significantly improved acute treatments to abort migraine attacks once started are becoming available, but are fully effective in no more than 50% of patients The mechanisms for how migraine attacks are triggered and begin are not known. Consequently, apart from a few modestly effective non-specific drugs, effective and well tolerated prophylactic agents to specifically prevent migraine attacks are not available. The Leiden Migraine Research Programme is focussing on dissecting the mechanisms for how migraine attacks are triggered and to identifying novel treatment targets to preventing migraine attacks.
Anyone may sometimes be struck by an incidental (partial) migraine attack. The disease migraine, however, is primarily characterised by recurrent attacks and a reduced triggering threshold for migraine-specific trigger factors provoking the attacks. In this respect migraine is very similar to epilepsy. Dissecting the triggering mechanisms for migraine attacks may help to identify prophylactic treatment targets to prevent migraine attacks.
In the presentation I shall focus on: (i) the identification of genes and gene mutations for different forms of migraine, including already established as well as recently identified new rare Monogenic Migraine Syndromes (MMS: clinical syndromes in which typical migraine is associated with a spectrum of other neurological features) as well as the common polygenic multifactorial forms of migraine with and without aura); (ii) how analysing the functional consequences of migraine gene mutation may uncover migraine triggering mechanisms; and (iii) how such an analysis may ultimately lead to future migraine-specific prophylactic treatments.
The following MMS will be discussed: (i) Familial Hemiplegic Migraine (FHM) which is genetically heterogeneous with mutations in the CACNA1A neuronal calcium channel (FHM1) gene, the ATP1A2 glial cell Na+/K+ pump ATPase (FHM2) gene, and the interneuronal Na+ channel SCN1A (FHM3) gene that was previously known to cause a number of severe forms of epilepsy at young age;. (ii) the second MMS to be discussed is CADASIL which is caused by mutations in the Notch3 gene; and (iii) the third MMS is the newly identified syndrome of Retinal Vasculopathy and Cerebral Leucodystrophy (RVCL) which is caused by certain mutations in the Trex1 gene while other mutations in this gene may cause other rare SLE-like brain disorders.
It is important to realise that although the MMS genes themselves may not play important roles in the common forms of migraine, the unravelling of the functional consequences of MMS gene mutations may lead to the identification of general pathways for the triggering of common migraine attacks.