Centre for Medical Systems Biology

Migraine

Migraine is a hereditary chronic multifactorial neurological disorder that affects 12% of the general population (2 million patients in the Netherlands). The disease is characterized by recurring attacks of severe, disabling headaches that also cause nausea, vomiting and, and in one third of the patients are accompanied by neurological aura symptoms (migraine with aura; MA). On average, patients suffer 2 attacks a month, each lasting 1 – 3 days. Approximately 10% of the migraine patients (200,000 Dutch patients) are affected almost weekly. Although considered an episodic disorder, recent neuroimaging work by us clearly shows that patients with severe migraine are at risk for significant brain damage.
There is strong association between migraine and depression. Patients suffering from migraine have a three-fold increased risk of depression, which is not caused by the migraine. Vice versa, depression also increases the risk of migraine, suggesting common pathogenic mechanisms (denominators) in both disorders.
The World Health Organization (WHO) ranks migraine in the highest class of most disabling disorders. Within the EU, the annual costs associated with migraine exceeds € 10 billion.

Problem

To abort the attacks, currently so-called triptans (serotonin receptor agonists) are used, but their efficacy and applicability leaves much to be desired. Attempts to prevent attacks through daily doses of current migraine prophylactics show disappointing results. Furthermore, these drugs are accompanied by a range of side-effects, including chronification of migraine because of drug overuse.
To develop novel (prophylactic) treatment strategies, we need to know much more on the molecular mechanisms and genetic factors involved in migraine pathophysiology. Recent research by us and others has demonstrated that migraine can be considered, at least in part, a channelopathy, leading to a hyperexitable state of certain brain structures. Moreover, migraine patients may show progressive abnormalities in the brain that point to recurrent blood circulation problems. This underlines the importance of developing migraine prophylactics; they may also counteract these abnormalities that progress with the number of attacks a patient suffers.

Approach

Our approach focuses on unraveling the genetic and neurobiological basis of migraine. We will pay particular attention to the susceptibility for migraine aura, the role of stress as a trigger of attacks, chronification of attacks and comorbidity with depression.

The large collections of patient material within the LUMC, and complemented with cohorts within the CMSB (Erasmus Rucphen Family; ERF and Netherlands Twin Register; NTR) and two European consortia (EUROHEAD and GENOMEUTWIN), will be screened to identify patients and families that show the above migraine types. Genome-wide linkage and association studies will be performed to identify and subsequently validate candidate genes.
In parallel, we will characterize the migraine phenotypes and mechanisms through Systems Biology approaches in particular in cerebrospinal fluid and various structural and functional neuroimaging techniques. This detailed and integrated multidisciplinary approach might allow stratification of patients and yield useful biomarkers itself and might facilitate the gene identification process.
Transgenic mouse models will be generated and employed to study the functional in vivo consequences of mutations associated with migraine. The processes in the brain will be studied by molecular, electrophysiological, Systems Biology and high-resolution imaging techniques. Findings in these models will be validated in human patients.

Objectives

The migraine research within CMSB aims at unraveling the pathogenesis of a migraine, in particular the mechanisms triggering an attack. We expect our research to substantially contribute to gaining insight into the causal basis of migraine within five years. This will result in improved diagnostics (using biochemical and genetic markers) and more patient-specific means of treatment. In the longer term, new drug targets for specific migraine prophylactics may be identified.

Besides migraine, genetically determined defects in ion transport molecules (channels, transporters) are associated with other episodic brain disorders, including cluster headache, epilepsy and narcolepsy. Therefore, the results of our research into migraine may lead to interesting insights into this broader field of neurological brain disorders.

Resources

LUMC cohort. Extended families (n=100; over 2000 samples) with migraine with and without aura.
Genetic determinants of migraine; GEM population-based Dutch cohort. Sample of 863 migraineurs and >5000 healthy control subjects.
CAMERA cohort. 150 patients with migraine without aura, 150 patients with migraine wit aura and 150 controls selected from GEM and submitted to extensive MRI analysis.
Costa Rica cohort. Trios (n=250 patients and parents) with severe migraine with aura from the genetic isolate of the Central Valley of Costa Rica.
Erasmus Rucphen Family (ERF). Trios (n=150 patients and parents) from the genetic isolate of St. Willibrord.
Netherlands Twin Register (NTR). Monozygotic and dizygotic twin pairs from cohort of 26,000 twin pairs.
GENOMEUTWIN project. Twins from seven European countries and Australia; basis cohort of 800.000 twins.
PAREL and NESDA. Patients (and parents) with depression (n=4,000) from the PAREL (Psychiatric Academic Registration Leiden and environment) and NESDA (Netherlands Study on Depression and Anxiety) studies.

Publications

Ophoff RA, Terwindt GM, Vergouwe MN, Van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, Van Ommen GJB, Hofker MH, Ferrari MD, Frants RR. Familial Hemiplegic Migraine and Episodic Ataxia type-2 are caused by mutations in the Ca⁺⁺ channel gene CACNL1A4. Cell 1996;87:543-552. (IF: 27.3)
Ferrari MD. Migraine. Lancet 1998;351:1043-1052. (IF: 15.4)
Launer LJ, Terwindt GM, Ferrari MD. The prevalence and characteristics of migraine in a population-based cohort. The GEM study. Neurology 1999;53:537-542. (IF: 5.4)
Plomp JJ, Vergouwe MN, Van den Maagdenberg AM, Ferrari MD, Frants RR, Molenaar PC. Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering α_1A Ca²⁺ channel mutation. Brain 2000;123:463-471. (IF: 7.1)
Terwindt GM, Ophoff RA, van Eijk R, Vergouwe MN, Haan J, Frants RR, Sandkuijl LA, Ferrari MD. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001; 56:1028-1032. (IF: 5.4)
Kors EE, Terwindt GM, Vermeulen FLMG, Fitzsimons RB, Jardine PE, Heywood P, Love S, van den Maagdenberg AMJM, Haan J, Frants RR, Ferrari MD. Delayed cerebral edema and fatal coma after minor head trauma. Role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 2001; 49: 753-760. (IF: 8.6)
Goadsby, PJ, Lipton RB, Ferrari MD. Migraine, current understanding and management. New Eng J Med 2002: 346 (4): 257-270. (IF: 31.7)
Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WA, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, Van Den Maagdenberg AM. Novel mutations in the Na⁺, K⁺ ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003; 54(3):360-6. (IF: 8.6)
Kruit MC, van Buchem MA, Hofman PAM, Bakkers JTN, Terwindt GM, Ferrari MD, Launer LJ. Migraine as a Risk Factor for Subclinical Brain Lesions. JAMA 2004; 291:427-434 (IF: 16.8)
Van den Maagdenberg AMJM, Pietrobon D, Pizzorusso, Kaja S, Broos LAM, Cesetti T, van de RCG Ven, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41: 701-710. (IF: 13.8)