A gene for a new monogenic neurovascular migraine syndrome: a next step in unravelling molecular pathways for migraine?

Migraine is a multifactorial disorder in which both multiple genetic (estimated at up to 61%) and nongenetic factors are contributing to the disease risk (for review see 1). Unravelling its molecular basis will undoubtedly help to elucidate the underlying mechanisms for the migraine trigger threshold and may ultimately lead to novel prophylactic treatment targets (2). Finding genes for the common multifactorial types of migraine with and without aura and dissecting their pathogenic role has proven difficult (3). Alternative approaches are to identify genes for monogenic subtypes of migraine or for monogenic syndromes of which migraine is part of the clinical spectrum, and then study the functional consequences of migraine-associated mutations in these genes (4). Familial hemiplegic migraine (FHM) is a monogenic subtype of migraine associated with hemiparesis during aura (5). The headache and aura symptoms are otherwise identical to those of the common types of migraine, and the majority of FHM patients also have attacks of ‘normal nonhemiplegic migraine’. This would suggest that FHM is a true subtype of migraine rather than a different disease. In the past decade, three genes have been discovered for FHM (5). The CACNA1A FHM1 gene encodes the a1 subunit of neuronal Cav2.1 calcium channels that, among other functions, control the release of neurotransmitters such as glutamate (5, 6). The ATP1A2 FHM2 gene encodes the a2 subunit of glial sodium-potassium ATPase pumps that control the re-uptake of K+ from the synaptic cleft into glial cells (7, 8). The SCN1A FHM3 gene encodes the a1 subunit of neuronal Nav1.1 voltage-gated sodium channels, which are responsible for the initiation and propagation of neuronal action potentials (9). All three genes are involved in ion transport and FHM gene mutations all seem to lead to increased levels of K+ and glutamate within the synaptic cleft, facilitating the initiation and propagation of cortical spreading depression (CSD) (10). CSD is the underlying mechanism for the migraine aura (11) and may possibly also activate the trigeminovascular system, thereby triggering the migraine headache mechanisms (12; for discussion of the arguments in favour and against this hypothesis, see 4). In addition, neuronal Cav2.1 channels also play a role within the trigeminovascular system controlling trigeminal firing (13) and nociceptive transmission (14), fitting well with the hypothesis that migraine might be a ‘cerebral ionopathy with abnormal central processing’ (4). Examples of monogenic neurovascular syndromes with a high prevalence of migraine are cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL, OMIM#125310) and infantile hemiparesis, retinal arteriolar tortuosity, and leucoencephalopathy (OMIM#607595) (15–17). CADASIL is caused by mutations in the NOTCH3 gene, encoding the Notch3 receptor (18). This receptor plays a key role in the development, survival and function of vascular smooth muscle cells and is thought to be essential for the maintenance of healthy smooth muscle cells in small arteries and arterioles in the brain. The high prevalence of migraine in CADASIL (up to 40% and often as presenting symptom 10 years ahead of the other symptoms) suggests a role of endothelial/vascular dysfunction in migraine. Infantile hemiparesis, retinal arteriolar tortuosity, and leucoencephalopathy is a rare angiopathy caused by mutations in COL4A1, which encodes type IV collagen, an integral component of the vascular basement membrane (16). Very recently, the causal gene for a third monogenic neurovascular migraine syndrome was identified: autosomal dominant retinal vasculopathy with cerebral leucodystrophy (AD-RVCL, OMIM#192315) (19). RVCL is characterized primarily by progressive loss of visual perception secondary to retinal vasculopathy; in addition, patients may have a wide range of both cerebral and systemic vascular symptoms, such as cerebral infarcts and white matter lesions, vascular-type of dementia, migraine, Raynaud’s phenomenon, and liver and kidney dysfunction (20–25). Although migraine and Raynaud’s phenomenon may not always be prominent features in all nine families with RVCL doi:10.1111/j.1468-2982.2007.01511.x