Familial Hemiplegic Migraine – Within and Beyond Genes
Migraine is a common, disabling, and highly prevalent disorder of neurovascular origin, leading to a diminished quality of life in both those affected and their relatives. It’s not an uncommon disorder either, affecting between 12% and 15% in most populations. But what do we understand of migraine’s genetic and non-genetic causes?
Migraine attacks are characterized by a throbbing, often unilateral, headache, accompanied by symptoms such as nausea, vomiting, and sensitivity to light and sound. In about one third of patients, the headache is preceded by an aura phase, consisting of visual and sometimes sensory symptoms, known as migraine with aura (MA) rather than migraine without aura (MO). Migraine is also defined by the recurrence of attacks. As things stand, it is largely unknown why migraine patients suffer so many attacks.
Migraine episodes seem to be triggered by specific events, when a certain internal threshold is reached which the nervous system cannot cope with. Internal and environmental factors such as hormonal, emotional, nutritional, physiological or weather changes may act as triggers, leading to the activation of several pathophysiological mechanisms. However, pathophysiology of migraine is still being widely discussed since it is still not well understood.
Migraine clusters in families and it is well established that it has a strong genetic component. But unraveling the genetic determinants for the common forms of migraine has been challenging, because of its high prevalence and complexity, and because both genetic and environmental factors are involved.
However, genetic studies of familial hemiplegic migraine (FHM), a monogenic subtype of MA have identified three genes of importance. All of these genes code for ion transporters: one is a calcium channel subunit gene (CACNA1A), one is a sodium potassium pump subunit gene (ATP1A2), and one is a sodium channel subunit gene (SCN1A).
FHM is a rare form of migraine with aura characterized by reversible motor weakness (hemiparesis). With the exception of motor weakness, FHM episodes are similar to MA. Typically, at least three or four aura symptoms occur during an FHM attack (frequently in the temporal order: visual, sensory, motor, aphasic). To be considered as familial, at least one first or second degree-relative must have also hemiplegic migraine.
The familial clustering of migraine is largely assessed by calculation of relative risk (RR), although twin studies have also been reported. Methodological differences have provided variations in familial aggregation results, evaluated by calculation of RR, ranging from 1.5 to 11.8.
RR estimations suggest that familial factors — environmental and/or genetic — account for less than half of all cases, and that RR is higher in families of affected relatives. A pivotal study showed that there is an increased disease risk for relatives, with first-degree relatives of those with MO having 1.9 times the risk of MO and 1.4 times the risk of MA; while first-degree relatives of those with MA have nearly 4 times the risk of MA but no increased risk of MO. Earlier onset and greater severity of migraine are associated with higher familial aggregation.
Another intriguing question that has been addressed is how characteristics such gender can influence RR estimation. In addition, higher risks have also been shown among siblings from three-generation families with MA, when compared to families with fewer generations. One study presented young age, female gender, no education, familial history and high workload as factors of increased risk for migraine. Therefore, despite its name, familial hemiplegic migraine is likely to be influenced by different genetic and non-genetic factors.
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