Familial hemiplegic migraine: A model for the genetic studies of migraine

Abstract

FHM3 is a rare subtype of familial hemiplegic migraine (FHM) caused by mutations in the neuronal sodium channel gene SCN1A (1). Only five FHM3 mutations have been described in a few families since the identification of SCN1A as the third FHM gene in 2005 (1–4). In the present issue of Cephalalgia, Weller et al. (5) report the identification of two novel SCN1A FHM3 mutations in two families with pure FHM. This study is important for clinicians managing patients with FHM, and should also encourage geneticists to consider or reconsider FHM as one of the major targets in the continuing quest for migraine genes. Despite extensive studies, migraine genes remain difficult to identify (6). The common migraines (migraine without aura and migraine with aura) are characterized by high prevalence in the general population, high phenotypic variability, absence of any objective diagnosis marker and polygenic inheritance. Therefore, a successful approach in the search for migraine genes has been the study of FHM, a rare autosomal dominant subform of migraine with aura characterized by the presence of a motor weakness during the aura phase. However, studies of FHM have shown that being monogenic does not imply being a ‘‘simple’’ model. Indeed, FHM is genetically heterogeneous, i.e. mutations in different genes can cause the same phenotype of recurrent migraine attacks with complex aura. From 1996 to 2005, three FHM genes have been identified that all encode ion transporters: a neuronal calcium channel (CACNA1A, FHM1) (7), a glial sodium/potassium pump (ATP1A2, FHM2) (8) and a neuronal sodium channel (SCN1A, FHM3) (1). In 2012, the proline-rich transmembrane protein 2 gene (PRRT2), encoding a protein associated with the exocytosis complex, was proposed as the fourth FHM gene (9,10). Mutations in CACNA1A, ATP1A2 and PRRT2 have also been found in patients with sporadic hemiplegic migraine (SHM) and are often de novo mutations (9,11–13). Study of cellular and murine models have shown that FHM mutations in CACNA1A and ATP1A2 facilitated the initiation of cortical spreading depression waves, the mechanism underlying the migraine aura, and increased neuronal excitability with an excess of glutamatergic neurotransmission (11,13). A proportion of cases with FHM or SHM do not harbor a mutation in the four known genes, indicating that other FHM genes are still to be discovered. Furthermore, genotype-phenotype correlations studies have described the wide clinical spectrum of FHM and the high clinical variability among patients with the same mutation (13). While most cases have so-called ‘‘pure’’ hemiplegic migraine, a small subset of familial and sporadic cases have associated manifestations including permanent cerebellar signs (nystagmus and/ or ataxia), epilepsy, cognitive impairment, elicited repetitive daily blindness and paroxysmal dyskinesia. Some patients can present with early-onset severe attacks with coma, prolonged hemiplegia, fever and brain edema (13). Moreover, different mutations in FHM genes induce other monogenic neurological disorders. CACNA1A mutations can cause episodic ataxia type 2 and spinocerebellar ataxia type 6 (7,13). PRRT2 mutations are associated with benign familial infantile convulsions, infantile convulsions with choreoathetosis, and paroxysmal dyskinesias (10). SCN1A was already known as an epilepsy gene previous to its identification as the FHM3 gene (1). Diagnosing HM might be a challenge. The first step relies on a detailed description of the aura (13). Apart from the presence of a motor weakness during the aura and the frequency of prolonged auras, most HM attacks are similar to attacks of migraine with typical or with brain stem aura. Single cases are diagnosed as sporadic HM, while at least two affected firstand/or