Etiology and pathogenesis
Familial hemiplegic migraine is an autosomal dominant, genetically heterogeneous disorder. Mutations in 3 genes are responsible for 50% to 70% of published families with familial hemiplegic migraine. The FHM-1 (CACNA1A) gene is located on chromosome 19p13. The FHM-2 (ATP1A2) gene is located on chromosome 1q23. The FHM-3 (SCN1A) gene is located on chromosome 2q24. Sporadic hemiplegic migraine has been associated with CACNA1A, ATP1A2, and SCN1A gene mutations. PRRT-2 mutations have been identified in hemiplegic migraine patients.
CACNA1A, the first gene associated with familial hemiplegic migraine (on chromosome 19), encodes the α1A subunit of voltage-gated P/Q-type calcium channels (111; 153; 151; 27). FHM-1 with cerebellar signs has been linked to mutations in CACNA1A in some families (151; 198; 12; 61; 74; 215). As of 2005, 17 different missense mutations in CACNA1A have been linked with FHM-1 (163). The T666M mutation is the major CACNA1A mutation. Haplotype studies suggested that this mutation arose independently on different chromosomes by recurrent mutational events (61). In 2006, new families with a CACNA1A mutation were reported. An S218L mutation was found in a patient with sporadic hemiplegic migraine and minor head trauma-induced hemiplegic migraine coma (46), which confirmed the role of this specific mutation in (fatal) coma after minor head trauma (121). The mechanisms underlying a dramatic hemiplegic migraine syndrome in S218L CACNA1A mutation is the particularly low cortical spreading depression (CSD) threshold and the strong tendency to respond with multiple CSD events after a single stimulus (216). The clinical manifestation found in the S218L mutation was reported in a child with a mutation in CACNA1A (p.Arg1349Gln) (135). This patient had reduced level of consciousness, seizure, and cerebral edema after a head injury and returned to her previous clinical state subsequently. The cortical spreading depression in familial hemiplegic migraine knock-in mice expressing the S218L (seizure, coma, hemiplegia) or R192Q (hemiplegia only) propagated into subcortical structures; the subcortical spread was limited to the striatum in R192Q but spread to the hippocampus and thalamus in S218L mutants (67). The thalamic nuclei of knock-in mice expressing the CACNA1A R192Q mutation suggested that the mutation affects more rostral brain structures (155). Other manifestations found in a novel missense CACNA1A mutation include an EA-2-like phenotype (G533A), nonfluctuating limb and trunk ataxia with an early age at onset, and childhood periodic syndromes that evolved into hemiplegic migraine (Y1245C) (186; 208; 188). The susceptibility to spreading depression and neurologic deficits in FHM-1 is affected by allele dosage and hormonal factors (64). Coexistence of 2 single nucleotide polymorphisms of the CACNA1A gene may influence the calcium channel function in migraine with brainstem aura, hemiplegic migraine, migraine with aura, and migraine without aura (59).
There is also a polymorphism of the CACNA1E gene that is more common in patients with hemiplegic and brain stem migraine (04).
A region on chromosome 1q21-23 was found to cosegregate with the FHM-2 in 3 French families (63). Marconi and colleagues refined the 1q23 locus for FHM-2 by studying a large Italian family affected by this disease (138). They showed that mutations in the ATP1A2 gene encoding the alpha2 subunit of the Na+,K+-ATPase pump are associated with FHM-2 on 1q23 (48).
FHM-2 has been found to be associated with 27 different missense mutations in the ATP1A2 gene. Cerebellar signs are rare in FHM-2 families; however, transient and permanent cerebellar signs were reported in an Italian family with a G301R mutation (190). ATP1A2 mutations have also been associated with migraine with brainstem aura and alternating hemiplegia of childhood. Many patients also suffer from epilepsy (53). In 26 unrelated familial hemiplegic migraine probands in whom CACNA1A screening was negative, a total of 8 different ATP1A2 mutations were identified in 11 of the probands (41%) (170). A novel mutation in the ATP1A2 gene (R548H) has been detected in members of a family with migraine with brainstem aura, suggesting that this and familial hemiplegic migraine may be allelic disorders (05). Many novel ATP1A2 mutations manifested as pure familial hemiplegic migraine were revealed in different families: R593W in a Dutch family, V628M in a Turkish family, and M731T and T376M in 2 Portuguese families (218; 31). Some patients with novel ATP1A2 mutations had additional clinical features, including mood alteration and mental impairment (30). The ATP1A2 mutation in a proband of a Dutch familial hemiplegic migraine family had a clinical phenotype consisting of both episodic and permanent severe neurologic features and mental retardation. The episodic symptoms were precipitated by mild head trauma and included hemiplegia, epileptic seizures, and cortical blindness (220). A case of 2 allelic, novel ATP1A2 missense mutations in a patient with hemiplegic migraine was described (219). The presence of 2 ATP1A2 mutations in the proband causes a more severe phenotype, compared with the milder familial hemiplegic phenotype of an aunt, who carries only 1 mutation.
Patients with both epilepsy and migraine and a positive family history of either migraine or epilepsy can be screened for mutations in the ATP1A2 gene (50; 75). Mutations in the ATP1A3 gene can also present with dystonia, alternating hemiplegia, EEG abnormalities, and seizure (157).
In 2005, a Q1489K mutation in SCN1A, the gene encoding the neuronal voltage-gated sodium channel type 1A (FHM-3), was identified in 3 German familial hemiplegic migraine families of common ancestry. The missense mutation encodes the neuronal voltage-gate sodium channel Nav1.1 on chromosome 2q24 (55). SCN1A mutations were found in a familial hemiplegic migraine family with or without associated diseases such as ataxia, epilepsy, and myoclonus (78; 217; 32). Visual disturbances, including severe vision loss, due to SCN1A has been described (183).
Mutations in the CACNA1A, ATP1A2, and SCN1A genes explain 50% to 70% of published families with familial hemiplegic migraine. However, these families are selected from hospitals or specialist practices and very likely represent families with higher penetrance and more severe symptomatology compared with cases from the general population. It is, therefore, possible that the frequency of mutations in the CACNA1A, ATP1A2, and SCN1A genes may be different in families with familial hemiplegic migraine than those from the general population (202). Novel gene mutations were detected in CACNA1A, ATP1A2, and SCN1A genes during the past few years.
The possibility of developing either migraine or epilepsy from mutations in the same gene establishes the link between the disorders. In epilepsy, the hyperexcitable brain leads to discharges characterized by hypersynchronous neuronal firing and rhythmic recruitment of large populations of neurons, whereas in migraine cortical spreading depression leads to neuronal and glial depolarization, which propagates much more slowly (137).
A study in the Danish population identified 147 familial hemiplegic migraine patients from 44 different families. The linkage analysis showed clear linkage to the FHM-1 locus, supportive linkage to the FHM-2 locus, but no linkage to the FHM-3 locus. CACNA1A gene mutations were identified in 3 familial hemiplegic migraine families: 2 known familial hemiplegic migraine mutations, R583Q and T666M, and 1 novel C1369Y mutation. Three familial hemiplegic migraine families had novel mutations in the ATP1A2 gene: 1 has a V138A mutation, 1 has a R202Q mutation, and another a R763C mutation. None of the Danish familial hemiplegic migraine families had the Q1489K mutation in the SCN1A gene. Only 14% of familial hemiplegic migraine families in the general Danish population have familial hemiplegic migraine mutations in the CACNA1A or ATP1A2 gene. The families with familial hemiplegic migraine mutations in the CACNA1A and ATP1A2 genes were extended, multiple-affected families, whereas the remaining familial hemiplegic migraine families were smaller. The existence of many small families in the Danish familial hemiplegic migraine cohort may reflect less bias in familial hemiplegic migraine family ascertainment and/or more locus heterogeneity than described previously (202). Linkage analysis in a large Spanish kindred with familial hemiplegic migraine revealed a disease locus in a 4.15 Mb region on 14q32, which does not overlap with the reported migraine loci on 14q21-22. This finding suggested that genetic heterogeneity in familial hemiplegic migraine may be greater than previously suspected (45).
No mutations have been found in any of the 3 familial hemiplegic migraine genes among patients with migrainous vertigo (118; 225). CACNA1A mutations can cause atypical alternating hemiplegia of childhood, indicating an overlap of molecular mechanisms causing alternating hemiplegia of childhood and familial hemiplegic migraine (54).
Sporadic hemiplegic migraine is a heterogenous disorder. Three patients with sporadic hemiplegic migraine who had cerebellar signs were analyzed for mutations in the familial hemiplegic migraine gene CACNA1A. Two mutations were found: a T666M mutation in a patient with sporadic hemiplegic migraine and cerebellar ataxia and a Y1384C mutation in a woman with mental retardation, sporadic hemiplegic migraine, coma, seizures, and permanent cerebellar ataxia and atrophy (214). In another 27 sporadic hemiplegic migraine patients, 2 mutations were found: a T666M mutation in a patient with sporadic hemiplegic migraine and cerebellar ataxia and an R583Q mutation in a patient with sporadic hemiplegic migraine but without cerebellar ataxia. No mutations were identified in the remaining 25 sporadic hemiplegic migraine patients (197). A systematic analysis of 3 familial hemiplegic migraine genes was performed in 39 well-characterized patients with sporadic hemiplegic migraine without associated neurologic features. Sequence variants were identified in 7 sporadic hemiplegic migraine patients: 1 CACNA1A mutation (R583Q), 5 ATP1A2 mutations (E120A, E492K, P786L, R908Q, R834X), and 1 SCN1A polymorphism (R1928G). All 6 mutations caused functional changes in cellular assays. One sporadic hemiplegic migraine patient was reclassified to familial hemiplegic migraine when another family member developed familial hemiplegic migraine attacks. An ATP1A2 sequence variant was found in 5 of the 7 sporadic hemiplegic migraine cases, which is 13% of the overall sporadic hemiplegic migraine sample (52). In a population-based sample of sporadic hemiplegic migraine, all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients were sequenced to search for sporadic hemiplegic migraine mutations. Very few DNA variants were identified and the causal role of the variants is unknown. Thus, the CACNA1A and ATP1A2 genes may not be major genes in sporadic hemiplegic migraine (203). In a group of sporadic hemiplegic migraine patients referred for a genetic diagnosis, familial hemiplegic migraine gene mutations in CACNA1A or ATP1A2 were identified in 23 of the 25 patients (171). SCN1A analysis did not show any mutation. The results from this study were different from the previous studies, which could be due to early-onset cases (age at onset below 16 years) and associated neurologic signs, including cerebellar ataxia, epileptic seizures, or various degrees of intellectual disability. In some sporadic hemiplegic migraine patients, the diagnosis was changed into familial hemiplegic migraine after 9 to 14 years (191). Long-term follow-up of the patients and families is important.
FHM-1 mutations produce gain-of-function of the Ca(V)2.1 channel. This increases calcium influx into presynaptic terminals, enhances glutamate release at pyramidal cell synapses without altered inhibitory neuron transmission at fast-spiking interneuron synapses (210), and facilitates induction and propagation of cortical spreading depression. Functional consequence of FHM-1 mutations appears as the consequence of the alteration of intrinsic biophysical properties and of the main inhibitory G-protein pathway of Ca(V)2.1 channels (229). Alternative splicing in FHM-1 mutations generate multiple functional, distinct calcium channel variants that affect the recovery from inactivation and accumulation of inactivation during tonic and burst firing differently (02). In the mutant mouse central nervous system, FHM-1 mutations affect both P/Q-type channel Ca(2+)-dependent facilitation and short-term synaptic facilitation (03).
In a knock-in mouse model of FHM-1, TNFα was a major factor in sensitizing trigeminal ganglia and contributing to migraine pain (72). Culture of a knock-in mouse model with a R192Q mutation had a basal neuroinflammatory profile that might facilitate the release of endogenous mediators to activate hyperfunctional P2X3 receptors and amplify nociceptive signaling by trigeminal sensory neurons (71). ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of pain. The role of calcium/calmodulin-dependent serine protein kinase (CASK) in controlling P2X3 receptor expression and function in trigeminal ganglia from a FHM-1 genetic model showed more abundant CASK/P2X3 receptor complex at the membrane level and resulted in gain of function. The expression of this complex depends on intracellular calcium and related signaling (82). Mutations W1684E and V1696I, which cause FHM-1 with and without cerebellar ataxia, respectively, altered the G protein-Ca(2+) channel affinity (80). The significant reduction of the extent of G-protein-mediated inhibition in the K1336E mutant CaV2.1 Ca2+ channels renders the neuronal network hyperexcitable (79). The functional impact of the E1015K amino acid substitution located in the synprint domain of the alpha-1A subunit is characterized by a gain-of-function. This variant is associated with hemiplegic migraine and migraine with aura (41).
FHM-2 mutations result in loss or diminished function of the sodium potassium pump and reduced uptake of potassium and glutamate into glial cells. The uptake is slowed because of Na+,K+-ATPase haploinsufficiency (48). Functional properties of ATP1A2 mutation are diverse, and mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences (195). Temperature-sensitive effects on protein stability were proposed as an underlying cause of ATP1A2 loss of function (194). An additional pathway in the Na(+)/K(+)-ATPase pump function is the C terminus, which controls the gate to the pathway. Mutations in the region cause severe neurologic disease and are established as the cause of FHM-2 (167). In a study of 9 FHM-2 mutations, different mechanisms of phosphorylation inhibition of Na+, K+-ATPase were demonstrated (182).
FHM-3 mutation accelerates recovery from fast inactivation of Na(V)1.5 (presumably Na(V)1.1) channels. SCN1A mutation has effects on the gating properties of neuronal voltage-gated Na(V)1.1 Na+channel consistent with both hyperexcitability and hypoexcitability. This self-limited capacity may be a specific characteristic of migraine mutations (34). Some FHM-3 mutations resulted in gain of function (familial hemiplegic migraine and generalized epilepsy) such as L263V and L1649Q, but some mutations resulted in loss of function (typical familial hemiplegic migraine) such as Q1489K (113; 35). These results emphasize that migraine and epilepsy may share common molecular mechanisms. These findings are consistent with the hypothesis that familial hemiplegic migraine mutations share the ability to render the brain more susceptible to cortical spreading depression by causing either excessive synaptic glutamate release (FHM-1), decreased removal of K+ and glutamate from the synaptic cleft (FHM-2), or excessive extracellular K+ (FHM-3) (164).
The T1174S SCN1A mutation can lead to a gain of function in some conditions and loss of function in other conditions. These findings may help to explain the coexistence of epilepsy and familial hemiplegic migraine without epilepsy in the same family (33). Bioinformatics analysis of the 3 familial hemiplegic migraine mutations shows that FHM-3 is more resistant to mutation within the amino acid sequence when compared with others (232).
Accumulating evidence found in familial hemiplegic migraine patients suggest that the pathophysiology of migraine headache in FHM-1 and FHM-2 may be different from common types of migraine. These include calcitonin gene-related peptide, a migraine trigger that did not induce an aura in familial hemiplegic migraine patients (95; 93). FHM-1 and FHM-2 patients do not show hypersensitivity of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, as seen in migraine patients with and without aura (96; 94; 97). Possible differences in frontal cortical nitric oxide vascular sensitivity between pure familial hemiplegic migraine patients and familial hemiplegic migraine patients with a coexisting common type of migraine have been suggested (185). Other evidence suggests that the difference between familial hemiplegic migraine and common forms of migraine is an increased habituation in cortical/brainstem-evoked activities in familial hemiplegic migraine, not a habituation deficit found in common forms of migraine (91). However, in certain families, it is possible that the hemiplegic aura is a more severe and complex form of typical aura due to the combination of polygenic traits and endogenous or environmental factors (09). To explain unusual and severe aura signs and symptoms in familial hemiplegic migraine patients, spreading depression may propagate between cortex and subcortical structures. The reciprocal spread and reverberating waves can explain protracted attacks (66).
Common trigger factors for familial hemiplegic migraine are stress, bright light, intense emotional influences, and sleeping too much or too little. These triggers are the same as for migraine with aura (91).
In 2012, proline-rich transmembrane protein (PRRT2) mutations have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. The paroxysmal disorders include paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, and episodic ataxia (76; 172; 29; 141).