Sporadic and Familial Hemiplegic Migraines

Anne Ducros

Lise Lykke Thomsen

FAMILIAL HEMIPLEGIC MIGRAINE

Definition

International Headache Society (IHS) code and diagnosis: 1.2.4 Familial hemiplegic migraine

World Health Organization (WHO) code and diagnosis: G43.1 × 5 Familial hemiplegic migraine

Short description (Headache Classification Committee, 2004): Migraine with aura including motor weakness and where at least one first- or second-degree relative has migraine with aura including motor weakness

Previously used terms: Complicated migraine

Epidemiology

Since the first description in 1910 (13) up to today, about 150 highly selected families affected by familial hemiplegic migraine (FHM) have been described worldwide (1, 2, 3,5, 6, 7, 9,10,12,14, 15, 16,18,21,23, 24, 25, 26, 27,30,31,34,35,37,38,40,46, 47, 48,50, 51,53, 54, 55,59, 60, 61, 62,66, 67, 68, 69,71,72,75,77,79,81,84,85,87,98,100, 101, 102, 103,106). Due to difficulties using traditional population-based methods when studying the prevalence of a rare disorder, the true prevalence of FHM is still unknown. Only recently a systematic nationwide epidemiologic survey of the entire Danish population of 5.2 million inhabitants estimated the prevalence of FHM to be 0.005% in 1999 in Denmark (88). Despite some limitations in the applicability of the statistical method used, known as capture-recapture, the study may provide a useful approximation of the number of affected subjects.

Published descriptions of families have enabled two clinical forms of the disorder to be distinguished: “pure FHM,” in which the neurologic examination of all affected patients between two attacks is strictly normal, and “FHM with permanent cerebellar signs,” in which at least one member has nystagmus or ataxia during attack-free intervals. The percentage of families affected by FHM with permanent cerebellar signs is close to 20% in the literature (2,3,5,12,14,18,19,25,27,30,37,46,47,53, 54, 55,66,71,72,79,81,83,84,100,102,106). This percentage is probably overestimated due to several publication biases, including the interesting character of this association and the fact that the first FHM gene to be localized and identified was responsible for the majority of FHM cases with cerebellar signs. In a systematic nationwide epidemiologic survey of the entire Danish population, 44 FHM families were identified, including only 2 with cerebellar signs (4.5%). (87) The true prevalence of FHM families with cerebellar signs is most likely less than 20%.

Besides the familial form of HM, sporadic cases of HM exist (see next chapter).

Genetics

FHM is the only migraine subtype for which a monogenic mode of inheritance, autosomal dominant, has been clearly established. Like other autosomal dominant conditions, FHM affects males and females equally and is transmitted by fathers as well as mothers to 50% of their offspring. Penetrance of the condition is incomplete: not all mutated gene carriers have FHM (18,20,23), as demonstrated by a pair of monozygotic twin sisters (20). The twins were discordant for FHM, and the unaffected sister had a son with hemiplegic migraine. This incomplete penetrance has several implications for clinicians as well as for geneticists. First, an affected individual may have no first- or even second-degree affected relative, making it difficult to diagnose familial hemiplegic migraine. Second, an asymptomatic family member may have affected children. Third, in the mapping of FHM genes, only affected recombinants should be considered. Finally, the incomplete penetrance suggests that modifying genetic or environmental factors play a role in the expression of the FHM phenotype.

FHM is genetically heterogeneous and at least three different genes exist (16,23,71). The first responsible gene, CACNA1A (71), mapped on chromosome 19p13 (46), is involved in approximately 50% of unselected families (FHM1) and in the vast majority of families with permanent cerebellar signs (47,72). The second gene, ATP1A2 (16), mapped on chromosome 1q21-q23 (23,31), is involved in about 20% of FHM families (FHM2) (23). Finally, about 30% of FHM families are unlinked to the chromosome 19 FHM1 locus and to the chromosome 1 FHM2 locus, demonstrating the existence of at least a third gene (23).

FHM1 and CACNA1A Mutations

CACNA1A, the FHM1 gene, encodes the pore-forming α1A subunit of P/Q-type voltage-dependent neuronal calcium channels (71). These calcium channels, also called Ca_v2.1 channels, are expressed exclusively in neurons from the central as well as the peripheral nervous system. They play a major role in the control of neurotransmitter release (including glutamate), postsynaptic calcium fluxes, and neuronal excitability. A total of 15 different CACNA1A mutations have been identified in 38 FHM1 families (including 29 with cerebellar signs) and in 4 sporadic cases (2,5,10,18,19,30,32,53,54,71,81,82,95,100). Five of these mutations (S218L, R583Q, T666M, R1668W, and I1811L) were recurrent in the absence of any founder effect. The most frequent mutation, T666M, was found in half the families and sporadic cases. All these mutations are missense mutations altering important functional domains of the predicted protein.

The consequences of FHM1 mutations have been studied by electrophysiology and by the analysis of mutant mice. Seven FHM1 mutations (R192Q, R583Q, V714A, D715E, T666M, V1457L, and I1811L) have been investigated so far to detect their putative effects on Ca_v2.1 currents (39,56,57). In these studies, calcium fluxes were compared in cells expressing wild-type and mutant CACNA1A. All analyzed mutations induced a lower activation threshold and an increased opening probability of Ca_v2.1 channels. FHM1 mutations are thus “gain-of-function,” responsible for an enhanced calcium influx through single Ca_v2.1 channels. No difference was observed between mutations associated with pure FHM and mutations associated with FHM and permanent cerebellar signs. However, in vitro experimental conditions probably do not reflect the complexity of the situation in vivo.

CACNA1A knockout mice are born with severe ataxia and die within a few days (29). These mice have no P/Q-type calcium currents. Mice with various recessive CACNA1A mutations display different phenotypes called tottering, leaner, or rocker, characterized by the association of various paroxysmal manifestations (absence epilepsy, motor attacks) with a permanent cerebellar ataxia of variable severity (28,107). Tottering mice have an abnormal control of acetylcholine release at the neuromuscular junction (74). Leaner mice have a decrease in depolarization-induced glutamate release with almost no changes in γ-aminobutyric acid (GABA) (4). Leaner mice also have an increased threshold for initiating cortical spreading depression (CSD) and a slower propagation of CSD (4). Knocking mice with the FHM1 mutation R192Q display an increased cerebellar Ca_v2.1 current, increased neuromuscular transmission, and a lowered threshold for initiating CSD with a higher velocity of CSD propagation (97). This mutant mouse represents the first animal model of FHM. Altogether, these different abnormalities suggest that the increased susceptibility to initiate CSD and aura in FHM are due to cortical hyperexcitability.

Finally, mutations in CACNA1A cause two other autosomal dominant conditions: episodic ataxia type 2 (EA2) (71) and spinocerebellar ataxia type 6 (SCA6) (105). EA2 is responsible for paroxysmal attacks of gait ataxia with limb incoordination, dysarthria, and nystagmus (17,96). Acetazolamide responsiveness is a common feature. Between attacks, nystagmus and mild ataxia are often noted. EA2 is due to missense or truncating mutations within the CACNA1A gene, which are responsible for a loss of function, the mutated channels being unable to generate any calcium current (17,36). SCA6 is a late-onset progressive neurologic condition responsible for gait and limb ataxia. SCA6 is caused by small expansions of a CAG repeat, located within the 3′ end of CACNA1A and predicted to code for a polyglutamine tract in three of the six known human splice variants (105).

FHM2 and ATP1A2 Mutations

ATP1A2, the FHM2 gene, encodes the catalytic subunit of Na+/K+ ATPase. This pump is expressed mainly in neurones in neonates and mainly in astrocytes in adults. The pump utilizes ATP hydrolysis to actively maintain the sodium gradient across the cell membrane. A total of 12 different ATP1A2 mutations have been identified in 12 families and 1 sporadic case (R763H) (16,33,48,51,98). One mutation was found in two unrelated families (33,48). In another family with the R689Q mutation, FHM was found to be associated with benign familial infantile convulsions; all family members affected by FHM, infantile convulsions or both, had the R689Q mutation (98). Electrophysiologic studies have shown that FHM2 mutations induce a loss of function with a complete inhibition of pumping activity in cells expressing the mutated gene (16).

In addition, a novel ATP1A2 mutation (T378N) has been identified in a family affected by a disease showing features of FHM associated with alternating hemiplegia of
childhood, hemiplegic and quadriplegic spells, headache, hemidystonic spells, paroxysmal ocular abnormalities, generalized tonic-clonic seizures, cognitive impairment, autonomic involvement of the affected limb, and flunarizine responsiveness (80).

Pathophysiology

The mechanisms leading from CACNA1A or ATP1A2 mutations to hemiplegic migraine attacks are still unknown; however, most agree that the clinical presentation (phenotype) is the result of an inherited susceptibility (genotype) that is strongly modulated by both internal and external environmental factors. According to the main hypothesis, migraine is a continuum with migraine without aura at one end and familial hemiplegic migraine at the other end. Mechanisms underlying attacks of FHM are thus thought to be closely related to those underlying attacks of migraine with typical aura: sustained CSD for the aura phase and activation of the trigeminovascular system for the headache phase. Moskowitz et al. (64) recently suggested that FHM mutations render the brain more susceptible to prolonged CSD caused by either excessive synaptic glutamate release (FHM1) or decreased removal of glutamate and K⁺ from the synaptic cleft (FHM2). By accepting this hypothesis, it is theoretically possible to comprehend how a gain-of-function mutation (FHM1) and a loss-of-function mutation (FHM2) expressed in distinct cell types and encoding different ion channels fluxing either monovalent or divalent cations generate a remarkably overlapping migraine phenotype.

Clinical Features

IHS diagnosis criteria for familial hemiplegic migraine (Headache Classification Committee, 2004) (43):

A. At least two attacks fulfilling criteria B and C

B. Aura consisting of fully reversible motor weakness and at least one of the following:

1. Fully reversible visual symptoms including positive features (e.g., flickering lights, spots, or lines) and/or negative features (i.e., loss of vision)

2. Fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness)

3. Fully reversible dysphasic speech disturbance

C. At least two of the following:

1. At least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes.

2. Each aura symptom lasts ≥5 minutes and <24 hours.

3. Headache fulfilling criteria B through D for 1.1 Migraine without aura begins during the aura or follows onset of aura within 60 minutes.

D. At least one first- or second-degree relative has had attacks fulfilling these criteria A to E.

E. Not attributed to another disorder. History and physical and neurologic examinations do not suggest any of the disorders listed in groups 5 to 12, or history and/or physical and/or neurologic examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur for the first time in close temporal relation to the disorder.

FHM is a migraine with aura characterized by the presence of a motor weakness during the aura (7,101). Since the first description by Clarke in 1910 (13), more than 150 families have been reported in the literature. Their clinical description, when available, strongly suggests a high variability in the HM attacks’ symptoms and the disease course among the patients.

Migraine Attacks

Trigger factors are reported by about two-thirds of the patients, the most frequent being stress and minor head trauma (18,31,83). Less then 10% of patients point out triggers of other forms of migraine, such as dietary factors, visual or auditory stimulation, climatic factors, and menstruation (18). In several cases, a severe HM episode was precipitated by injection of contrast enhancement products during cerebral or extracerebral angiography (6,7,18,48). Finally, attacks occur spontaneously in one-third of patients.

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