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Abstract & Commentary
Source: Ducros A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med. 2001;345:17-24.
Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by episodes of transient hemiparesis followed by migraine headaches. Episodes have also been characterized by periods of coma in association with prolonged hemiparesis. Some patients even demonstrate permanent neurologic disability between attacks, such as nystagmus and ataxia. The variability in clinical spectrum has lead some clinicians to distinguish families affected by pure hemiplegic migraine from families affected by hemiplegic migraine and cerebellar signs.
FHM is genetically heterogeneous. CACNA1A, the first gene associated with the disorder, is located on chromosome 19 and encodes for the a-1a subunit of the voltage gated P/Q-type calcium channels in neurons. FHM associated with cerebellar signs has been linked to mutations in the CACNA1A gene. Cases of pure FHM have been linked to both defects in CACNA1A and a locus on chromosome 1. In others, the disorder is not linked to either site suggesting the existence of a third locus. As this study shows, 8 mutations in CACNA1A have been identified in 18 families affected by FHM and 2 with sporadic hemiplegic migraine. So far, no detailed clinical data have been reported on these patients. The current study has screened for mutations in CACNA1A in 28 families and 3 patients with sporadic hemiplegic migraine in an attempt to detail a clinical description of the disorder and identify correlations between genotype and phenotype.
Twenty-eight unrelated families were studied. Sixteen were affected by hemiplegic migraine with cerebellar signs as defined by the presence of ataxia and nystagmus (FHMwC). Twelve families were affected by pure FHM without cerebellar signs. Three subjects with sporadic hemiplegic migraine with cerebellar signs were also studied. DNA analysis was performed using a technique of single strand conformational polymorphism (SSCP). Overall, 9 missense mutations in the CACAN1A gene were identified: 15 of the 16 probands (87 subjects) with FHMwC, 4 of 12 pure FHM (28 subjects), and 2 of 3 sporadic cases. All variants were located in important functional domains of the channel protein.
Ducros and colleagues characterized the clinical features of FHM in the 117 subjects and contrasted them to typical migraine with aura.
The mean age of onset was 11.7 years (range, 1-51). The mean frequency of attacks was 2 or 3 per year. The headache itself was typical. The hemiparesis during the aura was never isolated; it was always associated with sensory, language or visual disturbances.
One-fourth of the patients affected by FHM did not have visual symptoms, whereas in more common varieties of migraine with aura, visual symptoms were almost universal. Bilateral motor signs are observed in one-third of patients affected by hemiplegic migraine, but very rarely in patients affected by the other varieties of migraine with aura. One-third of subjects had attacks with bilateral signs and symptoms. Another one-third of the subjects described atypical attacks characterized by prolonged aura lasting up to 5 days or signs of diffuse encephalopathy. Attacks of encephalopathy occurred mostly in younger subjects and included confusion, coma, fever, and seizures. These severe attacks were often triggered by head trauma, and could last up to 6 weeks but, nevertheless, with full recovery. Sixty-two subjects had permanent cerebellar signs which included nystagmus, gait ataxia, dysarthria, and tremor. The frequency of atypical and severe attacks was higher in the group of FHMwC compared to pure FHM (49% vs 21%, P = 0.02). The data strongly suggest that pure FHM and FHMwC, which were previously considered to be 2 clinical subtypes, are associated with distinct mutations in CACNA1A.
The current study is an excellent contribution to the growing field of migraine genetics. Though FHM represents a distinct clinical rarity, unraveling the genetics of this disorder has broader implications. The real question is whether typical migraine with and without aura (a condition affecting 12% of the population) represents a forme fruste of this more severe channel protein defect. Indeed, the idea of migraine as a "channelopathy" is appealing on many levels. It is consistent with it being transient, reversible, and triggered under physiological stress. Defining the underlying mechanism and genetics of migraine will go a long way in establishing migraine as a "real disease" and pave the way for more effective treatment. —Jeffrey Reich