CACNA1A mutations

FHM and EA2: Two clinically distinct conditions.

FHM is an autosomal dominant form of migraine with aura in which the aura is characterized by motor weakness of variable intensity.7 Symptoms include both typical migraine and severe episodes with prolonged aura (up to several days or weeks), impaired consciousness ranging from confusion to profound coma, fever, and meningismus.8 In 20% of unselected FHM families, some patients also have fixed cerebellar symptoms and signs such as nystagmus and progressive ataxia. Cerebellar ataxia may even be noted prior to the first hemiplegic migraine attack, and it progresses independently of the frequency or severity of hemiplegic migraine attacks.

EA2 is also an autosomal dominant disorder. However, sporadic cases have been reported. EA2 patients have paroxysmal attacks of ataxia lasting for 15 minutes to hours or days, often provoked by emotional or physical stress, alcohol, or coffee, but not by startle, and associated with interictal nystagmus.9 Acetazolamide responsiveness is a common feature. Less common symptoms include vertigo, nausea, diplopia, headache, confusion, generalized sweating, and oscillopsia. Age at onset is usually during childhood or adolescence, but varies from 1 to 30 years. The frequency of attacks is highly variable and sometimes decreases with age. Between attacks, nystagmus on lateral or vertical gaze is the most prominent sign. In addition, some patients develop a mild progressive cerebellar ataxia, with gait unsteadiness, limb uncoordination, and dysarthria.

EA2 and FHM diagnosis depend on clinical investigation of the patient, including family history. In EA2 patients, additional investigations are often indicated to exclude other hereditary and nonhereditary conditions causing ataxia, particularly when there is no family history.

FHM and EA2 are caused by distinct types of mutations within CACNA1A.

FHM is a genetically heterogenous condition for which two genes have been mapped so far, on chromosomes 19 and 1.1,10 Only one of the two, CACNA1A, has been identified.1 On the other hand, all EA2 families have been linked to chromosome 19. Mutations within CACNA1A, a gene encoding for the α1A subunit of a neuronal P/Q type calcium channel, cause both FHM and EA2.1 In this issue of Neurology, Battistini et al.4 and Carrera et al.5 showed the presence within two unrelated FHM families of two different CACNA1A missense mutations cosegregating with the affected phenotype and absent in control individuals. One of these nucleotide substitutions occurred within exon 13 and would lead to the replacement of an arginine (R) to a glutamine (Q) at codon 583 within the putative IIS4 transmembrane segment. This mutation was detected in two sisters. Interestingly, there were clinical differences between the two sisters; although both of them had typical hemiplegic migraine attacks, one of them had severe attacks accompanied by confusion, coma, and fever, symptoms which are often misleading for the clinician, especially when they occur in children or in sporadic cases. This patient also had interictal nystagmus as well as a fixed cerebellar ataxia. Interestingly, this R583Q mutation has also been observed in three FHM families with permanent cerebellar ataxia.3 Additional information provided by this report is the seeming effectiveness of acetazolamide in preventing hemiplegic migraine attacks, although proof will need controlled studies.

Carrera et al.5 analyzed five FHM families and seven hemiplegic migraine sporadic cases and identified within one family a nucleotide substitution at position 4644 within exon 27. This mutation would lead to the replacement of a valine for a leucine in the P-loop within domain III. Mutations were not detected within any of the other FHM families, which suggests genetic heterogeneity. The authors did not detect mutations in their sporadic cases. However, CACNA1A mutations were detected recently in two sporadic FHM patients, one of whom clearly had a de novo mutation.11

Jen et al.6 report in this issue a large chromosome 19–linked autosomal dominant pedigree with EA2. The authors identify the deleterious mutation as being a C to T change within exon 29 leading to a premature stop codon that would result in a truncated CACNA1A protein. The truncating nature of the mutations observed in EA2 patients has been recently confirmed in a larger series of EA2 multiple-case families as well as EA2 sporadic cases.12

Genotype-phenotype correlations in CACNA1A-related conditions: A broader than expected clinical spectrum.

In most instances, two distinct types of CACNA1A mutations have been identified in hemiplegic migraine and EA2. However, Jen et al.6 suggest that truncating mutations within CACNA1A may in some EA2 patients cause paroxysmal episodes combining ataxia and hemiplegia. Indeed, 2 of the 13 patients in the pedigree experienced hemiparesia during their ataxic spells. One of these two patients complained since infancy of paroxysmal attacks of vertigo and ataxia accompanied by headaches with nausea and photophobia. During pregnancy she stopped acetazolamide and reported spells characterized by ataxia and right-sided weakness and headaches. The second patient, who never had migraine, reported ataxic spells during which she noticed an inability to lift her arm. In both patients hemiparetic symptoms always occurred during ataxic spells. In my opinion, this observation does not mean that this family is affected by both FHM and episodic ataxia but rather that the clinical symptoms observed in EA2 patients during ataxic spells may include nonataxic manifestations. Indeed, other paroxysmal symptoms have been observed in EA2 patients such as pure intermittent diplopia.12 To my knowledge no families include hemiplegic migraine patients and paroxysmal ataxia patients as well as patients who have both hemiplegic migraine and episodic ataxia attacks. Great intra- and interfamilial variability exists in the symptoms experienced by EA2 patients.12 This variability concerns both episodic symptoms and permanent symptoms and suggests that environmental or genetic factors other than the CACNA1A mutation are important for the phenotype. With regard to genetic modifying factors, the length of the CACNA1A intragenic CAG repeat of which expansion causes another autosomal dominant neurological condition, spinocerebellar ataxia type 6,13 does not seem to account for this variability.

The main question now to be solved is to understand how these various mutations lead to the observed phenotypes. In vitro study by electrophysiologic analysis of these mutated CACNA1A channels14 as well as in vivo study of animal models with lesions in the CACNA1A gene, such as tottering and leaner, will help to resolve these questions.