The Clinical Spectrum of Familial Hemiplegic Migraine Associated with Mutations in a Neuronal Calcium Channel

Ducros, Anne; Denier, Christian; Joutel, Anne; Cécillon, Michaelle; Lescoat, Christelle; Vahedi, Katayoun; Darcel, Françoise; Vicaut, Éric; Bousser, Marie‐Germaine; Tournier‐Lasserve, Elisabeth

doi:10.1056/nejm200107053450103

Cited by 503 publications

(522 citation statements)

References 33 publications

Supporting

Mentioning

488

Contrasting

Unclassified

Order By: Relevance

“…Pure FHM1 and FHM1 with cerebellar symptoms are associated with distinct mutations. 7 Symptom variability among subjects with the same mutation suggests that other genetic or environmental factors also influence the phenotype.…”

Section: Familial Hemiplegic Migraine Type 1 (Fhm1)mentioning

confidence: 99%

“…7,8 Moreover, about 20% of FHM fam-ilies show permanent cerebellar symptoms consisting of progressive cerebellar ataxia with or without nystagmus. 5 Emotional stress and minor head trauma are among the most common triggers of FHM attacks.…”

Section: Introductionmentioning

confidence: 99%

“…5 Emotional stress and minor head trauma are among the most common triggers of FHM attacks. 7,8 FHM is genetically heterogeneous. Mutations in the genes CACNA1A at chromosome 19p13 (see Ophoff et al 9 ), ATP1A2 at 1q23 (see De Fusco et al 10 ), and SCNA1A at 2q24 (see Dichgans et al 11 ) are responsible for type 1 (FHM1, up to 50% of the cases), type 2 (FHM2, 20% to 30% of the cases), and type 3 FHM (FHM3), respectively.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Familial Hemiplegic Migraine

2007

View full text Add to dashboard Cite

Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

show abstract

Section: Familial Hemiplegic Migraine Type 1 (Fhm1)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Familial Hemiplegic Migraine

2007

View full text Add to dashboard Cite

show abstract

“…Although the T666M mutation is the most frequently identified mutation in CACNA1A among FHMs [6], [15], [17], the clinical phenotype of patients with the T666M mutation has been shown to be strikingly variable [1], [5], [15], [17]. Furthermore, many families with mutations in CACNA1A, including T666M, have also been reported to suffer from progressive cerebellar ataxia [5], [6].…”

Section: Discussionmentioning

confidence: 99%

“…Although gaze-evoked nystagmus is known to be frequent in FHM1 [6], DPN in patients with FHM1 has not gained much attention and the precise incidence has not yet been investigated. In the present study, we report a Japanese family with a T666M missense mutation in the protein encoded by CACNA1A.…”

Section: Introductionmentioning

confidence: 99%

Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family

et al. 2008

View full text Add to dashboard Cite

Clinical examination and mutational analysis were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.

show abstract

Mutation Analysis of the CACNA1A Calcium Channel Subunit Gene in 27 Patients With Sporadic Hemiplegic Migraine

Terwindt

Kors²,

Haan³

et al. 2002

Arch Neurol

View full text Add to dashboard Cite

show abstract

The Clinical Spectrum of Familial Hemiplegic Migraine Associated with Mutations in a Neuronal Calcium Channel

Abstract: Hemiplegic migraine in subjects with mutations in CACNA1A has a broad clinical spectrum. This clinical variability is partially associated with the various types of mutations.

Cited by 503 publications

References 33 publications

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine

Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family

Mutation Analysis of the CACNA1A Calcium Channel Subunit Gene in 27 Patients With Sporadic Hemiplegic Migraine

Contact Info

Product

Resources

About