A population‐based study of familial hemiplegic migraine suggests revised diagnostic criteria

Thomsen, Laura H.; Eriksen, Marie; Roemer, Shanu F.; Andersen, Ingelise; Olesen, Jes; Russell, M. B.

doi:10.1093/brain/awf132

Cited by 201 publications

(289 citation statements)

References 37 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…Also, the duration of the headache is usually longer in FHM than MA, but all other headache characteristics are similar. 5 FHM and MA attacks may alternate in patients and cooccur within FHM families, and compared with the general population FHM probands have an almost eight times increased risk of MA, 6 suggesting that FHM and MA may be part of the same spectrum and may share some pathogenetic mechanisms. The study of FHM mechanisms may thus provide unique insights into the pathophysiology of migraine.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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: Introductionmentioning

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. 7,8 FHM is genetically heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

View full text Add to dashboard Cite

show abstract

“…Familial hemiplegic migraine (FHM) 1 is a rare autosomal dominant subtype of migraine with aura. Apart from the characteristic transient hemiparesis, typical attacks of FHM are similar to those of the common migraine with aura (1).…”

mentioning

confidence: 99%

“…Apart from the characteristic transient hemiparesis, typical attacks of FHM are similar to those of the common migraine with aura (1). Some FHM patients also show atypical attacks, either with a prolonged aura or with signs of diffuse encephalopathy; moreover, 20% of FHM families show permanent cerebellar symptoms (2).…”

mentioning

confidence: 99%

Specific Kinetic Alterations of Human CaV2.1 Calcium Channels Produced by Mutation S218L Causing Familial Hemiplegic Migraine and Delayed Cerebral Edema and Coma after Minor Head Trauma

Tottene

Pivotto

Fellin

et al. 2005

Journal of Biological Chemistry

130

144

View full text Add to dashboard Cite

Mutation S218L in the Ca V 2.1 ␣ 1 subunit of P/Q-type Ca 2؉ channels produces a severe clinical phenotype in which typical attacks of familial hemiplegic migraine (FHM) triggered by minor head trauma are followed, after a lucid interval, by deep (even fatal) coma and long lasting severe cerebral edema. We investigated the functional consequences of this mutation on human Ca V 2.1 channels expressed in human embryonic kidney 293 cells and in neurons from Ca V 2.1 ␣ 1 ؊/؊ mice by combining single channel and whole cell patch clamp recordings. Mutation S218L produced a shift to lower voltages of the single channel activation curve and a consequent increase of both single channel and whole cell Ba 2؉ influx in both neurons and human embryonic kidney 293 cells. Compared with the other FHM-1 mutants, the S218L shows one of the largest gains of function, especially for small depolarizations, which are insufficient to open the wild-type channel. S218L channels open at voltages close to the resting potential of many neurons. Moreover, the S218L mutation has unique effects on the kinetics of inactivation of the channel because it introduces a large component of current that inactivates very slowly, and it increases the rate of recovery from inactivation. During long depolarizations at voltages that are attained during cortical spreading depression, the extent of inactivation of the S218L channel is considerably smaller than that of the wild-type channel. We discuss how the unique combination of a particularly slow inactivation during cortical spreading depression and a particularly low threshold of channel activation might lead to delayed severe cerebral edema and coma after minor head trauma. Familial hemiplegic migraine (FHM)1 is a rare autosomal dominant subtype of migraine with aura. Apart from the characteristic transient hemiparesis, typical attacks of FHM are similar to those of the common migraine with aura (1). Some FHM patients also show atypical attacks, either with a prolonged aura or with signs of diffuse encephalopathy; moreover, 20% of FHM families show permanent cerebellar symptoms (2). In about half of the families, FHM is caused by missense mutations in the CACNA1A gene, encoding the pore-forming ␣ 1 subunit of voltage-gated neuronal Ca V 2.1 (P/Q-type) Ca 2ϩ channels (FHM-1) (3). Ca V 2.1 channels are located at presynaptic terminals and somatodendritic membranes (4) and are expressed in all brain structures that have been implicated in the pathogenesis of migraine (5). They play a prominent role in controlling neurotransmitter release (6) and also exert postsynaptic effects, such as on neuronal excitability (7).17 different missense mutations have been associated with FHM-1 (8 -10). The functional consequences of 10 mutations have been investigated by expressing Ca V 2.1 channel subunits in heterologous systems (11-15). Because Ca V 2.1 channel expression is almost exclusively restricted to neuronal cells, 4 of these mutations have also been analyzed in neurons from Ca V 2.1 ␣ 1 Ϫ/Ϫ mice expressing hu...

show abstract

“…Заболевание обычно начинается в детском возрасте [7]. У наших пациентов первые атаки мигрени были зарегистрирова-ны в возрасте 2 (маленькая пациентка), 3 (девочка-под-росток) и 7 лет (мальчик).…”

Section: Introductionunclassified