Familial hemiplegic migraine
4206029
222883486
2008-07-01T16:04:19Z
131.175.127.80
/* Classification */
{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 4693 |
ICD10 = {{ICD10|G|43|1|g|40}}|
ICD9 = {{ICD9|346.8}} |
ICDO = |
OMIM = 141500 |
OMIM_mult = {{OMIM2|602481}} {{OMIM2|609634}} {{OMIM2|607516}} |
MedlinePlus = |
eMedicineSubj = neuro |
eMedicineTopic = 219 |
}}
'''Familial hemiplegic migraine''' (FHM) is an [[autosomal dominant]] classical [[migraine]] subtype that typically includes [[hemiparesis]] (weakness of half the body) during the [[Aura (symptom)|aura]] phase. It can be accompanied by other symptoms, such as [[ataxia]], [[coma]] and epileptic [[seizure]]s. There is clinical overlap in some FHM patients with [[episodic ataxia]] type 2 and [[spinocerebellar ataxia]] type 6, benign familial infantile [[convulsion]]s, and [[alternating hemiplegia of childhood]]. There are 3 known [[Locus (genetics)|loci]] for FHM. FHM1, which accounts for approximately 50% of FHM patients, is caused by mutations in a gene coding for the P/Q-type [[calcium channel]] α subunit, CACNA1A. FHM1 is also associated with cerebellar degeneration. FHM2, which accounts for <25% of FHM cases, is caused by mutations in the [[Na+/K+-ATPase|Na<sup>+</sup>/K<sup>+</sup>-ATPase]] gene ATP1A2. FHM3 is a rare subtype of FHM and is caused by mutations in a [[sodium channel]] α-subunit coding gene, SCNA1. These three subtypes do not account for all cases of FHM, suggesting the existence of at least one other locus (FHM4). Many of the non-familial cases of hemiplegic migraine (sporadic hemiplegic migraine) are also caused by mutations at these loci.
==Classification==
FHM can be loosely divided into two categories: with and without cerebellar signs. Cerebellar signs refer to [[ataxia]], sometimes episodic and other times progressive, that can accompany FHM1 mutations and is caused by degeneration of the [[cerebellum]]. These cerebellar signs result in a [[phenotype|phenotypic]] overlap between FHM and both [[episodic ataxia]] and [[spinocerebellar ataxia]]. This is unsurprising as subtypes of these disorders (FHM1, EA2 and SCA6) are allelic, i.e., they result from mutations in the same gene. The other forms of FHM seem to be distinguishable only on the basis of their genetic cause.
There are also non-familial cases of hemiplegic migraine, termed sporadic hemiplegic migraine. These cases seem to have the same causes as the familial cases and represent [[de novo mutation]]s. Sporadic cases are also clinically identical to familial cases with the exception of a lack of family history of attacks.
==Signs and symptoms==
FHM signs overlap significantly with those of [[migraine with aura]]. In short, FHM is typified by migraine with aura associated with [[hemiparesis]] and, in FHM1, [[cerebellum|cerebellar]] degeneration. This cerebellar degeneration can result in episodic or progressive [[ataxia]]. FHM can also present with the same signs as benign familial infantile [[convulsion]]s (BFIC) and [[alternating hemiplegia of childhood]]. Other symptoms are altered consciousness (in fact, some cases seem related to head trauma), gaze-evoked [[nystagmus]] and [[coma]]. Aura symptoms, such as numbness and blurring of vision, typically persist for 30-60 minutes. These signs typically first manifest themselves in the first or second decade of life.
==Causes==
''See the equivalent section in the main [[Migraine#Pathophysiology|migraine article]].''
It is believed that FHM mutations lead to migraine susceptibility by lowering the threshold for cortical-spreading-depression generation. The FHM1 and FHM3 mutations are occur in [[ion channel]]s expressed in [[neuron]]s. These mutations may lead to both the hyper and hypoexcitable neurons that might underlie cortical-spreading-depression. It is even less clear how the mutations seen in FHM2 patients might lead to FHM symptoms as the gene mutated in FHM2 is expressed primarily in [[astrocyte]]s. One proposal states that the depolarization of astrocytes caused by [[haploinsufficiency]] of the ATP1A2 [[Na+/K+-ATPase]] causes increased release of compounds such as [[adenosine]] from astrocytes. These compounds then interact with neighboring neurons, altering their excitability and leading to cortical-spreading-depression and migraine.
==Diagnosis==
Diagnosis of FHM is made according to the following criteria:
*Two attacks of each of the following:
:*[[Aura (symptom)|Aura]] with motor weakness accompanied by either reversible visual symptoms (flickering lights, spots, lines, etc.), reversible sensory symptoms (pins and needles, numbness, etc.) or speech symptoms.
:*At least two occurrences of:
::*One or more [[Aura (symptom)|aura]] symptoms that develop over at least 5 minutes
::*These symptoms lasting more than 5 minutes and less than 24 hours
::*Headache beginning within 60 minutes of aura onset. These headaches can last 4-72 hours, occur on only one side of the head, pulsate, be of moderate to severe intensity, and may be aggravated by common physical activities such as walking. These headaches must also be accompanied by [[nausea]]/vomiting, [[phonophobia]] (avoidance of sound due to hypersensitivity) and/or [[photophobia]] (avoidance of light due to hypersensitivity).
*At least one close (first or second degree) relative with FHM
*No other likely cause
Sporadic forms follow the same diagnostic criteria, with the exception of family history.
In all cases, family and patient history is used for diagnosis. [[EEG]] and brain imaging techniques, such as [[MRI]] and [[CAT scan]]s, are used to rule out epilepsy and to test for cerebellar degeneration, respectively. With the discovery of causative genes, genetic sequencing can also be used to verify diagnosis (though not all genetic [[Locus (genetics)|loci]] are known).
==Pathophysiology==
===FHM1 (CACNA1A)===
The first discovered FHM [[locus (genetics)|locus]] was the CACNA1A gene (originally named CACNL1A4), which encodes the P/Q-type [[calcium channel]] Ca<sub>V</sub>2.1. There are currently 17 known [[mutation]]s in this channel, see Table 1, and these mutations are distributed throughout the channel. Some of these mutations result in patients with notable cerebellar degeneration or other dysfunction. 15 of these mutants have received at least some further analysis at the [[electrophysiology|electrophysiological]] level to attempt to determine how they might lead to the FHM1 phenotype. There is increasing contradiction in the literature as to the end result of these mutations on channel kinetics and neuronal excitability.
A good example of this contradiction can be seen in the literature regarding the R192Q mutation.<ref name="Ophoff_1996">{{cite journal | author = Ophoff R, Terwindt G, Vergouwe M, van Eijk R, Oefner P, Hoffman S, Lamerdin J, Mohrenweiser H, Bulman D, Ferrari M, Haan J, Lindhout D, van Ommen G, Hofker M, Ferrari M, Frants R | title = Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. | journal = Cell | volume = 87 | issue = 3 | pages = 543–52 | year = 1996 | pmid = 8898206 | doi = 10.1016/S0092-8674(00)81373-2}}</ref> The first investigation of this mutation, using the [[rabbit]] [[isoform]] of the channel expressed in [[oocyte]]s, found that it did not alter any measured channel properties.<ref name="Kraus_1998">{{cite journal | author = Kraus R, Sinnegger M, Glossmann H, Hering S, Striessnig J | title = Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics. | journal = J Biol Chem | volume = 273 | issue = 10 | pages = 5586–90 | year = 1998 | pmid = 9488686 | doi = 10.1074/jbc.273.10.5586}}</ref> A subsequent report, using human channels expressed in [[HEK293 Cells]], found a small hyperpolarizing shift in the midpoint for activation, a result common among FHM1 mutants.<ref name="Hans_1999">{{cite journal | author = Hans M, Luvisetto S, Williams M, Spagnolo M, Urrutia A, Tottene A, Brust P, Johnson E, Harpold M, Stauderman K, Pietrobon D | title = Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine. | journal = J Neurosci | volume = 19 | issue = 5 | pages = 1610–9 | year = 1999 | pmid = 10024348}}</ref> This shift results in channels that open at more negative potentials and, thus, have a higher open probability than wild-type channels at most potentials. This report also found that the R192Q mutant produced almost twice as much whole-cell current compared to wild-type channels. This is not due to a change in single channel conductance but to an equivalent increase in channel density. A subsequent group noticed that this mutation is in a region important for modulation by [[G protein-coupled receptor]]s (GPCRs).<ref name="Melliti_2003">{{cite journal | author = Melliti K, Grabner M, Seabrook G | title = The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells. | journal = J Physiol | volume = 546 | issue = Pt 2 | pages = 337–47 | year = 2003 | pmid = 12527722 | doi = 10.1113/jphysiol.2002.026716}}</ref> GPCR activation leads to inhibition of wild-type Ca<sub>V</sub>2.1 currents. R192Q mutant channel currents are also decreased by GPCR activation, but by a smaller amount. A more recent group has confirmed some of these results by creating a R192Q [[Genetically modified organism|knock-in mouse]].<ref name="Maagdenberg_2004">{{cite journal | author = van den Maagdenberg A, Pietrobon D, Pizzorusso T, Kaja S, Broos L, Cesetti T, van de Ven R, Tottene A, van der Kaa J, Plomp J, Frants R, Ferrari M | title = A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. | journal = Neuron | volume = 41 | issue = 5 | pages = 701–10 | year = 2004 | pmid = 15003170 | doi = 10.1016/S0896-6273(04)00085-6}}</ref> They confirmed that the R192Q mutant activates at more negative potentials and that neurons producing these channels have much larger whole-cell current. This resulted in a much larger quantal content (the number of [[neurotransmitter]] packets released per [[action potential]]) and generally enhanced neurotransmitter release in R192Q expressing neurons versus wild-type. Consequently, these mutant mice were more susceptible to cortical-spreading-depression than their wild-type counterparts. The most recent experiments on this mutant, however, have contradicted some of these results.<ref name="Cao_2005">{{cite journal | author = Cao Y, Tsien R | title = Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. | journal = Proc Natl Acad Sci U S A | volume = 102 | issue = 7 | pages = 2590–5 | year = 2005 | pmid = 15699344 | doi = 10.1073/pnas.0409896102}}</ref> In Ca<sub>V</sub>2.1 [[Gene knockout|knockout]] [[neuron]]s transfected with human channels, P/Q-type currents from mutant channels are actually smaller than their wild-type counterpart. They also found a significant decrease in [[calcium]] influx during depolarization, leading to decreased quantal content, in mutant versus wild-type expressing neurons. Neurons expressing mutant channels were also less able to mediate inhibitory input and have smaller [[inhibitory postsynaptic current]]s through P/Q-type channels. Further testing with this and other mutants is required to determine their end affect on human physiology.
{| class="wikitable" style="text-align:center"
|+'''Table 1.''' Summary of mutations in CACNA1A found in patients diagnosed with FHM type 1
|- valign="bottom"
! colspan="2" | Mutation
! rowspan="2" | Position
! rowspan="2" | Effect
! rowspan="2" | Cerebellar signs
! rowspan="2" | Reference
|- valign="bottom"
! [[Nucleotide]]
! [[Amino acid]]
|-
! c.G575A
! R192Q
| D1S4
| Increases G-protein mediated inhibition, activates at more negative potentials, increased expression, faster recovery from inactivation. In mice: greater current, activates at more negative potentials, enhances transmitter release
| ?
| <ref name="Ophoff_1996"/><sup>,</sup><ref name="Kraus_1998"/><sup>,</sup><ref name="Hans_1999"/><sup>,</sup><ref name="Melliti_2003"/><sup>,</sup><ref name="Maagdenberg_2004"/><sup>,</sup><ref name="Cao_2005"/>
|-
! c.G584A
! R195K
| D1S4
|
| No
| <ref name="Ducros_2001">{{cite journal | author = Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser M, Tournier-Lasserve E | title = The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. | journal = N Engl J Med | volume = 345 | issue = 1 | pages = 17–24 | year = 2001 | pmid = 11439943 | doi = 10.1056/NEJM200107053450103}}</ref>
|-
! c.C653T
! S218L
| D1S4-5
| Increases sojourns to subconductances, activates at more negative potentials, decreased slow inactivation, increased fast inactivation
| Yes
| <ref name="Kors_2001">{{cite journal | author = Kors E, Terwindt G, Vermeulen F, Fitzsimons R, Jardine P, Heywood P, Love S, van den Maagdenberg A, Haan J, Frants R, Ferrari M | title = Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. | journal = Ann Neurol | volume = 49 | issue = 6 | pages = 753–60 | year = 2001 | pmid = 11409427 | doi = 10.1002/ana.1031}}</ref><sup>,</sup><ref name="Tottene_2005">{{cite journal | author = Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg A, Pietrobon D | title = 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. | journal = J Biol Chem | volume = 280 | issue = 18 | pages = 17678–86 | year = 2005 | pmid = 15743764 | doi = 10.1074/jbc.M501110200}}</ref>
|-
! c.G1748A
! R583Q[[#Asterisks|*]]
| D2S4
| Activates at more negative potentials, faster current decay, faster inactivation, slower recovery from inactivation
| Yes
| <ref name="Ducros_2001"/><sup>,</sup><ref name="Battistini_1999">{{cite journal | author = Battistini S, Stenirri S, Piatti M, Gelfi C, Righetti P, Rocchi R, Giannini F, Battistini N, Guazzi G, Ferrari M, Carrera P | title = A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. | journal = Neurology | volume = 53 | issue = 1 | pages = 38–43 | year = 1999 | pmid = 10408534}}</ref><sup>,</sup><ref name="Kraus_2000">{{cite journal | author = Kraus R, Sinnegger M, Koschak A, Glossmann H, Stenirri S, Carrera P, Striessnig J | title = Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics. | journal = J Biol Chem | volume = 275 | issue = 13 | pages = 9239–43 | year = 2000 | pmid = 10734061 | doi = 10.1074/jbc.275.13.9239}}</ref><sup>,</sup><ref name="Tottene_2002">{{cite journal | author = Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D | title = Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. | journal = Proc Natl Acad Sci U S A | volume = 99 | issue = 20 | pages = 13284–9 | year = 2002 | pmid = 12235360 | doi = 10.1073/pnas.192242399}}</ref><sup>,</sup><ref name="Alonso_2003">{{cite journal | author = Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P | title = Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. | journal = Arch Neurol | volume = 60 | issue = 4 | pages = 610–4 | year = 2003 | pmid = 12707077 | doi = 10.1001/archneur.60.4.610}}</ref>
|-
! c.C1997T
! T666M
| D2-pore
| Activates at more negative potentials, faster current decay, slowed recovery from inactivation, smaller single channel conductance, higher i*Po, slower recovery from inactivation, Increased G-protein mediated inhibition, decreased gating charge (fewer channels available to open)
| Yes
| <ref name="Ophoff_1996"/><sup>,</sup><ref name="Kraus_1998"/><sup>,</sup><ref name="Hans_1999"/><sup>,</sup><ref name="Cao_2005"/><sup>,</sup><ref name="Ducros_2001"/><sup>,</sup><ref name="Tottene_2002"/><sup>,</sup><ref name="Ducros_1999">{{cite journal | author = Ducros A, Denier C, Joutel A, Vahedi K, Michel A, Darcel F, Madigand M, Guerouaou D, Tison F, Julien J, Hirsch E, Chedru F, Bisgård C, Lucotte G, Després P, Billard C, Barthez M, Ponsot G, Bousser M, Tournier-Lasserve E | title = Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. | journal = Am J Hum Genet | volume = 64 | issue = 1 | pages = 89–98 | year = 1999 | pmid = 9915947 | doi = 10.1086/302192}}</ref><sup>,</sup><ref name="Friend_1999">{{cite journal | author = Friend K, Crimmins D, Phan T, Sue C, Colley A, Fung V, Morris J, Sutherland G, Richards R | title = Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. | journal = Hum Genet | volume = 105 | issue = 3 | pages = 261–5 | year = 1999 | pmid = 10987655 | doi = 10.1007/s004390051099}}</ref><sup>,</sup><ref name="Barrett_2005">{{cite journal | author = Barrett C, Cao Y, Tsien R | title = Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel. | journal = J Biol Chem | volume = 280 | issue = 25 | pages = 24064–71 | year = 2005 | pmid = 15795222 | doi = 10.1074/jbc.M502223200}}</ref>
|-
! c.T2141C
! V714A
| D2S6
| Activates at more negative potentials, faster current decay, faster recovery from inactivation, decreases expression, faster recovery from inactivation, increases G-protein mediated inhibition
| No
| <ref name="Ophoff_1996"/><sup>,</sup><ref name="Kraus_1998"/><sup>,</sup><ref name="Hans_1999"/><sup>,</sup><ref name="Cao_2005"/><sup>,</sup><ref name="Tottene_2002"/>
|-
! c.C2145G
! D715E
| D2S6
| Activates at more negative potentials, faster current decay, faster inactivation
| Yes
| <ref name="Ducros_2001"/><sup>,</sup><ref name="Battistini_1999"/><sup>,</sup><ref name="Ducros_1999"/>
|-
! c.A4003G
! K1335E
| D3S3-4
| Activates at more negative potentials, inactivates at more negative potentials, slowed recovery from inactivation, increased frequency dependent rundown
| No
| <ref name="Ducros_2001"/><sup>,</sup><ref name="Mullner_2004">{{cite journal | author = Müllner C, Broos L, van den Maagdenberg A, Striessnig J | title = Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects. | journal = J Biol Chem | volume = 279 | issue = 50 | pages = 51844–50 | year = 2004 | pmid = 15448138 | doi = 10.1074/jbc.M408756200}}</ref>
|-
! c.G4037A
! R1346Q
| D3S4
|
| Yes
| <ref name="Alonso_2004">{{cite journal | author = Alonso I, Barros J, Tuna A, Seixas A, Coutinho P, Sequeiros J, Silveira I | title = A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q-type calcium-channel alpha-subunit in a family with progressive cerebellar ataxia and hemiplegic migraine. | journal = Clin Genet | volume = 65 | issue = 1 | pages = 70–2 | year = 2004 | pmid = 15032980 | doi = 10.1111/j..2004.00187.x}}</ref>
|-
! c.A4151G
! Y1384C
| D3S5
|
| Yes
| <ref name="Ducros_2001"/><sup>,</sup><ref name="Vahedi_2000">{{cite journal | author = Vahedi K, Denier C, Ducros A, Bousson V, Levy C, Chabriat H, Haguenau M, Tournier-Lasserve E, Bousser M | title = CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. | journal = Neurology | volume = 55 | issue = 7 | pages = 1040–2 | year = 2000 | pmid = 11061267}}</ref>
|-
! c.G4366T
! V1456L
| D3-pore
| Activates at more negative potentials, slower current decay, slower recovery from inactivation
| No
| <ref name="Kraus_2000"/><sup>,</sup><ref name="Carrera_1999">{{cite journal | author = Carrera P, Piatti M, Stenirri S, Grimaldi L, Marchioni E, Curcio M, Righetti P, Ferrari M, Gelfi C | title = Genetic heterogeneity in Italian families with familial hemiplegic migraine. | journal = Neurology | volume = 53 | issue = 1 | pages = 26–33 | year = 1999 | pmid = 10408532}}</ref>
|-
! c.C4636T
! R1546X[[#Asterisks|**]]
| D4S1
| Decreased current
| Yes
| <ref name="Denier_1999">{{cite journal | author = Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, Castelnovo G, Deonna T, Gérard P, Devoize J, Gayou A, Perrouty B, Soisson T, Autret A, Warter J, Vighetto A, Van Bogaert P, Alamowitch S, Roullet E, Tournier-Lasserve E | title = High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. | journal = Neurology | volume = 52 | issue = 9 | pages = 1816–21 | year = 1999 | pmid = 10371528}}</ref><sup>,</sup><ref name="Jen_1999">{{cite journal | author = Jen J, Yue Q, Nelson S, Yu H, Litt M, Nutt J, Baloh R | title = A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. | journal = Neurology | volume = 53 | issue = 1 | pages = 34–7 | year = 1999 | pmid = 10408533}}</ref><sup>,</sup><ref name="Jen_2001">{{cite journal | author = Jen J, Wan J, Graves M, Yu H, Mock A, Coulin C, Kim G, Yue Q, Papazian D, Baloh R | title = Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. | journal = Neurology | volume = 57 | issue = 10 | pages = 1843–8 | year = 2001 | pmid = 11723274}}</ref>
|-
! c.C4999T
! R1667W
| D4S4
|
| Yes
| <ref name="Ducros_2001"/>
|-
! c.T5047C
! W1683R
| D4S4-5
| Activates at more negative potentials, inactivates at more negative potentials, slowed recovery from inactivation, increased frequency dependent rundown
| Yes
| <ref name="Ducros_2001"/><sup>,</sup><ref name="Mullner_2004"/>
|-
! c.G5083A
! V1695I
| D4S5
| Slowed recovery from inactivation, increased frequency dependent rundown
| No
| <ref name="Ducros_2001"/><sup>,</sup><ref name="Mullner_2004"/>
|-
! c.T5126C
! I1709T
| D4S5
|
| Yes
| <ref name="Beauvais_2004">{{cite journal | author = Beauvais K, Cavé-Riant F, De Barace C, Tardieu M, Tournier-Lasserve E, Furby A | title = New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus. | journal = Eur Neurol | volume = 52 | issue = 1 | pages = 58–61 | year = 2004 | pmid = 15240985 | doi = 10.1159/000079546}}</ref><sup>,</sup><ref name="Kors_2004">{{cite journal | author = Kors E, Vanmolkot K, Haan J, Kheradmand Kia S, Stroink H, Laan L, Gill D, Pascual J, van den Maagdenberg A, Frants R, Ferrari M | title = Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2. | journal = Neuropediatrics | volume = 35 | issue = 5 | pages = 293–6 | year = 2004 | pmid = 15534763 | doi = 10.1055/s-2004-821082}}</ref>
|-
! c.A5428C
! I1810L
| D4S6
| Activates at more negative potentials, faster recovery from inactivation, decreased expression, faster recovery from inactivation, Increased G-protein mediated inhibition
| Yes
| <ref name="Ophoff_1996"/><sup>,</sup><ref name="Kraus_1998"/><sup>,</sup><ref name="Hans_1999">{{cite journal | author = Hans M, Luvisetto S, Williams M, Spagnolo M, Urrutia A, Tottene A, Brust P, Johnson E, Harpold M, Stauderman K, Pietrobon D | title = Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine. | journal = J Neurosci | volume = 19 | issue = 5 | pages = 1610–9 | year = 1999 | pmid = 10024348}}</ref><sup>,</sup><ref name="Cao_2005"/><sup>,</sup><ref name="Tottene_2002"/>
|-
| align="right" | <div id="Asterisks">*<br />**</div>
| align="left" colspan="5" | Also diagnosed as [[spinocerebellar ataxia]] type-6<br />Also diagnosed as [[episodic ataxia]] type-2
|-
| align="left" colspan="6" | Sequence numbering according to [[NCBI]] reference sequence [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=13386499 NM_000068.2]. Cerebellar signs refers to findings of cerebellar degeneration or ataxia upon clinical examination.
|}
===FHM2 (ATP1A2)===
[[Image:ATP1A2_structure_with_FHM2_mutations.png|right|thumb|The crystal structure of the [[Na+/K+-ATPase|Na<sup>+</sup>/K<sup>+</sup>-ATPase]] with FHM2 mutations noted in purple. The N-terminus is colored blue and the C-terminus red. The approximate location of the cell membrane is noted. The original pdb file is available [http://www.pdb.org/pdb/explore.do?structureId=1SU4 here].]]
The second subtype of familial hemiplegic migraine, FHM2, is caused by mutations in the gene ATP1A2 that encodes a [[Na+/K+-ATPase|Na<sup>+</sup>/K<sup>+</sup>-ATPase]]. This Na<sup>+</sup>/K<sup>+</sup>-ATPase is heavily expressed in [[astrocyte]]s and helps to set and maintain their reversal potential. There are 29 known mutations in this gene associated with FHM2, Table 2, many clustering in the large intracellular loop between membrane-spanning segments 4 and 5, Figure 1. 12 of these mutations have been studied by expression in model cells. All but one have shown either complete loss of function or more complex decreases in ATPase activity or potassium sensitivity. Astrocytes expressing these mutant [[ion pump]]s will have much higher resting potentials and are believed to lead to disease through a poorly understood mechanism.
{| class="wikitable" style="text-align:center"
|+'''Table 2.''' Summary of mutations in ATP1A2 found in patients diagnosed with FHM type 2
|- valign="bottom"
!Mutation
!Location
!Physiological result
!Reference(s)
|-
! E174K
| M2-3
| No change
| <ref name="Todt_2005">{{cite journal | author = Todt U, Dichgans M, Jurkat-Rott K, Heinze A, Zifarelli G, Koenderink J, Goebel I, Zumbroich V, Stiller A, Ramirez A, Friedrich T, Göbel H, Kubisch C | title = Rare missense variants in ATP1A2 in families with clustering of common forms of migraine. | journal = Hum Mutat | volume = 26 | issue = 4 | pages = 315–21 | year = 2005 | pmid = 16110494 | doi = 10.1002/humu.20229}}</ref>
|-
! T263M
| M2-3
|
| <ref name="Riant_2005">{{cite journal | author = Riant F, De Fusco M, Aridon P, Ducros A, Ploton C, Marchelli F, Maciazek J, Bousser M, Casari G, Tournier-Lasserve E | title = ATP1A2 mutations in 11 families with familial hemiplegic migraine. | journal = Hum Mutat | volume = 26 | issue = 3 | pages = 281 | year = 2005 | pmid = 16088919 | doi = 10.1002/humu.9361}}</ref>
|-
! G301R
| M3
|
| <ref name="Spadaro_2004">{{cite journal | author = Spadaro M, Ursu S, Lehmann-Horn F, Veneziano L, Liana V, Antonini G, Giovanni A, Giunti P, Paola G, Frontali M, Jurkat-Rott K | title = A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. | journal = Neurogenetics | volume = 5 | issue = 3 | pages = 177–85 | year = 2004 | pmid = 15459825 | doi = 10.1007/s10048-004-0183-2}}</ref>
|-
! T345A
| M4-5
| Decreased K influx
| <ref name="Kaunisto_2004">{{cite journal | author = Kaunisto M, Harno H, Vanmolkot K, Gargus J, Sun G, Hämäläinen E, Liukkonen E, Kallela M, van den Maagdenberg A, Frants R, Färkkilä M, Palotie A, Wessman M | title = A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2. | journal = Neurogenetics | volume = 5 | issue = 2 | pages = 141–6 | year = 2004 | pmid = 15133718 | doi = 10.1007/s10048-004-0178-z}}</ref><sup>,</sup><ref name="Segall_2004">{{cite journal | author = Segall L, Scanzano R, Kaunisto M, Wessman M, Palotie A, Gargus J, Blostein R | title = Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2. | journal = J Biol Chem | volume = 279 | issue = 42 | pages = 43692–6 | year = 2004 | pmid = 15308625 | doi = 10.1074/jbc.M407471200}}</ref>
|-
! T376M
| M4-5
|
| <ref name="Riant_2005"/>
|-
! R383H
| M4-5
|
| <ref name="Jurkatt-Rott_2004">{{cite journal | author = Jurkat-Rott K, Freilinger T, Dreier J, Herzog J, Göbel H, Petzold G, Montagna P, Gasser T, Lehmann-Horn F, Dichgans M | title = Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants. | journal = Neurology | volume = 62 | issue = 10 | pages = 1857–61 | year = 2004 | pmid = 15159495}}</ref>
|-
! T387N
| M4-5
|
| <ref name="Swoboda_2004">{{cite journal | author = Swoboda K, Kanavakis E, Xaidara A, Johnson J, Leppert M, Schlesinger-Massart M, Ptacek L, Silver K, Youroukos S | title = Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. | journal = Ann Neurol | volume = 55 | issue = 6 | pages = 884–7 | year = 2004 | pmid = 15174025 | doi = 10.1002/ana.20134}}</ref>
|-
! C515Y
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Todt_2005"/>
|-
! R548H
| M4-5
|
| <ref name="Ambrosini_2005">{{cite journal | author = Ambrosini A, D'Onofrio M, Grieco G, Di Mambro A, Montagna G, Fortini D, Nicoletti F, Nappi G, Sances G, Schoenen J, Buzzi M, Santorelli F, Pierelli F | title = Familial basilar migraine associated with a new mutation in the ATP1A2 gene. | journal = Neurology | volume = 65 | issue = 11 | pages = 1826–8 | year = 2005 | pmid = 16344534 | doi = 10.1212/01.wnl.0000187072.71931.c0}}</ref>
|-
! R593W
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Vanmolkot_2006">{{cite journal | author = Vanmolkot K, Kors E, Turk U, Turkdogan D, Keyser A, Broos L, Kia S, van den Heuvel J, Black D, Haan J, Frants R, Barone V, Ferrari M, Casari G, Koenderink J, van den Maagdenberg A | title = Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine. | journal = Eur J Hum Genet | volume = 14 | issue = 5 | pages = 555–60 | year = 2006 | pmid = 16538223 | doi = 10.1038/sj.ejhg.5201607}}</ref>
|-
! A606T
| M4-5
|
| <ref name="Riant_2005"/>
|-
! G615R
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Vanmolkot_2006b">{{cite journal | author = Vanmolkot K, Stroink H, Koenderink J, Kors E, van den Heuvel J, van den Boogerd E, Stam A, Haan J, De Vries B, Terwindt G, Frants R, Ferrari M, van den Maagdenberg A | title = Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation. | journal = Ann Neurol | volume = 59 | issue = 2 | pages = 310–4 | year = 2006 | pmid = 16437583 | doi = 10.1002/ana.20760}}</ref>
|-
! V628M
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Vanmolkot_2006"/>
|-
! R689Q
| M4-5
| Decreased catalytic turnover
| <ref name="Segall_2004"/><sup>,</sup><ref name="Vanmolkot_2003">{{cite journal | author = Vanmolkot K, Kors E, Hottenga J, Terwindt G, Haan J, Hoefnagels W, Black D, Sandkuijl L, Frants R, Ferrari M, van den Maagdenberg A | title = Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. | journal = Ann Neurol | volume = 54 | issue = 3 | pages = 360–6 | year = 2003 | pmid = 12953268 | doi = 10.1002/ana.10674}}</ref><sup>,</sup><ref name="Segall_2005">{{cite journal | author = Segall L, Mezzetti A, Scanzano R, Gargus J, Purisima E, Blostein R | title = Alterations in the alpha2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2. | journal = Proc Natl Acad Sci U S A | volume = 102 | issue = 31 | pages = 11106–11 | year = 2005 | pmid = 16037212 | doi = 10.1073/pnas.0504323102}}</ref>
|-
! E700K
| M4-5
|
| <ref name="Pierelli_2006">{{cite journal | author = Pierelli F, Grieco G, Pauri F, Pirro C, Fiermonte G, Ambrosini A, Costa A, Buzzi M, Valoppi M, Caltagirone C, Nappi G, Santorelli F | title = A novel ATP1A2 mutation in a family with FHM type II. | journal = Cephalalgia | volume = 26 | issue = 3 | pages = 324–8 | year = 2006 | pmid = 16472340 | doi = 10.1111/j.1468-2982.2006.01002.x}}</ref>
|-
! D718N
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Jurkatt-Rott_2004"/>
|-
! M731T
| M4-5
| Decreased catalytic turnover
| <ref name="Segall_2004"/><sup>,</sup><ref name="Vanmolkot_2003"/><sup>,</sup><ref name="Segall_2005"/>
|-
! R763H
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Jurkatt-Rott_2004"/>
|-
! L764P
| M4-5
| Loss of function (haploinsufficiency)
| <ref name="Segall_2004"/><sup>,</sup><ref name="De_Fusco_2003">{{cite journal | author = De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G | title = Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. | journal = Nat Genet | volume = 33 | issue = 2 | pages = 192–6 | year = 2003 | pmid = 12539047 | doi = 10.1038/ng1081}}</ref><sup>,</sup><ref name="Koenderink_2005">{{cite journal | author = Koenderink J, Zifarelli G, Qiu L, Schwarz W, De Pont J, Bamberg E, Friedrich T | title = Na,K-ATPase mutations in familial hemiplegic migraine lead to functional inactivation. | journal = Biochim Biophys Acta | volume = 1669 | issue = 1 | pages = 61–8 | year = 2005 | pmid = 15843000 | doi = 10.1016/j.bbamem.2005.01.003}}</ref>
|-
! P796R
| M5-6
|
| <ref name="Jurkatt-Rott_2004"/>
|-
! M829R
| M6-7
|
| <ref name="Riant_2005"/>
|-
! R834Q
| M6-7
|
| <ref name="Riant_2005"/>
|-
! W887R
| M7-8
| Loss of function (haploinsufficiency)
| <ref name="Todt_2005"/><sup>,</sup><ref name="Segall_2004"/><sup>,</sup><ref name="De_Fusco_2003"/><sup>,</sup><ref name="Koenderink_2005"/>
|-
! E902K
| M7-8
|
| <ref name="Jurkatt-Rott_2004"/>
|-
! 935K_940SdelinsI
| M8-9
|
| <ref name="Riant_2005"/>
|-
! R937P
| M8-9
|
| <ref name="Riant_2005"/>
|-
! S966LfsX998
| M9
|
| <ref name="Riant_2005"/>
|-
! P979L
| M9-10
|
| <ref name="Jurkatt-Rott_2004"/>
|-
! X1021RextX28
| C-Terminus
|
| <ref name="Jurkatt-Rott_2004"/>
|-
| colspan="4" align="left" | Numbering according to the [[NCBI]] reference sequence [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=48762683 NM_000702.2].
|}
===FHM3 (SCN1A)===
The final known [[Locus (genetics)|locus]] for FHM is the SCN1A gene, which encodes a [[sodium channel]] α subunit. The only study so far that has found mutations in this gene discovered the same Q1489K mutation in 3 of 20 families (15%) with 11 other kindreds (55%) already having mutations in CACNA1A or ATP1A2. This mutation is located in a highly conserved region of an intracellular loop connecting domains three and four. This mutation results in a greatly hastened (2-4 fold) recovery from inactivation compared to wild-type.<ref name="Dichgans_2005">{{cite journal | author = Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari M, Herzog J, van den Maagdenberg A, Pusch M, Strom T | title = Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. | journal = Lancet | volume = 366 | issue = 9483 | pages = 371–7 | year = 2005 | pmid = 16054936 | doi = 10.1016/S0140-6736(05)66786-4}}</ref> As this channel is important for [[action potential]] generation in [[neuron]]s, it is expected that the Q1489K mutant results in hyperexcitable neurons.
===FHM4 (1q31)===
The final known locus for FHM maps to the q-arm of [[chromosome 1]]. There are a number of attractive candidate genes in this area, though no mutations in them have yet been linked to FHM4.<ref name="Gardner_1997">{{cite journal | author = Gardner K, Barmada M, Ptacek L, Hoffman E | title = A new locus for hemiplegic migraine maps to chromosome 1q31. | journal = Neurology | volume = 49 | issue = 5 | pages = 1231–8 | year = 1997 | pmid = 9371899}}</ref>
==Treatment/Management==
''See the equivalent section in the [[Migraine#Treatment|main epilepsy article]].''
Patients with FHM are encouraged to avoid activities that may trigger their attacks. Minor head trauma is a common attack precipitant, so FHM sufferers should avoid contact sports. [[Acetazolamide]] or standard drugs are often used to treat attacks, though those leading to vasoconstriction should be avoided due to the risk of [[stroke]].
==Prevention/Screening==
Prenatal screening is not typically done for FHM, however it may be performed if requested. As [[penetrance]] is high, individuals found to carry mutations should be expected to develop signs of FHM at some point in life.
==Epidemiology==
Migraine itself is a very common disorder, occurring in 15-20% of the population. Hemiplegic migraine, be it familial or spontaneous, is less prevalent, 0.01% prevalence according to one report.<ref name="Lykke_2002">{{cite journal | author = Lykke Thomsen L, Kirchmann Eriksen M, Faerch Romer S, Andersen I, Ostergaard E, Keiding N, Olesen J, Russell M | title = An epidemiological survey of hemiplegic migraine. | journal = Cephalalgia | volume = 22 | issue = 5 | pages = 361–75 | year = 2002 | pmid = 12110112 | doi = 10.1046/j.1468-2982.2002.00371.x}}</ref> Women are three times more likely to be affected than males.
==See also==
*[[Channelopathy]]
*[[Calcium channel]]
*[[Migraine]]
Also caused by calcium channel mutations:
*[[Childhood absence epilepsy]]
*[[Hypokalemic periodic paralysis]]
*[[Juvenile myoclonic epilepsy]]
*[[Malignant hyperthermia]]
*[[Timothy syndrome]]
==External links==
* {{GeneTests|fhm}}
*[http://headaches.about.com/od/migrainediseas1/a/hemiplegic_mig.htm About.com page regarding FHM]]
*[http://www.blackwell-synergy.com/toc/cha/24/s1 International Classification of Headache Disorders]
==References==
{{Reflist|2}}
{{CNS diseases of the nervous system}}
[[Category:Channelopathy]]
[[Category:Neurological disorders]]
[[Category:Genetic disorders]]