Familial hemiplegic migraine

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Familial hemiplegic migraine
ICD-10 G43.1
ICD-9 346.8
OMIM 141500 602481 609634 607516
DiseasesDB 4693
eMedicine neuro/219 

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Overview

Familial hemiplegic migraine (FHM) is an autosomal dominant classical migraine subtype that typically includes hemiparesis (weakness of half the body) during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures. There is clinical overlap in some FHM patients with episodic ataxia type 2 and spinocerebellar ataxia type 6, benign familial infantile convulsions, and alternating hemiplegia of childhood. There are 3 known 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 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 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 mutations. 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, cerebellar degeneration. This cerebellar degeneration can result in episodic or progressive ataxia. FHM can also present with the same signs as benign familial infantile convulsions (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 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 channels expressed in neurons. 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 astrocytes. 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 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 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 scans, 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 loci are known).

Pathophysiology

FHM1 (CACNA1A)

The first discovered FHM locus was the CACNA1A gene (originally named CACNL1A4), which encodes the P/Q-type calcium channel CaV2.1. There are currently 17 known mutations 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 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.[1] The first investigation of this mutation, using the rabbit isoform of the channel expressed in oocytes, found that it did not alter any measured channel properties.[2] 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.[3] 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 receptors (GPCRs).[4] GPCR activation leads to inhibition of wild-type CaV2.1 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 knock-in mouse.[5] 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.[6] In CaV2.1 knockout neurons 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 currents through P/Q-type channels. Further testing with this and other mutants is required to determine their end affect on human physiology.

Table 1. Summary of mutations in CACNA1A found in patients diagnosed with FHM type 1
Mutation Position Effect Cerebellar signs Reference
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 ? [1],[2],[3],[4],[5],[6]
c.G584A R195K D1S4 No [7]
c.C653T S218L D1S4-5 Increases sojourns to subconductances, activates at more negative potentials, decreased slow inactivation, increased fast inactivation Yes [8],[9]
c.G1748A R583Q* D2S4 Activates at more negative potentials, faster current decay, faster inactivation, slower recovery from inactivation Yes [7],[10],[11],[12],[13]
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 [1],[2],[3],[6],[7],[12],[14],[15],[16]
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 [1],[2],[3],[6],[12]
c.C2145G D715E D2S6 Activates at more negative potentials, faster current decay, faster inactivation Yes [7],[10],[14]
c.A4003G K1335E D3S3-4 Activates at more negative potentials, inactivates at more negative potentials, slowed recovery from inactivation, increased frequency dependent rundown No [7],[17]
c.G4037A R1346Q D3S4 Yes [18]
c.A4151G Y1384C D3S5 Yes [7],[19]
c.G4366T V1456L D3-pore Activates at more negative potentials, slower current decay, slower recovery from inactivation No [11],[20]
c.C4636T R1546X** D4S1 Decreased current Yes [21],[22],[23]
c.C4999T R1667W D4S4 Yes [7]
c.T5047C W1683R D4S4-5 Activates at more negative potentials, inactivates at more negative potentials, slowed recovery from inactivation, increased frequency dependent rundown Yes [7],[17]
c.G5083A V1695I D4S5 Slowed recovery from inactivation, increased frequency dependent rundown No [7],[17]
c.T5126C I1709T D4S5 Yes [24],[25]
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 [1],[2],[3],[6],[12]
*
**
 Also diagnosed as spinocerebellar ataxia type-6
Also diagnosed as episodic ataxia type-2
Sequence numbering according to NCBI reference sequence NM_000068.2. Cerebellar signs refers to findings of cerebellar degeneration or ataxia upon clinical examination.

FHM2 (ATP1A2)

The crystal structure of the Na+/K+-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 here.

The second subtype of familial hemiplegic migraine, FHM2, is caused by mutations in the gene ATP1A2 that encodes a Na+/K+-ATPase. This Na+/K+-ATPase is heavily expressed in astrocytes 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 pumps will have much higher resting potentials and are believed to lead to disease through a poorly understood mechanism.

Table 2. Summary of mutations in ATP1A2 found in patients diagnosed with FHM type 2
Mutation Location Physiological result Reference(s)
E174K M2-3 No change [26]
T263M M2-3 [27]
G301R M3 [28]
T345A M4-5 Decreased K influx [29],[30]
T376M M4-5 [27]
R383H M4-5 [31]
T387N M4-5 [32]
C515Y M4-5 Loss of function (haploinsufficiency) [26]
R548H M4-5 [33]
R593W M4-5 Loss of function (haploinsufficiency) [34]
A606T M4-5 [27]
G615R M4-5 Loss of function (haploinsufficiency) [35]
V628M M4-5 Loss of function (haploinsufficiency) [34]
R689Q M4-5 Decreased catalytic turnover [30],[36],[37]
E700K M4-5 [38]
D718N M4-5 Loss of function (haploinsufficiency) [31]
M731T M4-5 Decreased catalytic turnover [30],[36],[37]
R763H M4-5 Loss of function (haploinsufficiency) [31]
L764P M4-5 Loss of function (haploinsufficiency) [30],[39],[40]
P796R M5-6 [31]
M829R M6-7 [27]
R834Q M6-7 [27]
W887R M7-8 Loss of function (haploinsufficiency) [26],[30],[39],[40]
E902K M7-8 [31]
935K_940SdelinsI M8-9 [27]
R937P M8-9 [27]
S966LfsX998 M9 [27]
P979L M9-10 [31]
X1021RextX28 C-Terminus [31]
Numbering according to the NCBI reference sequence NM_000702.2.

FHM3 (SCN1A)

The final known 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.[41] As this channel is important for action potential generation in neurons, 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.[42]

Treatment/Management

See the equivalent section in the 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.[43] Women are three times more likely to be affected than males.

See also

Also caused by calcium channel mutations:

External links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 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 (1996). "Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4". Cell. 87 (3): 543–52. PMID 8898206.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Kraus R, Sinnegger M, Glossmann H, Hering S, Striessnig J (1998). "Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics". J Biol Chem. 273 (10): 5586–90. PMID 9488686.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Hans M, Luvisetto S, Williams M, Spagnolo M, Urrutia A, Tottene A, Brust P, Johnson E, Harpold M, Stauderman K, Pietrobon D (1999). "Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine". J Neurosci. 19 (5): 1610–9. PMID 10024348.
  4. ↑ 4.0 4.1 Melliti K, Grabner M, Seabrook G (2003). "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". J Physiol. 546 (Pt 2): 337–47. PMID 12527722.
  5. ↑ 5.0 5.1 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 (2004). "A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression". Neuron. 41 (5): 701–10. PMID 15003170.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Cao Y, Tsien R (2005). "Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission". Proc Natl Acad Sci U S A. 102 (7): 2590–5. PMID 15699344.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser M, Tournier-Lasserve E (2001). "The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel". N Engl J Med. 345 (1): 17–24. PMID 11439943.
  8. ↑ Kors E, Terwindt G, Vermeulen F, Fitzsimons R, Jardine P, Heywood P, Love S, van den Maagdenberg A, Haan J, Frants R, Ferrari M (2001). "Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine". Ann Neurol. 49 (6): 753–60. PMID 11409427.
  9. ↑ Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg A, Pietrobon D (2005). "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". J Biol Chem. 280 (18): 17678–86. PMID 15743764.
  10. ↑ 10.0 10.1 Battistini S, Stenirri S, Piatti M, Gelfi C, Righetti P, Rocchi R, Giannini F, Battistini N, Guazzi G, Ferrari M, Carrera P (1999). "A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia". Neurology. 53 (1): 38–43. PMID 10408534.
  11. ↑ 11.0 11.1 Kraus R, Sinnegger M, Koschak A, Glossmann H, Stenirri S, Carrera P, Striessnig J (2000). "Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics". J Biol Chem. 275 (13): 9239–43. PMID 10734061.
  12. ↑ 12.0 12.1 12.2 12.3 Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D (2002). "Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons". Proc Natl Acad Sci U S A. 99 (20): 13284–9. PMID 12235360.
  13. ↑ Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P (2003). "Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family". Arch Neurol. 60 (4): 610–4. PMID 12707077.
  14. ↑ 14.0 14.1 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 (1999). "Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia". Am J Hum Genet. 64 (1): 89–98. PMID 9915947.
  15. ↑ Friend K, Crimmins D, Phan T, Sue C, Colley A, Fung V, Morris J, Sutherland G, Richards R (1999). "Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM". Hum Genet. 105 (3): 261–5. PMID 10987655.
  16. ↑ Barrett C, Cao Y, Tsien R (2005). "Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel". J Biol Chem. 280 (25): 24064–71. PMID 15795222.
  17. ↑ 17.0 17.1 17.2 Müllner C, Broos L, van den Maagdenberg A, Striessnig J (2004). "Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects". J Biol Chem. 279 (50): 51844–50. PMID 15448138.
  18. ↑ Alonso I, Barros J, Tuna A, Seixas A, Coutinho P, Sequeiros J, Silveira I (2004). "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". Clin Genet. 65 (1): 70–2. PMID 15032980.
  19. ↑ Vahedi K, Denier C, Ducros A, Bousson V, Levy C, Chabriat H, Haguenau M, Tournier-Lasserve E, Bousser M (2000). "CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy". Neurology. 55 (7): 1040–2. PMID 11061267.
  20. ↑ Carrera P, Piatti M, Stenirri S, Grimaldi L, Marchioni E, Curcio M, Righetti P, Ferrari M, Gelfi C (1999). "Genetic heterogeneity in Italian families with familial hemiplegic migraine". Neurology. 53 (1): 26–33. PMID 10408532.
  21. ↑ 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 (1999). "High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2". Neurology. 52 (9): 1816–21. PMID 10371528.
  22. ↑ Jen J, Yue Q, Nelson S, Yu H, Litt M, Nutt J, Baloh R (1999). "A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia". Neurology. 53 (1): 34–7. PMID 10408533.
  23. ↑ Jen J, Wan J, Graves M, Yu H, Mock A, Coulin C, Kim G, Yue Q, Papazian D, Baloh R (2001). "Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission". Neurology. 57 (10): 1843–8. PMID 11723274.
  24. ↑ Beauvais K, Cavé-Riant F, De Barace C, Tardieu M, Tournier-Lasserve E, Furby A (2004). "New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus". Eur Neurol. 52 (1): 58–61. PMID 15240985.
  25. ↑ 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 (2004). "Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2". Neuropediatrics. 35 (5): 293–6. PMID 15534763.
  26. ↑ 26.0 26.1 26.2 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 (2005). "Rare missense variants in ATP1A2 in families with clustering of common forms of migraine". Hum Mutat. 26 (4): 315–21. PMID 16110494.
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 Riant F, De Fusco M, Aridon P, Ducros A, Ploton C, Marchelli F, Maciazek J, Bousser M, Casari G, Tournier-Lasserve E (2005). "ATP1A2 mutations in 11 families with familial hemiplegic migraine". Hum Mutat. 26 (3): 281. PMID 16088919.
  28. ↑ Spadaro M, Ursu S, Lehmann-Horn F, Veneziano L, Liana V, Antonini G, Giovanni A, Giunti P, Paola G, Frontali M, Jurkat-Rott K (2004). "A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs". Neurogenetics. 5 (3): 177–85. PMID 15459825.
  29. ↑ 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 (2004). "A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2". Neurogenetics. 5 (2): 141–6. PMID 15133718.
  30. ↑ 30.0 30.1 30.2 30.3 30.4 Segall L, Scanzano R, Kaunisto M, Wessman M, Palotie A, Gargus J, Blostein R (2004). "Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2". J Biol Chem. 279 (42): 43692–6. PMID 15308625.
  31. ↑ 31.0 31.1 31.2 31.3 31.4 31.5 31.6 Jurkat-Rott K, Freilinger T, Dreier J, Herzog J, Göbel H, Petzold G, Montagna P, Gasser T, Lehmann-Horn F, Dichgans M (2004). "Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants". Neurology. 62 (10): 1857–61. PMID 15159495.
  32. ↑ Swoboda K, Kanavakis E, Xaidara A, Johnson J, Leppert M, Schlesinger-Massart M, Ptacek L, Silver K, Youroukos S (2004). "Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation". Ann Neurol. 55 (6): 884–7. PMID 15174025.
  33. ↑ 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 (2005). "Familial basilar migraine associated with a new mutation in the ATP1A2 gene". Neurology. 65 (11): 1826–8. PMID 16344534.
  34. ↑ 34.0 34.1 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 (2006). "Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine". Eur J Hum Genet. 14 (5): 555–60. PMID 16538223.
  35. ↑ 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 (2006). "Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation". Ann Neurol. 59 (2): 310–4. PMID 16437583.
  36. ↑ 36.0 36.1 Vanmolkot K, Kors E, Hottenga J, Terwindt G, Haan J, Hoefnagels W, Black D, Sandkuijl L, Frants R, Ferrari M, van den Maagdenberg A (2003). "Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions". Ann Neurol. 54 (3): 360–6. PMID 12953268.
  37. ↑ 37.0 37.1 Segall L, Mezzetti A, Scanzano R, Gargus J, Purisima E, Blostein R (2005). "Alterations in the alpha2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2". Proc Natl Acad Sci U S A. 102 (31): 11106–11. PMID 16037212.
  38. ↑ Pierelli F, Grieco G, Pauri F, Pirro C, Fiermonte G, Ambrosini A, Costa A, Buzzi M, Valoppi M, Caltagirone C, Nappi G, Santorelli F (2006). "A novel ATP1A2 mutation in a family with FHM type II". Cephalalgia. 26 (3): 324–8. PMID 16472340.
  39. ↑ 39.0 39.1 De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G (2003). "Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2". Nat Genet. 33 (2): 192–6. PMID 12539047.
  40. ↑ 40.0 40.1 Koenderink J, Zifarelli G, Qiu L, Schwarz W, De Pont J, Bamberg E, Friedrich T (2005). "Na,K-ATPase mutations in familial hemiplegic migraine lead to functional inactivation". Biochim Biophys Acta. 1669 (1): 61–8. PMID 15843000.
  41. ↑ 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 (2005). "Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine". Lancet. 366 (9483): 371–7. PMID 16054936.
  42. ↑ Gardner K, Barmada M, Ptacek L, Hoffman E (1997). "A new locus for hemiplegic migraine maps to chromosome 1q31". Neurology. 49 (5): 1231–8. PMID 9371899.
  43. ↑ Lykke Thomsen L, Kirchmann Eriksen M, Faerch Romer S, Andersen I, Ostergaard E, Keiding N, Olesen J, Russell M (2002). "An epidemiological survey of hemiplegic migraine". Cephalalgia. 22 (5): 361–75. PMID 12110112.

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