Familial Hemiplegic Migraine 2 (FHM2) via the ATP1A2 Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 4631 | ATP1A2 | 81406 | 81406,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Familial hemiplegic migraine (FHM) is a rare neurologic condition that belongs to the category of migraine with aura, which is an idiopathic, episodic disorder involving the cerebral cortex or the brain stem. The aura generally develops within 5 to 20 minutes after exposure to typical migraine triggers such as food, odor, stress, exertion and head trauma. The aura could then persist for almost an hour. Headache, nausea, or hypersensitivity to light (photophobia) usually develops after the occurrence of aura symptoms, which could last from 4 to 72 hours; however, some FHM cases are headache-free (Thomsen et al. 2002). FHM also results in sensory loss such as paresthesia or numbness of the limbs or the face, and dysphasia or speech impairment (Terwindt et al. 1998). It also affects motor functions, thus resulting in hemiparesis or weakness of the limbs. Most episodes of FHM with aura occur with at least another symptom such as mental retardation, ataxia (lack of muscle coordination), dysarthia (motor speech disorder), or recurrent coma (Jurkat-Rott et al. 2004; Spadaro et al. 2004; Barros et al. 2012). Neurologic symptoms associated with an FHM episode may last for several hours or days, significantly longer than the common migraine headache (Ducros et al. 2001). The onset of FHM is usually earlier than typical cases of migraine headaches, often beginning in the first or second decade of life. The number of FHM attacks decreases with age.
Familial hemiplegic migraine type 2 (FHM2) frequently develops with epilepsy; however, epileptic episodes are less prevalent in FHM2 than in FHM1 (Deprez et al. 2008). FHM is diagnosed when the following criteria are observed: occurrence of migraine with aura with epilepsy, the developed aura is coupled with prolonged hemiparesis, and the same condition occurs in at least one first-degree relative such as a parent, sibling, or child. Other forms of FHM include FHM1 and FHM3 (Ophoff et al. 1996).
Genetics
FHM2 is a rare autosomal dominant neurologic disorder caused by sequence variations in the ATP1A2 gene, which encodes the alpha-2 isoform of sodium (Na+), potassium (K+)-transporting ATPase, an integral membrane protein that establishes and maintains electrochemical gradients of Na+ and K+ ions across the plasma membrane. This protein pump consists of two subunits, a large catalytic subunit (alpha), which is encoded by several genes, and a smaller glycoprotein subunit (beta) (Shull and Lingrel 1987). The ATP1A2 gene is located on chromosomal band 1q23.2, consists of 23 exons, and is approximately 27.862 kb in length (Shull et al. 1989). 10% to 56% of FHM cases have been linked to mutations in the ATP1A2 gene, depending on the specific population being screened. For example, a population-based investigation conducted in Denmark showed that only 7% to 14% of FHM cases were of the FHM2 type (Thomsen et al. 2002, 2007), whereas another investigation based in Italy showed that 41% of FHM patients who earlier tested negative for sequence variants in another FHM gene, CACNA1A, were of the FHM2 type (Riant et al. 2004). Another study conducted in France showed that 56% of hemiplegic migraine cases harbored variants in the ATP1A2 gene (Riant et al. 2010). A total of 82 causative sequence variants have been reported in the ATP1A2 gene, which include 76 missense/nonsense variants, 1 splicing variant, and 4 small deletions (Jurkat-Rott et al. 2004; Riant et al. 2005; Jen et al. 2007; Vanmolkot et al. 2007).
Clinical Sensitivity - Sequencing with CNV PG-Select
Previous studies have shown that 10% to 56% of FHM cases may be FHM2, depending on the specific population being assessed. For example, in a study involving 18 Spanish patients with hemiplagic migraine, 2 cases were determined to harbor sequence variants in the ATP1A2 gene (11.11%; Carreno et al. 2013). Novel ATP1A2 sequence variants were also detected in 2 out of 20 Belgian families with epilepsy and migraine (10%; Deprez et al. 2008). In another study consisting of 30 unrelated cases of FHM, causative variants in the ATP1A2 were observed in 3 German FHM patients (10%; Jurkat-Rott et al. 2004). In a study involving 26 Italian patients with FHM, 11 (41%) showed causative sequence variants in the ATP1A2 gene (Riant et al. 2004). In another study involving 25 French patients with hemiplegic migraine, 14 harbored pathogenic sequence variants in the ATP1A2 gene (56%; Riant et al. 2010).
Testing Strategy
This test provides full coverage of all coding exons of the ATP1A2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
The ideal ATP1A2 test candidates are individuals who experience hemiplegic migraine with aura involving the cerebral cortex or the brain stem, visual disturbances, paresthesia, and dysphasia. The most significant criterion in diagnosing FHM is hemiparesis or weakness of a limb (Thomsen et al. 2002). Visual disturbances may occur in the form of blind spots (scotoma), flashing lights (photopsia), zigzag patterns (fortification spectra), and double vision (diplopia). Dyphasia usually develops in right-sided hemiplegia.
The ideal ATP1A2 test candidates are individuals who experience hemiplegic migraine with aura involving the cerebral cortex or the brain stem, visual disturbances, paresthesia, and dysphasia. The most significant criterion in diagnosing FHM is hemiparesis or weakness of a limb (Thomsen et al. 2002). Visual disturbances may occur in the form of blind spots (scotoma), flashing lights (photopsia), zigzag patterns (fortification spectra), and double vision (diplopia). Dyphasia usually develops in right-sided hemiplegia.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| ATP1A2 | 182340 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Familial Hemiplegic Migraine Type 2 | AD | 602481 |
Citations
- Barros J, Mendes A, Matos I, Pereira-Monteiro J. 2012. Psychotic aura symptoms in familial hemiplegic migraine type 2 (ATP1A2). Journal of Headache Pain 13(7): 581-585. PubMed ID: 22661290
- Carreño O, Corominas R, Serra SA, Sintas C, Fernández-Castillo N, Vila-Pueyo M, Toma C, Gené GG, Pons R, Llaneza M, Sobrido MJ, Grinberg D, Valverde MÁ, Fernández-Fernández JM, Macaya A, Cormand B. 2013. Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies. Molecular Genetics and Genomic Medicine 1(4): 206-222. PubMed ID: 24498617
- Deprez L, Weckhuysen S, Peeters K, Deconinck T, Claeys KG, Claes LR, Suls A, Van Dyck T, Palmini A, Matthijs G, Van Paesschen W, De Jonghe P. 2008. Epilepsy as part of the phenotype associated with ATP1A2 mutations. Epilepsia 49(3): 500-508. PubMed ID: 18028407
- Deprez L. et al. 2008. Epilepsia. 49(3): 500-8.
- Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser MG, Tournier-Lasserve E. 2001. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. New England Journal of Medicine 345: 17–24. PubMed ID: 11439943
- Jen JC, Klein A, Boltshauser E, Cartwright MS, Roach ES, Mamsa H, Baloh RW. 2007. Prolonged hemiplegic episodes in children due to mutations in ATP1A2. Journal of Neurology, Neurosurgery, and Psychiatry 78(5): 523-526. PubMed ID: 17435187
- Jurkat-Rott K, Freilinger T, Dreier JP, Herzog J, Göbel H, Petzold GC, 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): 1857-1861. PubMed ID: 15159495
- Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR. 1996. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87: 543–552. PubMed ID: 8898206
- Riant F, De Fusco M, Aridon P, Ducros A, Ploton C, Marchelli F, Maciazek J, Bousser MG, Casari G, Tournier-Lasserve E. 2005. ATP1A2 mutations in 11 families with familial hemiplegic migraine. Human Mutation 26: 281. PubMed ID: 16088919
- Riant F, Ducros A, Ploton C, Barbance C, Depienne C, Tournier-Lasserve E. 2010. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology 75(11): 967-972. PubMed ID: 20837964
- Shull M.M. et al. 1989. Journal of Biological Chemistry 264(29): 17532-43. PubMed ID: 2477373
- Shull MM, Lingrel JB. 1987. Multiple genes encode the human Na+,K+-ATPase catalytic subunit. Proceedings of the National Academy of Sciences U S A 84(12): 4039-4043. PubMed ID: 3035563
- Spadaro M, Ursu S, Lehmann-Horn F, Veneziano L, Antonini G, Giunti P, Frontali M, Jurkat-Rott K. 2004. A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. Neurogenetics 5(3): 177-185. PubMed ID: 15459825
- Terwindt G, Kors E, Haan J, Vermeulen F, Van Den Maagdenberg A, Frants R, Ferrari M. 2003. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Headache 43:303. PubMed ID: 12056940
- Thomsen LL, Eriksen MK, Roemer SF, Andersen I, Olesen J, Russell MB. 2002. A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain 125: 1379–1391. PubMed ID: 12023326
- Thomsen LL, Kirchmann M, Bjornsson A, Stefansson H, Jensen RM, Fasquel AC, Petursson H, Stefansson M, Frigge ML, Kong A, Gulcher J, Stefansson K, Olesen J. 2007. The genetic spectrum of a population-based sample of familial hemiplegic migraine. Brain 130(Pt 2): 346-356. PubMed ID: 17142831
- Vanmolkot KR, Stam AH, Raman A, Koenderink JB, de Vries B, van den Boogerd EH, van Vark J, van den Heuvel JJ, Bajaj N, Terwindt GM, Haan J, Frants RR, Ferrari MD, van den Maagdenberg AM. 2007. First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine. European Journal of Human Genetics 15(8): 884-888. PubMed ID: 17473835
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