Familial Hemiplegic Migraine 2 (FHM2) via the ATP1A2 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4631 ATP1A2$640.00 81406 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ATP1A2$990.00 81479 Add to Order
Pricing Comment

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Over 100

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Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

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).


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).

Testing Strategy

For this NextGen test, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by 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. 


Official Gene Symbol OMIM ID
ATP1A2 182340
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Familial Hemiplegic Migraine Type 2 602481


Genetic Counselors
  • 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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NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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