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Familial Hemiplegic Migraine 1 (FHM1) via the CACNA1A Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
4293 CACNA1A 81185 81185,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4293CACNA1A81185 81185,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Kym Bliven, PhD

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 1 (FHM1) presents with cerebellar symptoms that range from involuntary eye movements (nystagmus) to late-onset, progressive disambiguation (ataxia) (Ophoff et al. 1996). FHM is diagnosed when the following criteria are observed: occurrence of migraine with aura, 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 FHM2 and FHM3 (Jurkat-Rott et al. 2004; Vahedi et al. 2009).

Support and information for individuals with CACNA1A-related disease and their families is available through the CACNA1A Foundation. This organization can be contacted through their website: http://www.cacna1a.org.

Genetics

FHM1 is a rare autosomal dominant neurologic disorder caused by variations in the CACNA1A gene, which encodes a voltage-dependent P/Q-type calcium channel subunit alpha-1A. The gene is located on chromosomal band 19p13.2, consists of 47 exons, and is approximately 417 kb in length (Ophoff et al. 1996). A total of 160 pathogenic sequence variants have been reported in the CACNA1A gene, which consist of ~100 missense/nonsense, 11 splicing, 11 small insertions, 15 gross deletions, 1 complex rearrangement, and 4 repeat variations (Stenson et al. 2014). Two other disorders have been associated with sequence variations occurring in the CACNA1A gene, namely episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) (Ishikawa et al. 1997; Riant et al. 2010). Phenotype overlap has been reported between FHM1 and SCA6 and EA2; however, significantly greater overlap has been reported between EA2 and SCA6 (Jodice et al. 1997; Alonso et al. 2003).

Clinical Sensitivity - Sequencing with CNV PG-Select

Previous studies have shown that 4% to 94% of FHM cases may be FHM1, depending on the specific population being assessed. For example, in a study conducted in the United States, 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs harbored sequence variants in the CACNA1A gene (94%; Ducros et al. 2001). On the other hand, in a study involving Spanish patients with FHM, 4 out of 18 patients presented causative sequence variants in the CACNA1A gene (22%; Carreno et al. 2013). A Danish investigation showed that only 7% of FHM cases were of the FHM1 type (Thomsen et al. 2007). An Australian-based study reported that 7 out of 168 patients with FHM tested positive for pathogenic CACNA1A sequence variants (4%; Stuart et al. 2012).

Testing Strategy

This test provides full coverage of all coding exons of the CACNA1A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

This test is currently not validated to identify pathogenic variants in the CAG repeat region that lie in the 3’ region of CACNA1A; such mild CAG expansions have been primarily associated with spinocerebellar ataxia 6 (Ishikawa et al. 1997).

Indications for Test

The ideal CACNA1A 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
CACNA1A 601011
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Familial Hemiplegic Migraine Type 1 AD 141500

Citations

  • 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. Archives of Neurology 60: 610–614. PubMed ID: 12707077
  • 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. Molecular Genetics and Genomic Medicine 1(4): 206-222. PubMed ID: 24498617
  • 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
  • Ishikawa K, Tanaka H, Saito M, Ohkoshi N, Fujita T, Yoshizawa K, Ikeuchi T, Watanabe M, Hayashi A, Takiyama Y, Nishizawa M, Nakano I, Matsubayashi K, Miwa M, Shoji S, Kanazawa I, Tsuji S, Mizusawa H. 1997. Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1. Amercan Journal of Human Genetics 61(2): 336-346. PubMed ID: 9311738
  • Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff RA, Frants RR, Frontali M. 1997. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Human Molecular Genetics 6:1973–1978. PubMed ID: 9302278
  • 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
  • Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. 2006. C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Human Molecular Genetics 15(10): 1587-1599. PubMed ID: 16595610
  • Ophoff R.A. et al. 1996. Cell 87: 543-52. PubMed ID: 8898206
  • Riant F, Lescoat C, Vahedi K, Kaphan E, Toutain A, Soisson T, Wiener-Vacher SR, Tournier-Lasserve E. 2010. Identification of CACNA1A large deletions in four patients with episodic ataxia. Neurogenetics 11(1): 101-106. PubMed ID: 19633872
  • 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
  • Stenson P.D. et al. 2014. Human Genetics. 133: 1-9. PubMed ID: 24077912
  • Stuart S. et al. 2012. Twin Research and Human Genetics 15: 120-5. PubMed ID: 22784462
  • 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(Pt 6): 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
  • Vahedi K, Depienne C, Le Fort D, Riant F, Chaine P, Trouillard O, Gaudric A, Morris MA, Leguern E, Tournier-Lasserve E, Bousser MG. 2009. Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology 72(13): 1178-1183. PubMed ID: 19332696

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page


Specimen Types

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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