Hemiplegic Migraine and PRRT2-Related Disorders via the PRRT2 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 | |
|---|---|---|---|---|---|
| 8989 | PRRT2 | 81479 | 81479,81479 | $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
Hemiplegic migraine is a rare neurologic disorder 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 (Headache Classification Committee of the International Headache Society 2013). Hemiplegic migraine also results in sensory loss such as paresthesia or numbness of the limbs or the face, and dysphasia or speech impairment (Sheerin et al. 2013). It also affects motor functions, thus resulting in hemiparesis or weakness of the limbs. Neurologic symptoms associated with a hemiplegic migraine episode may last for several hours or days, significantly longer than the common migraine headache (Dale et al. 2012). The onset of hemiplegic migraine is usually earlier than typical cases of migraine headaches, often beginning in the first or second decade of life.
Hemiplegic migraine with aura is generally the predominant phenotype of individuals harboring pathogenic sequence variants in the PRRT2 gene. However, these patients are also often diagnosed with: paroxysmal kinesigenic choreoathetosis (PKC) also known as paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis (ICCA), benign familial infantile epilepsy (BFIE), episodic ataxia (EA), or paroxysmal torticollis, which are episodic neurologic disorders (Cloarec et al. 2012; Dale et al. 2012; Gardiner et al. 2012; Sheerin et al. 2013; Yang et al. 2013).
Genetics
Hemiplegic migraine is a rare, autosomal dominant neurologic disorder caused by sequence variations in the proline-rich transmembrane protein 2 (PRRT2) gene, which is located on chromosome 16p11.2 and consists of three exons (Weber et al. 2004). The full length of the PRRT2 protein consists of 394 amino acid residues, with a proline-rich region at the N-terminal and two putative transmembrane domains at the C-terminal. The PRRT2 protein plays a major role in synaptic regulation in the cortex and basal ganglia (Heron et al. 2012). Most sequence variants in the PRRT2 gene result in a dysfunctional protein leading to neuronal hyperexcitability (Lee et al. 2012; Ji et al. 2014). Based on the extensive distribution of the PRRT2 protein in the central nervous system, the phenotypic spectrum of PRRTS2 sequence variants consists of various paroxysmal (episodic) conditions such as dyskinesias, infantile seizures, torticollis, migraine, and hemiplegic migraine (Terwindt et al. 1997; de Vries et al. 2012; Marini et al. 2012; Scheffer et al. 2012). Around 70 causative sequence variants have been reported in the PRRT2 gene, consisting mostly of missense/nonsense sequence changes and small deletions, and a few splicing variants and small insertions (Gardiner et al. 2012). Homozygous PRRT2 variants often result in a more severe phenotype that includes mental retardation and episodic ataxia (Labate et al. 2012). Other genes that are involved in hemiplegic migraine of the familial form include CACNA1A, ATP1A2, and SCN1A (Jurkat-Rott et al. 2004). Hemiplegic migraine resulting from causative variants in the PRRT2 gene can be familial or de novo (Marini et al. 2012; Riant et al. 2012).
Clinical Sensitivity - Sequencing with CNV PG-Select
In a study involving 128 patients with hemiplegic migraine, one patient harbored mutations in the PRRT2 gene (Gardiner et al. 2012). In another study involving 101 patients with hemiplegic migraine who tested negative for causative sequence variants in the three major hemiplegic migraine genes (i.e., CACNA1A, ATP1A2, and SCN1A), 4 patients showed pathogenic mutations in the PRRT2 gene (Riant et al. 2012). In an investigation on the phenotypic spectrum of the PRRT2 gene, 18 out of 34 families with paroxysmal kinesigenic dyskinesia/infantile convulsions harbored causative variants in the PRRT2 gene, and 4 of these 18 patients presented hemiplegic migraine as a comorbidity (Cloarec et al. 2012). In another study involving a cohort of 33 families with benign familial infantile seizures (BFIS), 11 probands showed causative sequence variants in the PRRT2 gene (9 were familial and 2 were sporadic; mutation rate: 33%), and 1 of these 11 probands showed the occurrence of hemiplegic migraine (Marini et al. 2012). A family study of PKD showed that three of the four affected family members who harbored causative PRRT2 sequence variants presented with hemiplegic migraine/migraine with aura (Dale et al. 2012).
Testing Strategy
This test provides full coverage of all coding exons of the PRRT2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
The ideal PRRT2 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 hemiplegic migraine is hemiparesis or weakness of a limb (Meneret et al. 2013). This test can be offered to patients whose test results are negative for pathogenic sequence variants in the three major familial hemiplegic migraine genes, namely ATP1A2, CACNA1A, and SCN1A (Marini et al. 2012; Riant et al. 2012).
The ideal PRRT2 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 hemiplegic migraine is hemiparesis or weakness of a limb (Meneret et al. 2013). This test can be offered to patients whose test results are negative for pathogenic sequence variants in the three major familial hemiplegic migraine genes, namely ATP1A2, CACNA1A, and SCN1A (Marini et al. 2012; Riant et al. 2012).
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| PRRT2 | 614386 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Convulsions, Familial Infantile, with Paroxysmal Choreoathetosis | AD | 602066 |
| Episodic Kinesigenic Dyskinesia 1 | AD | 128200 |
| Seizures, Benign Familial Infantile, 2 | AD | 605751 |
Citations
- Cloarec R, Bruneau N, Rudolf G, Massacrier A, Salmi M, Bataillard M, Boulay C, Caraballo R, Fejerman N, Genton P, Hirsch E, Hunter A, Lesca G, Motte J, Roubertie A, Sanlaville D, Wong SW, Fu YH, Rochette J, Ptácek LJ, Szepetowski P. 2012. PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine. Neurology 79(21): 2097-2103. PubMed ID: 23077017
- Dale RC, Gardiner A, Antony J, Houlden H. 2012. Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. Developmental Medicine and Child Neurology 54(10): 958-960. PubMed ID: 22845787
- de Vries B, Callenbach PM, Kamphorst JT, Weller CM, Koelewijn SC, ten Houten R, de Coo IF, Brouwer OF, van den Maagdenberg AM. 2012. PRRT2 mutation causes benign familial infantile convulsions. Neurology 79(21): 2154-2155. PubMed ID: 23077019
- Gardiner A.R. et al. 2012. Neurology 79: 2115-21. PubMed ID: 23077024
- Headache Classification Committee of the International Headache Society (IHS). 2013. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33(9): 629-808. PubMed ID: 23771276
- Heron S.E. et al. 2012. American Journal of Human Genetics 90: 152-60. PubMed ID: 22243967
- Ji Z, Su Q, Hu L, Yang Q, Liu C, Xiong J, Xiong F. 2014. Novel loss-of-function PRRT2 mutation causes paroxysmal kinesigenic dyskinesia in a Han Chinese family. BMC Neurology 14: 146. PubMed ID: 25027704
- 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
- Labate A, Tarantino P, Viri M, Mumoli L, Gagliardi M, Romeo A, Zara F, Annesi G, Gambardella A. 2012. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia 53(12): e196-199. PubMed ID: 23126439
- Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohammed S, Müller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock AM, Szepetowski P, Fu YH, Ptáček LJ. 2012. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Reports 1(1): 2-12. PubMed ID: 22832103
- Marini C, Conti V, Mei D, Battaglia D, Lettori D, Losito E, Bruccini G, Tortorella G, Guerrini R. 2012. PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology 79: 2109-2114. PubMed ID: 23077026
- Méneret A, Gaudebout C, Riant F, Vidailhet M, Depienne C, Roze E. 2013. PRRT2 mutations and paroxysmal disorders. European Journal of Neurology 20(6): 872-878. PubMed ID: 23398397
- Riant F, Roze E, Barbance C, Méneret A, Guyant-Maréchal L, Lucas C, Sabouraud P, Trébuchon A, Depienne C, Tournier-Lasserve E. 2012. PRRT2 mutations cause hemiplegic migraine. Neurology 79(21): 2122-2124. PubMed ID: 23077016
- Scheffer IE, Grinton BE, Heron SE, Kivity S, Afawi Z, Iona X, Goldberg-Stern H, Kinali M, Andrews I, Guerrini R, Marini C, Sadleir LG, Berkovic SF, Dibbens LM. 2012. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 79(21): 2104-2108. PubMed ID: 23077018
- Sheerin UM, Stamelou M, Charlesworth G, Shiner T, Spacey S, Valente EM, Wood NW, Bhatia KP. 2013. Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation. Journal of Neurology 260(2): 656-660. PubMed ID: 23180180
- Terwindt GM, Ophoff RA, Lindhout D, Haan J, Halley DJ, Sandkuijl LA, Brouwer OF, Frants RR, Ferrari MD. 1997. Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome. Epilepsia 38(8): 915-921. PubMed ID: 9579893
- Weber YG, Berger A, Bebek N, Maier S, Karafyllakes S, Meyer N, Fukuyama Y, Halbach A, Hikel C, Kurlemann G, Neubauer B, Osawa M, Püst B, Rating D, Saito K, Stephani U, Tauer U, Lehmann-Horn F, Jurkat-Rott K, Lerche H. 2004. Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families. Epilepsia 45(6): 601-609. PubMed ID: 15144424
- Yang X, Zhang Y, Xu X, Wang S, Yang Z, Wu Y, Liu X, Wu X. 2013. Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis. BMC Neurology 13: 209. PubMed ID: 24370076
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