Hemiplegic Migraine and PRRT2-Related Disorders via the PRRT2 Gene
- Summary and Pricing
- Clinical Features and Genetics
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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).
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).
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).
Full Sanger gene sequencing of the two coding exons of the PRRT2 gene is performed. The full coding region of each exon plus ~20 bp of flanking non-coding DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
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).
|Official Gene Symbol||OMIM ID|
|Convulsions, Familial Infantile, with Paroxysmal Choreoathetosis||602066|
|Episodic Kinesigenic Dyskinesia 1||128200|
|Seizures, Benign Familial Infantile, 2||605751|
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- 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, PtÃ¡cek 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, GÃ¶bel 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, MÃ¼ller 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, PtÃ¡Äek 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
- MÃ©neret 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, MÃ©neret A, Guyant-MarÃ©chal L, Lucas C, Sabouraud P, TrÃ©buchon 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, PÃ¼st 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
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). As required, DNA is extracted from the patient specimen. PCR is used to amplify the indicated exons plus additional flanking non-coding sequence. After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions. In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.
As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.
Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).
In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.
Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.
In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.
In nearly all 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 for example 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 and cycle sequencing.
Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.
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