typical clinical setting precludes the use of animal model or functional validation studies to allow the confirmation of pathogenicity. Nevertheless, both variants predict to be pathogenic (appendix e-1) and compromise the same protein domain that was disrupted in the first patient described with ataxia caused by STUB1 mutations.3 A frequent approach is to wait until another case is published in the literature; when similar genetic findings are observed, the uncertainty is reduced. Our case illustrates this common situation in clinical genomics and points to a possible explanation for the apparent low diagnostic yield of exome sequencing. From the Hospital JM Ramos Mejia (M.C., S.R.-Q., M.A.K.), CONICET, Buenos Aires; Instituto Neurociencias de Buenos Aires (INEBA) (E.M.G.); and Hospital Caleta Olivia (A.A.), Santa Cruz, Argentina.
Nadine Pelzer, MD Boukje de Vries, PhD Jessica T. Kamphorst, BSc Lisanne S. Vijfhuizen, BSc Michel D. Ferrari, MD, PhD Joost Haan, MD, PhD Arn M.J.M. van den Maagdenberg, PhD Gisela M. Terwindt, MD, PhD
288
Study funding: No targeted funding reported. Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received January 13, 2014. Accepted in final form March 12, 2014.
Correspondence to Dr. Kauffman: [email protected] © 2014 American Academy of Neurology 1.
2.
3.
Hersheson J, Haworth A, Houlden H. The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Hum Mutat 2012;33:1324–1332. Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 2013;14:681–691. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164. Shi CH, Schisler JC, Rubel CE, et al. Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet 2013;23: 1013–1024. McDonough H, Patterson C. CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 2003;8:303–308. Kumar P, Pradhan K, Karunya R, Ambasta RK, Querfurth HW. Cross-functional E3 ligases Parkin and C-terminus Hsp70-interacting protein in neurodegenerative disorders. J Neurochem 2012;120:350–370. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502–1511.
Author contributions: Dr. Córdoba: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, statistical analysis, study supervision. Dr. Rodríguez-Quiroga: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, study supervision. Dr. Gatto: study concept or design, accepts responsibility for conduct of research and final approval, acquisition of data. Dr. Alurralde: drafting/revising the manuscript, accepts responsibility for conduct of research and final approval, acquisition of data. Dr. Kauffman: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, study supervision, obtaining funding.
4.
PRRT2 AND HEMIPLEGIC MIGRAINE: A COMPLEX ASSOCIATION
mutation. Because of this experience, we systematically and critically re-evaluated reports from literature suggesting that PRRT2 mutations cause HM. Furthermore, we screened 14 index cases with familial HM, but no mutation in CACNA1A, ATP1A2, or SCN1A, for PRRT2 mutations. We conclude that (1) contrary to our earlier report, a PRRT2 mutation rather than the ATP1A2 mutation is responsible for BFIS in our family; and (2) at present, there is insufficient evidence to support the claim that PRRT2 is the fourth gene for (familial) HM.
Hemiplegic migraine (HM) is a rare migraine subtype characterized by hemiparesis during the attack and is associated with at least 3 genes: CACNA1A, ATP1A2, and SCN1A.1 Recent reports suggested that the proline-rich transmembrane protein PRRT2 gene might be the fourth gene for HM.2 In the vast majority of cases, PRRT2 is associated with paroxysmal kinesigenic dyskinesia, benign familial infantile seizures (BFIS), or infantile convulsion choreoathetosis syndrome. In families with such a “typical PRRT2 phenotype,” HM was reported in a few PRRT2 mutation carriers. Most of these cases also had a “typical PRRT2 phenotype.”2 Vice versa, PRRT2 mutations were found in 5 out of over 200 index cases with HM; 2 of these 5 PRRT2 mutation carriers also had features of “typical PRRT2 phenotypes.”3,4 The discovery of PRRT2 as a BFIS gene prompted us to reinvestigate a family with an ATP1A2 mutation and partially cosegregating HM and BFIS (figure).5 Although we originally attributed both disorders to the ATP1A2 mutation, we now conclude that the ATP1A2 mutation is only responsible for the HM and that the BFIS phenotype is caused by a PRRT2 Neurology 83
July 15, 2014
5.
6.
7.
Methods. The clinical and genetic information (on ATP1A2) of the family with HM and BFIS has been published before.5 For the present study, we updated the clinical information on the 2 youngest generations and sequenced all 4 exons and flanking intronic sequences of PRRT2 in all available DNA samples of this family and in 14 index cases of HM families that were negative for mutations in the CACNA1A, ATP1A2, and SCN1A genes, and which had not reported BFIS. The study was approved by the Medical Ethics Committee of Leiden University Medical Center and all participants provided informed consent.
Figure
Pedigree of the family with familial hemiplegic migraine and benign familial infantile seizures
Pedigree of the family with familial hemiplegic migraine (FHM) (black lower right quarter) and benign familial infantile seizures (BFIS) (black upper right quarter). Occurrence of migraine with aura (black lower left quarter) and migraine without aura (black upper left quarter) is also indicated. The plus sign “1” and minus sign “2,” respectively, indicate the presence or absence of a mutation (upper right for the p.Arg217GlnfsX12 PRRT2 mutation and lower right for the p.Arg689Gln ATP1A2 mutation). II-4, III-11, III-17, and IV-28 are nonpenetrant BFIS cases. Where plus or minus signs are not indicated, individuals were not investigated and DNA samples were not available.
Results. At follow-up, individual IV-32 of our family was diagnosed with HM and individual III-12 reported a history of BFIS. A novel truncating deletion (c.650delG; p.Arg217GlnfsX12) in the PRRT2 gene was detected in all 4 patients with BFIS with available DNA as well as in 4 (II-4, III-11, III-17, IV-28) out of 14 relatives without a reported history of BFIS. The deleted guanine is the first nucleotide after the cytosine stretch that is also mutated in the highly recurrent c.649dupC p.Arg217ProfsX8 mutation.2 Consequently, our mutation is likely pathogenic as it introduces a premature stop at nearly the same location. Nine out of 10 available HM cases carry the reported p.Arg689Gln ATP1A2 mutation. Two relatives (III-12, IV-31) with common migraine subtypes also carry the ATP1A2 mutation and are regarded as reduced penetrant cases. In the 14 additional index cases with HM, no PRRT2 mutation was detected. Discussion. We re-evaluated our previously reported family with HM and BFIS, and found a pathogenic PRRT2 p.Arg217GlnfsX12 mutation in all available relatives with BFIS.5 Although we previously considered cosegregation of mutations in 2 different genes rather unlikely, we now conclude that in this family BFIS is caused by a PRRT2 mutation and HM by the ATP1A2 mutation. The first lesson here is that one must be very careful before attributing two different diseases to one and the same gene mutation even if both disorders are cosegregating in the same family.
We also critically reviewed the reports suggesting that PRRT2 might be the fourth gene for HM and conclude that at present the evidence supporting this claim is limited. First, in subjects who had both a PRRT2 mutation and HM, the presence of a coexisting mutation in one of the 3 known HM genes was not fully excluded.3,4,6,7 As exemplified in our family with HM and BFIS, co-occurring diseases may well be caused by coexisting different mutations in different genes. Second, most PRRT2 mutation carriers with HM were identified in families with a “typical PRRT2 phenotype.” The remaining mutation carriers came from HM cohorts with limited family histories. Altogether, a minority of mutation carriers with HM did not have symptoms of a “typical PRRT2 phenotype.”4,6,7 Furthermore, as the “typical PRRT2 phenotypes” can be mild or present at a very young age, these could have been missed in these cases. Thus, if PRRT2 mutations do cause HM, they seem to do this virtually always in combination with symptoms of “typical PRRT2 phenotypes.” Third, the vast majority of subjects with essentially the same truncating PRRT2 mutation do not seem to have HM. Apparently, a PRRT2 mutation alone is not sufficient to cause HM. In those few PRRT2 mutation carriers who display HM, additional gene variants interacting with the PRRT2 mutation may be involved. This would thus imply a complex genetic mechanism rather than the monogenic mechanism seen in “classical” familial HM due to mutations in CACNA1A, ATP1A2, or SCN1A.1 It would be Neurology 83
July 15, 2014
289
interesting to compare the phenotypic characteristics of HM due to such a putative PRRT2-related complex genetic mechanism with those found in “classical” HM due to a channelopathy caused by mutations in one of the 3 known HM genes. Finally, we screened 14 clinically well-characterized index cases from families with “classical” HM that had screened negative for mutations in CACNA1A, ATP1A2, or SCN1A, and failed to find mutations in PRRT2. Although we appreciate that a negative finding in only 14 patients does not exclude a role of PRRT2 in HM, it does not support an important role of this gene either.
Comment: Challenges in defining the clinical spectrum of neurogenetic disorders Diagnostic parsimony and a focus on single genes may encourage overinterpretation of the clinical import of specific genetic variants. With conditions as complex and common as migraine, there are additional confounding factors: clinical and genetic heterogeneity and incomplete penetrance. Pelzer et al.1 re-examined a family with both hemiplegic migraine (FHM) and benign familial infantile seizures (BFIS) previously attributed to a mutation in the FHM2 gene ATP1A2.2 The recent discovery of mutations in the proline-rich transmembrane protein 2 (PRRT2) gene primarily in familial paroxysmal kinesigenic dyskinesia but also in other childhoodonset episodic disorders (including FHM and BFIS) prompted the authors to reexamine this family to uncover a new mutation in PRRT2. The authors now conclude that the previously reported ATP1A2 mutation caused FHM in this family, while the newly discovered PRRT2 mutation caused BFIS. This report highlights the challenges and limitations of defining the clinical spectrum based on findings from one family, especially with respect to single nucleotide variants in single genes. FHM and BFIS cosegregated in only 4 individuals, 3 of whom carried heterozygous mutations in both ATP1A2 and PRRT2. Remarkably, 4 other individuals harbored mutations in both genes, yet only 1 was symptomatic for BFIS without FHM, while the other 3 were symptomatic for FHM without BFIS. The authors looked for PRRT2 mutations in 14 FHM probands and reviewed the literature to suggest that there is insufficient evidence to support PRRT2 as a new or important FHM gene. This seems curious, since not finding mutations in 14 persons would hardly invalidate the findings from other patients with FHM. Furthermore, the authors were involved in establishing SCN1A as the FHM3 gene in a handful of families,3 while SCN1A is a major gene in childhood seizures without hemiplegic migraine. The increasing accessibility and availability of exome and genome data will allow us to correlate the clinical phenotype with genetic variants in not one or two, but multiple loci. We anticipate future reports that rectify past misinterpretation of genetic findings and provide more nuanced insight for the phenotypic expression of genetic variations. 1. 2. 3.
Pelzer N, de Vries B, Kamphorst JT, et al. PRRT2 and hemiplegic migraine: a complex association. Neurology 2014;83:288–290. Vanmolkot KR, Kors EE, Hottenga JJ, et al. Novel mutations in the Na1, K1ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003;54:360–366. Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371–377.
Based on the available data, there is insufficient evidence to support the claim that PRRT2 is the fourth gene for HM. However, PRRT2 may be a genetic cofactor that under certain circumstances contributes to the risk of HM. From Leiden University Medical Center (N.P., B.d.V., J.T.K., L.S.V., M.D.F., J.H., A.M.J.M.v.d.M., G.M.T.); and Rijnland Hospital (J.H.), Leiderdorp, the Netherlands. Author contributions: Dr. Pelzer: acquisition and analysis of clinical/ genetic data, drafting/revising the manuscript. Dr. de Vries: analysis of genetic data, revising the manuscript. J.T. Kamphorst: acquisition and analysis of genetic data. L.S. Vijfhuizen: acquisition and analysis of genetic data. Dr. Ferrari: revising the manuscript, overall study supervision. Dr. Haan: revising the manuscript, clinical study supervision. Dr. van den Maagdenberg: revising the manuscript, genetic study supervision. Dr. Terwindt: revising the manuscript, clinical study supervision. Study funding: Supported by grants of the Netherlands Organization for Scientific Research (NWO) (903-52-291, M.D.F.; VICI 918.56.602, M.D.F.; VIDI 91711319, G.M.T.); the European Community (EC); and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) (M.D.F. and A.M.J.M.v.d.M.). They had no role in the design or conduct of the study. Disclosure: Dr. Pelzer reports support for conference visits from Menarini and Allergan UK. Dr. de Vries, J.T. Kamphorst, and L.S. Vijfhuizen report no disclosures relevant to the manuscript. Dr. Ferrari reports grants and consultancy or industry support from Medtronic, Menarini, and Merck and independent support from NWO, ZonMW, NIH, European Community, and the Dutch Heart Foundation. Dr. Haan and Dr. van den Maagdenberg report no disclosures relevant to the manuscript. Dr. Terwindt reports grants and consultancy/industry support from Merck and Menarini and independent support from NWO. Go to Neurology.org for full disclosures. Received September 7, 2013. Accepted in final form March 17, 2014.
Correspondence to Dr. Terwindt: [email protected] © 2014 American Academy of Neurology 1. 2.
3.
4. 5.
6.
Joanna C. Jen, MD, PhD From UCLA Neurology, Los Angeles, CA. Study funding: No targeted funding reported. Disclosure: J.C. Jen receives funding support from the FDA and serves on the editorial boards of Experimental Brain Research and Frontiers in Neurology.
290
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The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808. Heron SE, Dibbens LM. Role of PRRT2 in common paroxysmal neurological disorders: a gene with remarkable pleiotropy. J Med Genet 2013;50:133–139. Gardiner AR, Bhatia KP, Stamelou M, et al. PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 2012;79: 2115–2121. Riant F, Roze E, Barbance C, et al. PRRT2 mutations cause hemiplegic migraine. Neurology 2012;79:2122–2124. Vanmolkot KR, Kors EE, Hottenga JJ, et al. Novel mutations in the Na1, K1-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003;54: 360–366. Dale RC, Gardiner A, Antony J, Houlden H. Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. Dev Med Child Neurol 2012;54:958–960. Marini C, Conti V, Mei D, et al. PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology 2012;79:2109–2114.
Nadine Pelzer, MD Boukje de Vries, PhD Jessica T. Kamphorst, BSc Lisanne S. Vijfhuizen, BSc Michel D. Ferrari, MD, PhD Joost Haan, MD, PhD Arn M.J.M. van den Maagdenberg, PhD Gisela M. Terwindt, MD, PhD
288
Study funding: No targeted funding reported. Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received January 13, 2014. Accepted in final form March 12, 2014.
Correspondence to Dr. Kauffman: [email protected] © 2014 American Academy of Neurology 1.
2.
3.
Hersheson J, Haworth A, Houlden H. The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Hum Mutat 2012;33:1324–1332. Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 2013;14:681–691. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164. Shi CH, Schisler JC, Rubel CE, et al. Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet 2013;23: 1013–1024. McDonough H, Patterson C. CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 2003;8:303–308. Kumar P, Pradhan K, Karunya R, Ambasta RK, Querfurth HW. Cross-functional E3 ligases Parkin and C-terminus Hsp70-interacting protein in neurodegenerative disorders. J Neurochem 2012;120:350–370. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502–1511.
Author contributions: Dr. Córdoba: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, statistical analysis, study supervision. Dr. Rodríguez-Quiroga: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, study supervision. Dr. Gatto: study concept or design, accepts responsibility for conduct of research and final approval, acquisition of data. Dr. Alurralde: drafting/revising the manuscript, accepts responsibility for conduct of research and final approval, acquisition of data. Dr. Kauffman: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, study supervision, obtaining funding.
4.
PRRT2 AND HEMIPLEGIC MIGRAINE: A COMPLEX ASSOCIATION
mutation. Because of this experience, we systematically and critically re-evaluated reports from literature suggesting that PRRT2 mutations cause HM. Furthermore, we screened 14 index cases with familial HM, but no mutation in CACNA1A, ATP1A2, or SCN1A, for PRRT2 mutations. We conclude that (1) contrary to our earlier report, a PRRT2 mutation rather than the ATP1A2 mutation is responsible for BFIS in our family; and (2) at present, there is insufficient evidence to support the claim that PRRT2 is the fourth gene for (familial) HM.
Hemiplegic migraine (HM) is a rare migraine subtype characterized by hemiparesis during the attack and is associated with at least 3 genes: CACNA1A, ATP1A2, and SCN1A.1 Recent reports suggested that the proline-rich transmembrane protein PRRT2 gene might be the fourth gene for HM.2 In the vast majority of cases, PRRT2 is associated with paroxysmal kinesigenic dyskinesia, benign familial infantile seizures (BFIS), or infantile convulsion choreoathetosis syndrome. In families with such a “typical PRRT2 phenotype,” HM was reported in a few PRRT2 mutation carriers. Most of these cases also had a “typical PRRT2 phenotype.”2 Vice versa, PRRT2 mutations were found in 5 out of over 200 index cases with HM; 2 of these 5 PRRT2 mutation carriers also had features of “typical PRRT2 phenotypes.”3,4 The discovery of PRRT2 as a BFIS gene prompted us to reinvestigate a family with an ATP1A2 mutation and partially cosegregating HM and BFIS (figure).5 Although we originally attributed both disorders to the ATP1A2 mutation, we now conclude that the ATP1A2 mutation is only responsible for the HM and that the BFIS phenotype is caused by a PRRT2 Neurology 83
July 15, 2014
5.
6.
7.
Methods. The clinical and genetic information (on ATP1A2) of the family with HM and BFIS has been published before.5 For the present study, we updated the clinical information on the 2 youngest generations and sequenced all 4 exons and flanking intronic sequences of PRRT2 in all available DNA samples of this family and in 14 index cases of HM families that were negative for mutations in the CACNA1A, ATP1A2, and SCN1A genes, and which had not reported BFIS. The study was approved by the Medical Ethics Committee of Leiden University Medical Center and all participants provided informed consent.
Figure
Pedigree of the family with familial hemiplegic migraine and benign familial infantile seizures
Pedigree of the family with familial hemiplegic migraine (FHM) (black lower right quarter) and benign familial infantile seizures (BFIS) (black upper right quarter). Occurrence of migraine with aura (black lower left quarter) and migraine without aura (black upper left quarter) is also indicated. The plus sign “1” and minus sign “2,” respectively, indicate the presence or absence of a mutation (upper right for the p.Arg217GlnfsX12 PRRT2 mutation and lower right for the p.Arg689Gln ATP1A2 mutation). II-4, III-11, III-17, and IV-28 are nonpenetrant BFIS cases. Where plus or minus signs are not indicated, individuals were not investigated and DNA samples were not available.
Results. At follow-up, individual IV-32 of our family was diagnosed with HM and individual III-12 reported a history of BFIS. A novel truncating deletion (c.650delG; p.Arg217GlnfsX12) in the PRRT2 gene was detected in all 4 patients with BFIS with available DNA as well as in 4 (II-4, III-11, III-17, IV-28) out of 14 relatives without a reported history of BFIS. The deleted guanine is the first nucleotide after the cytosine stretch that is also mutated in the highly recurrent c.649dupC p.Arg217ProfsX8 mutation.2 Consequently, our mutation is likely pathogenic as it introduces a premature stop at nearly the same location. Nine out of 10 available HM cases carry the reported p.Arg689Gln ATP1A2 mutation. Two relatives (III-12, IV-31) with common migraine subtypes also carry the ATP1A2 mutation and are regarded as reduced penetrant cases. In the 14 additional index cases with HM, no PRRT2 mutation was detected. Discussion. We re-evaluated our previously reported family with HM and BFIS, and found a pathogenic PRRT2 p.Arg217GlnfsX12 mutation in all available relatives with BFIS.5 Although we previously considered cosegregation of mutations in 2 different genes rather unlikely, we now conclude that in this family BFIS is caused by a PRRT2 mutation and HM by the ATP1A2 mutation. The first lesson here is that one must be very careful before attributing two different diseases to one and the same gene mutation even if both disorders are cosegregating in the same family.
We also critically reviewed the reports suggesting that PRRT2 might be the fourth gene for HM and conclude that at present the evidence supporting this claim is limited. First, in subjects who had both a PRRT2 mutation and HM, the presence of a coexisting mutation in one of the 3 known HM genes was not fully excluded.3,4,6,7 As exemplified in our family with HM and BFIS, co-occurring diseases may well be caused by coexisting different mutations in different genes. Second, most PRRT2 mutation carriers with HM were identified in families with a “typical PRRT2 phenotype.” The remaining mutation carriers came from HM cohorts with limited family histories. Altogether, a minority of mutation carriers with HM did not have symptoms of a “typical PRRT2 phenotype.”4,6,7 Furthermore, as the “typical PRRT2 phenotypes” can be mild or present at a very young age, these could have been missed in these cases. Thus, if PRRT2 mutations do cause HM, they seem to do this virtually always in combination with symptoms of “typical PRRT2 phenotypes.” Third, the vast majority of subjects with essentially the same truncating PRRT2 mutation do not seem to have HM. Apparently, a PRRT2 mutation alone is not sufficient to cause HM. In those few PRRT2 mutation carriers who display HM, additional gene variants interacting with the PRRT2 mutation may be involved. This would thus imply a complex genetic mechanism rather than the monogenic mechanism seen in “classical” familial HM due to mutations in CACNA1A, ATP1A2, or SCN1A.1 It would be Neurology 83
July 15, 2014
289
interesting to compare the phenotypic characteristics of HM due to such a putative PRRT2-related complex genetic mechanism with those found in “classical” HM due to a channelopathy caused by mutations in one of the 3 known HM genes. Finally, we screened 14 clinically well-characterized index cases from families with “classical” HM that had screened negative for mutations in CACNA1A, ATP1A2, or SCN1A, and failed to find mutations in PRRT2. Although we appreciate that a negative finding in only 14 patients does not exclude a role of PRRT2 in HM, it does not support an important role of this gene either.
Comment: Challenges in defining the clinical spectrum of neurogenetic disorders Diagnostic parsimony and a focus on single genes may encourage overinterpretation of the clinical import of specific genetic variants. With conditions as complex and common as migraine, there are additional confounding factors: clinical and genetic heterogeneity and incomplete penetrance. Pelzer et al.1 re-examined a family with both hemiplegic migraine (FHM) and benign familial infantile seizures (BFIS) previously attributed to a mutation in the FHM2 gene ATP1A2.2 The recent discovery of mutations in the proline-rich transmembrane protein 2 (PRRT2) gene primarily in familial paroxysmal kinesigenic dyskinesia but also in other childhoodonset episodic disorders (including FHM and BFIS) prompted the authors to reexamine this family to uncover a new mutation in PRRT2. The authors now conclude that the previously reported ATP1A2 mutation caused FHM in this family, while the newly discovered PRRT2 mutation caused BFIS. This report highlights the challenges and limitations of defining the clinical spectrum based on findings from one family, especially with respect to single nucleotide variants in single genes. FHM and BFIS cosegregated in only 4 individuals, 3 of whom carried heterozygous mutations in both ATP1A2 and PRRT2. Remarkably, 4 other individuals harbored mutations in both genes, yet only 1 was symptomatic for BFIS without FHM, while the other 3 were symptomatic for FHM without BFIS. The authors looked for PRRT2 mutations in 14 FHM probands and reviewed the literature to suggest that there is insufficient evidence to support PRRT2 as a new or important FHM gene. This seems curious, since not finding mutations in 14 persons would hardly invalidate the findings from other patients with FHM. Furthermore, the authors were involved in establishing SCN1A as the FHM3 gene in a handful of families,3 while SCN1A is a major gene in childhood seizures without hemiplegic migraine. The increasing accessibility and availability of exome and genome data will allow us to correlate the clinical phenotype with genetic variants in not one or two, but multiple loci. We anticipate future reports that rectify past misinterpretation of genetic findings and provide more nuanced insight for the phenotypic expression of genetic variations. 1. 2. 3.
Pelzer N, de Vries B, Kamphorst JT, et al. PRRT2 and hemiplegic migraine: a complex association. Neurology 2014;83:288–290. Vanmolkot KR, Kors EE, Hottenga JJ, et al. Novel mutations in the Na1, K1ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003;54:360–366. Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371–377.
Based on the available data, there is insufficient evidence to support the claim that PRRT2 is the fourth gene for HM. However, PRRT2 may be a genetic cofactor that under certain circumstances contributes to the risk of HM. From Leiden University Medical Center (N.P., B.d.V., J.T.K., L.S.V., M.D.F., J.H., A.M.J.M.v.d.M., G.M.T.); and Rijnland Hospital (J.H.), Leiderdorp, the Netherlands. Author contributions: Dr. Pelzer: acquisition and analysis of clinical/ genetic data, drafting/revising the manuscript. Dr. de Vries: analysis of genetic data, revising the manuscript. J.T. Kamphorst: acquisition and analysis of genetic data. L.S. Vijfhuizen: acquisition and analysis of genetic data. Dr. Ferrari: revising the manuscript, overall study supervision. Dr. Haan: revising the manuscript, clinical study supervision. Dr. van den Maagdenberg: revising the manuscript, genetic study supervision. Dr. Terwindt: revising the manuscript, clinical study supervision. Study funding: Supported by grants of the Netherlands Organization for Scientific Research (NWO) (903-52-291, M.D.F.; VICI 918.56.602, M.D.F.; VIDI 91711319, G.M.T.); the European Community (EC); and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) (M.D.F. and A.M.J.M.v.d.M.). They had no role in the design or conduct of the study. Disclosure: Dr. Pelzer reports support for conference visits from Menarini and Allergan UK. Dr. de Vries, J.T. Kamphorst, and L.S. Vijfhuizen report no disclosures relevant to the manuscript. Dr. Ferrari reports grants and consultancy or industry support from Medtronic, Menarini, and Merck and independent support from NWO, ZonMW, NIH, European Community, and the Dutch Heart Foundation. Dr. Haan and Dr. van den Maagdenberg report no disclosures relevant to the manuscript. Dr. Terwindt reports grants and consultancy/industry support from Merck and Menarini and independent support from NWO. Go to Neurology.org for full disclosures. Received September 7, 2013. Accepted in final form March 17, 2014.
Correspondence to Dr. Terwindt: [email protected] © 2014 American Academy of Neurology 1. 2.
3.
4. 5.
6.
Joanna C. Jen, MD, PhD From UCLA Neurology, Los Angeles, CA. Study funding: No targeted funding reported. Disclosure: J.C. Jen receives funding support from the FDA and serves on the editorial boards of Experimental Brain Research and Frontiers in Neurology.
290
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