Florence Riant1, Caroline Roos2, Agathe Roubertie2, Cécile Barbance2, Jessica Hadjadj2, Stéphane Auvin2, Guillaume Baille2, Marion Beltramone2, Cécile Boulanger2, Alice Cahn2, Florina Cata2, Emmanuel Cheuret2, Jean-Christophe Cuvellier2, Antoine Defo2, Genevieve Demarquay2, Anne Donnet2, Nicolas Gaillard2, Evelyne Massardier2, Nathalie Guy2, Sylvie Lamoureux2, Laurence Le Moigno2, Christian Lucas2, Diana Ratiu2, Sylvain Redon2, Caroline Rey2, Christel Thauvin2, François Viallet2, Elisabeth Tournier-Lasserve2, Anne Ducros2. 1. From the Service de Génétique Moléculaire (F.R., C. Barbance, J.H., E.T.-L.), Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris; INSERM UMR-S1141 (F.R., E.T.-L.), Université Paris; Emergency Headache Centre (C. Roos), Lariboisière Hospital, Paris; INM (A.R.), Univ Montpellier, INSERM, CHU Montpellier, Département de Neuropédiatrie; Service de Neurologie Pédiatrique (S.A.), Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris; Service de Neurologie et Pathologie du Mouvement (G.B.), CHRU de Lille; Pain Department (M.B., A. Donnet, S.R.), FHU INNOVPAIN, Hôpital La Timone, Marseille; Equipe Douleur et Soins Palliatifs Pédiatriques (C. Boulanger), Hôpital des Enfants, CHU Toulouse; Service de Neuropédiatrie (A.C.), Centre Hospitalier d'Arras; Service de Pédiatrie-Néonatologie du CH Remiremont (F.C.); Service de Neurologie Pédiatrique (E.C.), Hôpital des Enfants, CHU de Toulouse; Service de Neuropédiatrie (J.-C.C.), Hôpital Roger-Salengro, CHRU de Lille; Service de Neuropédiatrie (A. Defo), CH de Cayenne, Guyane; Department of Neurology (G.D.), Hospices Civils de Lyon; Lyon Neuroscience Research Center (CRNL) (G.D.), Brain Dynamics and Cognition Team (Dycog), INSERM U1028, CNRS UMR5292; Neurology Department (N. Gaillard, A. Ducros), Montpellier University Hospital; Department of Neurology (E.M.), Rouen University Hospital; Service de Neurologie (N. Guy), CHU Clermont-Ferrand; Service de Pédiatrie (S.L.), Centre Hospitalier d'Avignon; Service de Pédiatrie et Unité d'Urgence Pédiatrique (L.L.M.), Centre Hospitalier de Cornouaille, Quimper; Centre d'Evaluation et de Traitement de la Douleur dans le service de Neurochirurgie (C.L.), CHU de Lille; Service de Neurologie Centre Hospitalier de Narbonne (C.R.); Service de Neurologie Vasculaire (C. Rey), CHU Timone, Marseille; Centre de Génétique et Centre de Référence des Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est (C.T.), Centre Hospitalier Universitaire Dijon; Département de Neurologie (F.V.), Centre Hospitalier Intercommunal d'Aix-Pertuis, Aix-en-Provence; and Charles Coulomb Laboratory (A. Ducros), UMR 5221 CNRS-UM, Montpellier University, France florence.riant@aphp.fr. 2. From the Service de Génétique Moléculaire (F.R., C. Barbance, J.H., E.T.-L.), Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris; INSERM UMR-S1141 (F.R., E.T.-L.), Université Paris; Emergency Headache Centre (C. Roos), Lariboisière Hospital, Paris; INM (A.R.), Univ Montpellier, INSERM, CHU Montpellier, Département de Neuropédiatrie; Service de Neurologie Pédiatrique (S.A.), Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris; Service de Neurologie et Pathologie du Mouvement (G.B.), CHRU de Lille; Pain Department (M.B., A. Donnet, S.R.), FHU INNOVPAIN, Hôpital La Timone, Marseille; Equipe Douleur et Soins Palliatifs Pédiatriques (C. Boulanger), Hôpital des Enfants, CHU Toulouse; Service de Neuropédiatrie (A.C.), Centre Hospitalier d'Arras; Service de Pédiatrie-Néonatologie du CH Remiremont (F.C.); Service de Neurologie Pédiatrique (E.C.), Hôpital des Enfants, CHU de Toulouse; Service de Neuropédiatrie (J.-C.C.), Hôpital Roger-Salengro, CHRU de Lille; Service de Neuropédiatrie (A. Defo), CH de Cayenne, Guyane; Department of Neurology (G.D.), Hospices Civils de Lyon; Lyon Neuroscience Research Center (CRNL) (G.D.), Brain Dynamics and Cognition Team (Dycog), INSERM U1028, CNRS UMR5292; Neurology Department (N. Gaillard, A. Ducros), Montpellier University Hospital; Department of Neurology (E.M.), Rouen University Hospital; Service de Neurologie (N. Guy), CHU Clermont-Ferrand; Service de Pédiatrie (S.L.), Centre Hospitalier d'Avignon; Service de Pédiatrie et Unité d'Urgence Pédiatrique (L.L.M.), Centre Hospitalier de Cornouaille, Quimper; Centre d'Evaluation et de Traitement de la Douleur dans le service de Neurochirurgie (C.L.), CHU de Lille; Service de Neurologie Centre Hospitalier de Narbonne (C.R.); Service de Neurologie Vasculaire (C. Rey), CHU Timone, Marseille; Centre de Génétique et Centre de Référence des Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est (C.T.), Centre Hospitalier Universitaire Dijon; Département de Neurologie (F.V.), Centre Hospitalier Intercommunal d'Aix-Pertuis, Aix-en-Provence; and Charles Coulomb Laboratory (A. Ducros), UMR 5221 CNRS-UM, Montpellier University, France.
Abstract
BACKGROUND AND OBJECTIVE: PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands. METHODS: PRRT2 was analyzed in 860 probands with hemiplegic migraine, and PRRT2 variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed. RESULTS: PRRT2 variations were found in 12 of 163 probands who previously tested negative for CACNA1A, ATP1A2, and SCN1A variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%). The PRRT2 variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole PRRT2 gene. Among the 49 patients with variations in PRRT2, 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic. DISCUSSION: PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.
BACKGROUND AND OBJECTIVE: PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands. METHODS: PRRT2 was analyzed in 860 probands with hemiplegic migraine, and PRRT2 variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed. RESULTS: PRRT2 variations were found in 12 of 163 probands who previously tested negative for CACNA1A, ATP1A2, and SCN1A variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%). The PRRT2 variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole PRRT2 gene. Among the 49 patients with variations in PRRT2, 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic. DISCUSSION: PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.
Authors: Neven Maksemous; Claire D Blayney; Heidi G Sutherland; Robert A Smith; Rod A Lea; Kim Ngan Tran; Omar Ibrahim; Jeffrey R McArthur; Larisa M Haupt; M Zameel Cader; Rocio K Finol-Urdaneta; David J Adams; Lyn R Griffiths Journal: Front Mol Neurosci Date: 2022-07-19 Impact factor: 6.261