Hemiplegic Migraine Associated With PRRT2 Variations
A Clinical and Genetic Study
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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.
Glossary
- BFIE=
- benign familial infantile epilepsy;
- FHM=
- familial hemiplegic migraine;
- HM=
- hemiplegic migraine;
- ICCA=
- infantile convulsions with choreoathetosis;
- PKD=
- paroxysmal kinesigenic dyskinesia;
- QMPSF=
- quantitative multiplex PCR of short fluorescent fragments
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
CME Course: NPub.org/cmelist
- Received April 29, 2021.
- Accepted in final form October 4, 2021.
- © 2021 American Academy of Neurology
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Letters: Rapid online correspondence
- Reader Response: Hemiplegic Migraine Associated With PRRT2 Mutations: A Clinical and Genetic Study
- Nadine Pelzer, Neurologist in training, Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
- Irene De Boer, PhD candidate, Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
- Arn M.J.M. Van den Maagdenberg, Professor of Molecular and Functional Neurogenetics, Department of Human Genetics & Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
- Gisela M. Terwindt, Professor of Neurology and neurologist, Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
Submitted November 03, 2021
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