Proline‐rich transmembrane protein 2–negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients |
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| Authors: | Wo‐Tu Tian MM Xiao‐Jun Huang MD Xiao Mao MM Qing Liu MM Xiao‐Li Liu MD Sheng Zeng MD Xia‐Nan Guo MD Jun‐Yi Shen MM Yang‐Qi Xu MM Hui‐Dong Tang MD Xiao‐Meng Yin MD Mei Zhang MB Wei‐Guo Tang MD Xiao‐Rong Liu MD PhD Bei‐Sha Tang MD PhD Sheng‐Di Chen MD PhD Li Cao MD PhD |
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| Institution: | 1. Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China;2. Department of Neurology, Xiangya Hospital, Central South University, State Key Laboratory of Medical Genetics, Changsha, Hunan Province, China;3. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China;4. Department of Neurology, Huainan First People's Hospital affiliated to Bengbu Medical College, Huainan, Anhui Province, China;5. Department of Neurology, Zhoushan Hospital, Zhoushan, Zhejiang Province, China;6. Institute of Neuroscience of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China |
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| Abstract: | Background : Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline‐rich transmembrane protein 2 mutations. Objective : The objective of this study was to investigate potential causative genes and clinical characteristics in proline‐rich transmembrane protein 2–negative patients with paroxysmal kinesigenic dyskinesia. Methods : We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline‐rich transmembrane protein 2–negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. Results : The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium‐activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage‐gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage‐gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl‐10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl‐10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. Conclusions : Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society |
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| Keywords: | paroxysmal kinesigenic dyskinesia (PKD) genotype phenotype clinical exome sequencing |
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