Clinical characteristics and genetics of ten Chinese children with PRRT2-associated neurological diseases

Meiyan Liu; Xiaoang Sun; Longlong Lin; Xiaona Luo; Simei Wang; Chunmei Wang; Yuanfeng Zhang; Quanmei Xu; Wuhen Xu; Shengnan Wu; Xiaoping Lan; Yucai Chen

doi:10.3389/fped.2022.997088

Clinical characteristics and genetics of ten Chinese children with PRRT2-associated neurological diseases

Front Pediatr. 2022 Nov 17:10:997088. doi: 10.3389/fped.2022.997088. eCollection 2022.

Authors

Meiyan Liu¹, Xiaoang Sun¹, Longlong Lin¹, Xiaona Luo¹, Simei Wang¹, Chunmei Wang¹, Yuanfeng Zhang¹, Quanmei Xu¹, Wuhen Xu², Shengnan Wu², Xiaoping Lan², Yucai Chen^{1

3}

Affiliations

¹ Department of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
² Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³ National Health Commission (NHC), Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology and Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China.

Abstract

Background: Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological disorders. This study aimed to summarize the clinical characteristics and gene expression analysis of neurological diseases related to the PRRT2 gene and explore the clinical characteristics, therapeutic effects, and possible pathogenic mechanisms of related diseases.

Methods: We enrolled 10 children with PRRT2 mutation-related neurological diseases who visited the Children's Hospital affiliated with the Shanghai Jiaotong University School of Medicine/Shanghai Children's Hospital between May 2017 and February 2022. Video electroencephalography (VEEG), cranial imaging, treatment regimens, gene results, and gene expression were analyzed. Genetic testing involved targeted sequencing or whole-exome genome sequencing (WES). We further analyzed the expression and mutation conservation of PRRT2 and synaptosome-associated protein 25 (SNAP25) in blood samples using quantitative polymerase chain reaction (qPCR) and predicted the protein structure. Summary analysis of the reported gene maps and domains was also performed.

Results: Ten children with PRRT2 gene mutations were analyzed, and 4 mutations were identified, consisting of 2 new (c.518A > C, p.Glu173 Ala; c.879 + 112G > A, p.?) and two known (c. 649 dup, p. Arg217Profs * 8; c. 649 del, p. Arg217Glufs * 12) mutations. Among these mutations, one was de novo(P6), and three could not be determined because one parent refused genetic testing. The clinical phenotypes were paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), epilepsy, infantile spasms, and intellectual disability. The qPCR results showed that PRRT2 gene expression levels were significantly lower in children and parent carriers than the control group. The SNAP25 gene expression level of affected children was significantly lower (P ≤ 0.001) than that of the control group. The mutation sites reported in this study are highly conserved in different species. Among the various drugs used, oxcarbazepine and sodium valproate were the most effective. All 10 children had a good disease prognosis, and 8 were completely controlled with no recurrence, whereas 2 had less severe and fewer seizures.

Conclusion: Mutation of PRRT2 led to a significant decrease in its protein expression level and that of SNAP25, suggesting that the mutant protein may lead to the loss of its function and that of related proteins. This mutation site is highly conserved in most species, and there was no significant correlation between specific PRRT2 genotypes and clinical phenotypes. Asymptomatic carriers also have decreased gene expression levels, suggesting that more factors are involved.

Keywords: expression; nervous system-related diseases; proline-rich transmembrane protein 2 (PRRT2); synaptosome-associated protein 25 (SNAP 25); whole-exome genome sequencing.