Clinical phenotype and molecular genetic analysis of 29 cases of epilepsy related to fever sensitivity_Journal of Epilepsy

Authors：

LIAN Zishuo , ZHANG Xiaoli , LI Lin , GUO Qiliang ,  JIA Tianming , DONG Yan , LI Xiaoli , CHEN Hao , LU Xiaoqing

Department of Pediatrics, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;

Corresponding author：

JIA Tianming, Email: jtm226@sina.com

Keywords：

Febrile Seizures; Fever sensitive; Epilepsy; Whole exome sequencing; Copy number variation sequencing

DOI：

10.7507/2096-0247.202502010

Video：

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Objective To analyze the clinical characteristics and corresponding genetic features of epilepsy related to fever sensitivity. Methods Retrospectively review 29 children with epilepsy related to fever sensitivity who were diagnosed and treated in the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University from January 2017 to December 2022, with complete clinical data and underwent molecular genetic testing. Fill in the clinical data registration form in detail, and retrospectively summarize their clinical characteristics, electroencephalogram (EEG) manifestations, neuroimaging examinations, the selection of antiepileptic drugs, curative effects, and evaluate and follow up the developmental indicators. Results Among the 29 children with epilepsy related to fever sensitivity, there were 13 males (44.8%) and 16 females (55.2%); 10 cases (34.5%) were Dravet syndrome, 3 cases (10.3%) were genetic epilepsy with febrile seizures plus (GEFS+), and 1 case (3.4%) was PCDH19 gene-related epilepsy. The age of onset ranged from 2 to 25 months. Among them, 19 cases (65.5%) had an onset age of 2 to 12 months, and 10 cases (34.5%) had an onset age greater than 12 months. In 1 case of GEFS+ child, all seizures occurred after fever, and in the other 28 children, afebrile seizures were present. The interval between the first febrile seizure and the appearance of afebrile seizures was 0.09 to 116 months; the age of appearance of afebrile seizures was 5 to 134 months. There were 6 cases (20.7%) with a single seizure type, and 23 cases (79.3%) with 2 or more seizure types. There were 24 cases (82.8%) with generalized tonic-clonic seizures, 9 cases (31.0%) with generalized tonic seizures, 18 cases (62.1%) with focal seizures, 4 cases (13.8%) with absence seizures, and 1 case (3.4%) with spasm seizures. 10 cases (34.5%) of children had status epilepticus, and 13 cases (44.8%) had cluster seizures. 16 cases (55.2%) of children had a positive family history, among which 8 cases (27.6%) had a family history of febrile seizures, and 11 cases (37.9%) had a family history of afebrile seizures/epilepsy; during the initial visit and follow-up, 22 cases (75.9%) were found to have developmental delays of varying degrees. Pathogenic/suspected pathogenic gene variants/copy number variants clearly related to epilepsy were detected in 20 cases, with a detection rate of 68.9%, including SCN1A gene variants (11 cases), GABRB2 gene variants (1 case), GABRG2 gene variants (1 case), PCDH19 gene variants (1 case), SPTBN1 gene variants (c.1081_c.1097delAACTTGGAAGTGCTGCTinsCA, 1 case), ASNS gene variants (c.146G>A, 1 case), copy number variants in the 4p16.3 region (3 cases), and copy number variants in the 16p11.2 region (1 case). Among them, the gene variants of SPTBN1 and ASNS are novel gene variants that have not been previously reported in China for epilepsy related to fever sensitivity. Conclusion Epilepsy related to fever sensitivity mostly occurs in infancy, with diverse seizure patterns, varying degrees of severity of clinical symptoms, often accompanied by status epilepticus and cluster seizures, and mostly combined with developmental delays of varying degrees. This study found that the gene variants of SPTBN1 and ASNS, which have not been previously reported in China, may be rare pathogenic genes for epilepsy related to fever sensitivity.

Citation： LIAN Zishuo, ZHANG Xiaoli, LI Lin, GUO Qiliang, JIA Tianming, DONG Yan, LI Xiaoli, CHEN Hao, LU Xiaoqing. Clinical phenotype and molecular genetic analysis of 29 cases of epilepsy related to fever sensitivity. Journal of Epilepsy, 2025, 11(3): 202-213. doi: 10.7507/2096-0247.202502010 Copy

1.	张月华. 热敏感相关的癫痫临床和分子遗传学研究. 中国实用儿科杂志, 2015, 30(7): 487-491.
2.	徐瑜欣, 钟建民. 热敏感相关癫痫的早期识别与诊断. 中国当代儿科杂志, 2021, 23(7): 749-754.
3.	冼慧文, 高平明. 儿童热敏感相关癫痫25例临床特征及分子遗传学分析. 中国临床医生杂志, 2022, 50(4): 487-492.
4.	黄广兰. 192例遗传性癫痫患儿的临床表型与基因型分析. 广西医科大学, 硕士学位论文, 2022.
5.	中华医学会儿科学分会神经学组. 热性惊厥诊断治疗与管理专家共识(2017实用版). 中华实用儿科临床杂志, 2017, 32(18): 1379-1382.
6.	Scheffer I E, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
7.	Jafarpour S, Hirsch L J, Gaínza-Lein M, et al. Seizure cluster: definition, prevalence, consequences, and management. Seizure, 2019, 68: 9-15.
8.	Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia, 2015, 56(10): 1515-1523.
9.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015, 17(5): 405-424.
10.	国家儿童医学中心, 首都医科大学附属北京儿童医院保健中心, 北京市儿科专业质量控制和改进中心, 等. 中国全面发育迟缓诊断指南. 中华实用儿科临床杂志, 2024, 39(7): 481-489.
11.	方志旭. SCN1A基因相关癫痫研究进展. 临床儿科杂志, 2021, 39(3): 231-236.
12.	Cetica V, Chiari S, Mei D, et al. Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations. Neurology, 2017, 88(11): 1037-1044.
13.	蒋永莉, 江文. GABRG2基因突变与癫痫相关性研究进展. 中华神经科杂志, 2020, 53(10): 824-829.
14.	杨莹, 张月华, 陈娇阳, 等. GABRB2基因变异相关癫痫的临床特点. 中华儿科杂志, 2019, 57(7): 532-537.
15.	李信晓, 郭胜楠, 蒋战胜, 等. GABRG2基因突变致遗传性癫痫伴热性惊厥附加症的分子遗传学研究进展. 癫痫杂志, 2023, 9(3): 235-242.
16.	Hernandez CC, Tian X, Hu N, et al. Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors. Brain Commun, 2021, 3(2): fcab033.
17.	Kowkabi S, Yavarian M, Kaboodkhani R, et al. PCDH19-clustering epilepsy, pathophysiology and clinical significance. Epilepsy Behav, 2024, 154: 109730.
18.	陈奕, 张月华. PCDH19基因相关癫痫治疗和预后研究进展. 中国实用儿科杂志, 2022, 37(7): 541-545.
19.	Cousin MA, Creighton BA, Breau KA, et al. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nat Genet, 2021, 53(7): 1006-1021.
20.	Ruzzo EK, Capo-Chichi JM, Ben-Zeev B, et al. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron, 2013, 80(2): 429-441.
21.	宋振凤, 易致, 李菲, 等. ASNS基因变异致天冬酰胺合成酶缺乏症一家系分析并文献复习. 中华实用儿科临床杂志, 2021, 36(9): 690-693.
22.	宋盼盼, 张晓莉, 李小丽, 等. 天冬酰胺合成酶缺乏症6例临床及遗传学特点. 中华儿科杂志, 2024, 62(4): 368-373.
23.	刘亚韦, 张颖, 曲政海. Wolf-Hirschhorn综合征一例及文献分析. 中国医师进修杂志, 2018, 41(4): 356-358.
24.	Friebe-Hoffmann U, Reister F, Gaspar H, et al. The Wolf-Hirschhorn Syndrome. Z Geburtshilfe Neonatol, 2016, 220(5): 195-199.
25.	Paprocka J, Kaminiów K, Yetkin O, et al. Clinical and epilepsy characteristics in Wolf-Hirschhorn syndrome (4p-): a review. Seizure, 2024, 116: 14-23.
26.	蒋萍, 张桐, 汤继宏, 等. 新生突变的16p11. 2微缺失综合征(附1例报告及文献复习). 中国临床神经科学, 2021, 29(3): 303-309.
27.	Chung WK, Roberts TP, Sherr EH, et al. 16p11. 2 deletion syndrome. Curr Opin Genet Dev, 2021, 68: 49-56.
28.	叶园珍, 麦嘉卉, 胡湛棋, 等. 以癫(癎)为主要表型的16p11. 2微缺失综合征11例病例系列报告. 中国循证儿科杂志, 2022, 17(2): 144-148.

1. 张月华. 热敏感相关的癫痫临床和分子遗传学研究. 中国实用儿科杂志, 2015, 30(7): 487-491.
2. 徐瑜欣, 钟建民. 热敏感相关癫痫的早期识别与诊断. 中国当代儿科杂志, 2021, 23(7): 749-754.
3. 冼慧文, 高平明. 儿童热敏感相关癫痫25例临床特征及分子遗传学分析. 中国临床医生杂志, 2022, 50(4): 487-492.
4. 黄广兰. 192例遗传性癫痫患儿的临床表型与基因型分析. 广西医科大学, 硕士学位论文, 2022.
5. 中华医学会儿科学分会神经学组. 热性惊厥诊断治疗与管理专家共识(2017实用版). 中华实用儿科临床杂志, 2017, 32(18): 1379-1382.
6. Scheffer I E, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
7. Jafarpour S, Hirsch L J, Gaínza-Lein M, et al. Seizure cluster: definition, prevalence, consequences, and management. Seizure, 2019, 68: 9-15.
8. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia, 2015, 56(10): 1515-1523.
9. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015, 17(5): 405-424.
10. 国家儿童医学中心, 首都医科大学附属北京儿童医院保健中心, 北京市儿科专业质量控制和改进中心, 等. 中国全面发育迟缓诊断指南. 中华实用儿科临床杂志, 2024, 39(7): 481-489.
11. 方志旭. SCN1A基因相关癫痫研究进展. 临床儿科杂志, 2021, 39(3): 231-236.
12. Cetica V, Chiari S, Mei D, et al. Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations. Neurology, 2017, 88(11): 1037-1044.
13. 蒋永莉, 江文. GABRG2基因突变与癫痫相关性研究进展. 中华神经科杂志, 2020, 53(10): 824-829.
14. 杨莹, 张月华, 陈娇阳, 等. GABRB2基因变异相关癫痫的临床特点. 中华儿科杂志, 2019, 57(7): 532-537.
15. 李信晓, 郭胜楠, 蒋战胜, 等. GABRG2基因突变致遗传性癫痫伴热性惊厥附加症的分子遗传学研究进展. 癫痫杂志, 2023, 9(3): 235-242.
16. Hernandez CC, Tian X, Hu N, et al. Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors. Brain Commun, 2021, 3(2): fcab033.
17. Kowkabi S, Yavarian M, Kaboodkhani R, et al. PCDH19-clustering epilepsy, pathophysiology and clinical significance. Epilepsy Behav, 2024, 154: 109730.
18. 陈奕, 张月华. PCDH19基因相关癫痫治疗和预后研究进展. 中国实用儿科杂志, 2022, 37(7): 541-545.
19. Cousin MA, Creighton BA, Breau KA, et al. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nat Genet, 2021, 53(7): 1006-1021.
20. Ruzzo EK, Capo-Chichi JM, Ben-Zeev B, et al. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron, 2013, 80(2): 429-441.
21. 宋振凤, 易致, 李菲, 等. ASNS基因变异致天冬酰胺合成酶缺乏症一家系分析并文献复习. 中华实用儿科临床杂志, 2021, 36(9): 690-693.
22. 宋盼盼, 张晓莉, 李小丽, 等. 天冬酰胺合成酶缺乏症6例临床及遗传学特点. 中华儿科杂志, 2024, 62(4): 368-373.
23. 刘亚韦, 张颖, 曲政海. Wolf-Hirschhorn综合征一例及文献分析. 中国医师进修杂志, 2018, 41(4): 356-358.
24. Friebe-Hoffmann U, Reister F, Gaspar H, et al. The Wolf-Hirschhorn Syndrome. Z Geburtshilfe Neonatol, 2016, 220(5): 195-199.
25. Paprocka J, Kaminiów K, Yetkin O, et al. Clinical and epilepsy characteristics in Wolf-Hirschhorn syndrome (4p-): a review. Seizure, 2024, 116: 14-23.
26. 蒋萍, 张桐, 汤继宏, 等. 新生突变的16p11. 2微缺失综合征(附1例报告及文献复习). 中国临床神经科学, 2021, 29(3): 303-309.
27. Chung WK, Roberts TP, Sherr EH, et al. 16p11. 2 deletion syndrome. Curr Opin Genet Dev, 2021, 68: 49-56.
28. 叶园珍, 麦嘉卉, 胡湛棋, 等. 以癫(癎)为主要表型的16p11. 2微缺失综合征11例病例系列报告. 中国循证儿科杂志, 2022, 17(2): 144-148.

Journal of Epilepsy

Clinical phenotype and molecular genetic analysis of 29 cases of epilepsy related to fever sensitivity

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