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：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

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.	張月華. 熱敏感相關的癲癇臨床和分子遺傳學研究. 中國實用兒科雜志, 2015, 30(7): 487-491.
2.	徐瑜欣, 鐘建民. 熱敏感相關癲癇的早期識別與診斷. 中國當代兒科雜志, 2021, 23(7): 749-754.
3.	冼慧文, 高平明. 兒童熱敏感相關癲癇25例臨床特征及分子遺傳學分析. 中國臨床醫生雜志, 2022, 50(4): 487-492.
4.	黃廣蘭. 192例遺傳性癲癇患兒的臨床表型與基因型分析. 廣西醫科大學, 碩士學位論文, 2022.
5.	中華醫學會兒科學分會神經學組. 熱性驚厥診斷治療與管理專家共識(2017實用版). 中華實用兒科臨床雜志, 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.	國家兒童醫學中心, 首都醫科大學附屬北京兒童醫院保健中心, 北京市兒科專業質量控制和改進中心, 等. 中國全面發育遲緩診斷指南. 中華實用兒科臨床雜志, 2024, 39(7): 481-489.
11.	方志旭. SCN1A基因相關癲癇研究進展. 臨床兒科雜志, 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.	蔣永莉, 江文. GABRG2基因突變與癲癇相關性研究進展. 中華神經科雜志, 2020, 53(10): 824-829.
14.	楊瑩, 張月華, 陳嬌陽, 等. GABRB2基因變異相關癲癇的臨床特點. 中華兒科雜志, 2019, 57(7): 532-537.
15.	李信曉, 郭勝楠, 蔣戰勝, 等. GABRG2基因突變致遺傳性癲癇伴熱性驚厥附加癥的分子遺傳學研究進展. 癲癇雜志, 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.	陳奕, 張月華. PCDH19基因相關癲癇治療和預后研究進展. 中國實用兒科雜志, 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.	宋振鳳, 易致, 李菲, 等. ASNS基因變異致天冬酰胺合成酶缺乏癥一家系分析并文獻復習. 中華實用兒科臨床雜志, 2021, 36(9): 690-693.
22.	宋盼盼, 張曉莉, 李小麗, 等. 天冬酰胺合成酶缺乏癥6例臨床及遺傳學特點. 中華兒科雜志, 2024, 62(4): 368-373.
23.	劉亞韋, 張穎, 曲政海. Wolf-Hirschhorn綜合征一例及文獻分析. 中國醫師進修雜志, 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.	蔣萍, 張桐, 湯繼宏, 等. 新生突變的16p11. 2微缺失綜合征(附1例報告及文獻復習). 中國臨床神經科學, 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.	葉園珍, 麥嘉卉, 胡湛棋, 等. 以癲(癎)為主要表型的16p11. 2微缺失綜合征11例病例系列報告. 中國循證兒科雜志, 2022, 17(2): 144-148.

1. 張月華. 熱敏感相關的癲癇臨床和分子遺傳學研究. 中國實用兒科雜志, 2015, 30(7): 487-491.
2. 徐瑜欣, 鐘建民. 熱敏感相關癲癇的早期識別與診斷. 中國當代兒科雜志, 2021, 23(7): 749-754.
3. 冼慧文, 高平明. 兒童熱敏感相關癲癇25例臨床特征及分子遺傳學分析. 中國臨床醫生雜志, 2022, 50(4): 487-492.
4. 黃廣蘭. 192例遺傳性癲癇患兒的臨床表型與基因型分析. 廣西醫科大學, 碩士學位論文, 2022.
5. 中華醫學會兒科學分會神經學組. 熱性驚厥診斷治療與管理專家共識(2017實用版). 中華實用兒科臨床雜志, 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. 國家兒童醫學中心, 首都醫科大學附屬北京兒童醫院保健中心, 北京市兒科專業質量控制和改進中心, 等. 中國全面發育遲緩診斷指南. 中華實用兒科臨床雜志, 2024, 39(7): 481-489.
11. 方志旭. SCN1A基因相關癲癇研究進展. 臨床兒科雜志, 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. 蔣永莉, 江文. GABRG2基因突變與癲癇相關性研究進展. 中華神經科雜志, 2020, 53(10): 824-829.
14. 楊瑩, 張月華, 陳嬌陽, 等. GABRB2基因變異相關癲癇的臨床特點. 中華兒科雜志, 2019, 57(7): 532-537.
15. 李信曉, 郭勝楠, 蔣戰勝, 等. GABRG2基因突變致遺傳性癲癇伴熱性驚厥附加癥的分子遺傳學研究進展. 癲癇雜志, 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. 陳奕, 張月華. PCDH19基因相關癲癇治療和預后研究進展. 中國實用兒科雜志, 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. 宋振鳳, 易致, 李菲, 等. ASNS基因變異致天冬酰胺合成酶缺乏癥一家系分析并文獻復習. 中華實用兒科臨床雜志, 2021, 36(9): 690-693.
22. 宋盼盼, 張曉莉, 李小麗, 等. 天冬酰胺合成酶缺乏癥6例臨床及遺傳學特點. 中華兒科雜志, 2024, 62(4): 368-373.
23. 劉亞韋, 張穎, 曲政海. Wolf-Hirschhorn綜合征一例及文獻分析. 中國醫師進修雜志, 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. 蔣萍, 張桐, 湯繼宏, 等. 新生突變的16p11. 2微缺失綜合征(附1例報告及文獻復習). 中國臨床神經科學, 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. 葉園珍, 麥嘉卉, 胡湛棋, 等. 以癲(癎)為主要表型的16p11. 2微缺失綜合征11例病例系列報告. 中國循證兒科雜志, 2022, 17(2): 144-148.

Journal of Epilepsy

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

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content