<i>COL4A1</i>和<i>COL4A2</i>基因變異相關發育性癲癇性腦病二例并文獻復習_Journal of Epilepsy

Authors：

韓雨 , 俞珞彬 , 姚靈 , 羅淑珍 , 周有峰 ,  胡春輝

福建醫科大學婦兒臨床醫學院·福建省兒童醫院神經內科（福州 350014）;

Corresponding?author：

胡春輝, Email: huchunhui1989@126.com

Keywords：

COL4A1基因; COL4A2基因; 膠原蛋白; 發育性癲癇性腦病

DOI：

10.7507/2096-0247.202603020

Video：

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Citation： 韓雨, 俞珞彬, 姚靈, 羅淑珍, 周有峰, 胡春輝. COL4A1和COL4A2基因變異相關發育性癲癇性腦病二例并文獻復習. Journal of Epilepsy, 2026, 12(4): 354-363. doi: 10.7507/2096-0247.202603020 Copy

1.	Jamshid K , Vadim P , Hudson BG. Mammalian collagen IV. Microscopy research and technique, 2008, 71(5): 357-370.
2.	Gasparini S, Balestrini S, Saccaro LF, et al. Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2024, 196(4): e32099.
3.	Hu C, Liu D, Wang H. Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation. Int J Med Sci, 2024, 21(9): 1756-1768.
4.	Neri S, Ferlazzo E, Africa E, et al. Novel COL4A2 mutation causing familial malformations of cortical development. Eur Rev Med Pharmacol Sci, 2021, 25(2): 898-905.
5.	Shi J, Lin J, Bai J, et al. Phenotype and surgical management of drug-resistant epilepsy in patients with COL4A1 and COL4A2 variants. Epilepsia Open, 2025, 10(3): 725-735.
6.	Wang QH, Zou LP, Zhang MN, et al. Phenotypic characterization of COL4A1-related West syndrome. Epilepsy Res, 2020, 164: 106349.
7.	Papandreou A, Tisdall MM, Chong WK, et al. COL4A1 mutations should not be a contraindication for epilepsy surgery. Childs Nerv Syst, 2014, 30(8): 1467-1469.
8.	Becker LL, Makridis KL, Abad-Perez AT, et al. The importance of routine genetic testing in pediatric epilepsy surgery. Epilepsia Open, 2024, 9(2): 800-807.
9.	Nishimura N, Kumaki T, Murakami H, et al. Expanding the phenotype of COL4A1-related disorders—Four novel variants. Brain Dev, 2020, 42(9): 639-645.
10.	Nakamura Y, Okanishi T, Yamada H, et al. Progressive cerebral atrophies in three children with COL4A1 mutations. Brain Dev, 2021, 43(10): 1033-1038.
11.	Duc NM, Thu NTM, Bui CB, et al. Genotype and phenotype characteristics of West syndrome in 20 Vietnamese children: Two novel variants detected by next-generation sequencing. Epilepsy Res, 2023, 190: 107094.
12.	Rim JH, Kim SH, Hwang IS, et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics, 2018, 11(1): 6.
13.	Fearns N, Wagner M, Borggr?fe I, et al. Good outcome of resective epilepsy surgery in a 1-year-old child with drug-resistant focal epilepsy with a novel pathogenic COL4A1 mutation. Neuropediatrics, 2024, 55(4): 255-259.
14.	Morsi A, Maldonado A, Lal D, et al. Vasospasm following hemispherectomy: a case report of a novel complication. World Neurosurg, 2020, 137: 357-361.
15.	Giorgio E, Vaula G, Bosco G, et al. Two families with novel missense mutations in COL4A1: When diagnosis can be missed. J Neurol Sci, 2015, 352(1-2): 99-104.
16.	Hino-Fukuyo N, Kikuchi A, Iwasaki M, et al. Dramatic response after functional hemispherectomy in a patient with epileptic encephalopathy carrying a de novo COL4A1 mutation. Brain Dev, 2017, 39(4): 337-340.
17.	Salinas V, Martínez N, Maturo JP, et al. Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation. Eur J Med Genet, 2021, 64(12): 104363.
18.	張鵬, 王秋紅, 鄒麗萍, 等. COL4A1/COL4A2基因變異相關嬰兒痙攣癥的臨床特點及預后. 解放軍醫學院學報, 2021, 42(06): 601-607.
19.	Tambala D, Vassar R, Snow J, et al. COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management. Genet Med, 2025, 27(9): 101514.
20.	Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science, 2005, 308: 1167-1171.
21.	Aguglia U, Gambardella A, Breedveld GJ, et al. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Neurology, 2004, 62: 1613-1615.
22.	Favor J, Gloeckner CJ, Janik D, et al. Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles. Genetics, 2007, 175: 725-736.
23.	Verbeek E, Meuwissen ME, Verheijen FW, et al. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet, 2012, 20: 844-851.
24.	Zagaglia S, Selch C, Nisevic JR, et al. Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease. Neurology, 2018, 91: e2078-e2088.
25.	Yaramis A, Lochmüller H, T?pf A, et al. COL4A1-related autosomal recessive encephalopathy in 2 Turkish children. Neurology Genetics, 2020, 6: e392.
26.	Jeanne M, Gould DB. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Matrix Biol, 2017, 57-58: 29-44.
27.	Labelle-Dumais C, Schuitema V, Hayashi G, et al. COL4A1 mutations cause neuromuscular disease with tissue-specific mechanistic heterogeneity. Am J Hum Genet, 2019, 104(5): 847-860.
28.	Meuwissen MEC, Halley DJJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med, 2015, 17(11): 843-853.
29.	Yoneda Y, Haginoya K, Kato M, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol, 2012, 73: 48-57.
30.	Dublin AB, French BN. Diagnostic image evaluation of hydranencephaly and pictorially similar entities, with emphasis on computed tomography. Radiology, 1980, 137: 81-91.
31.	K?rber-Rosso I. Epilepsy in patients carrying COL4A1/COL4A2 mutations with focus on neuroimaging, epilepsy surgery and histology: München. Ludwig-Maximilians-Universit?t (Dissertation, LMU München), 2021: 1-109.
32.	Marini S, Anderson CD, Rosand J. Genetics of cerebral small vessel disease. Stroke, 2020, 51: 12-20.
33.	Hagel C, Groden C, Niemeyer R, et al. Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL. Acta Neuropathol, 2004, 108: 231-240.
34.	Ayrignac X, Carra-Dalliere C, Menjot de Champfleur N, et al. Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients. Brain, 2015, 138: 284-292.
35.	Nandeesh BN, Bindu PS, Narayanappa G, et al. Cerebral small vessel disease with hemorrhagic stroke related to COL4A1 mutation: A case report. Neuropathology, 2020, 40(1): 93-98.
36.	Van Agtmael T, Schlotzer-Schrehardt U, McKie L, et al. Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy. Hum Mol Genet, 2005, 14: 3161-3168.
37.	Jones FE, Bailey MA, Murray LS, et al. ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice. Dis Model Mech, 2016, 9: 165-176.
38.	Jones FE, Murray LS, McNeilly S, et al. Sodium phenylbutyric acid has both efficacy and counterindicative effects in the treatment of Col4a1 disease. Hum Mol Genet, 2019, 28: 628-638.
39.	Shah S, Ellard S, Kneen R, et al. Childhood presentation of COL4A1 mutations. Dev Med Child Neurol, 2012, 54: 569-574.
40.	Gould B D, Phalan C F, Breedveld JG , et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science, 2005, 308(5725): 1167-1171.

1. Jamshid K , Vadim P , Hudson BG. Mammalian collagen IV. Microscopy research and technique, 2008, 71(5): 357-370.
2. Gasparini S, Balestrini S, Saccaro LF, et al. Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2024, 196(4): e32099.
3. Hu C, Liu D, Wang H. Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation. Int J Med Sci, 2024, 21(9): 1756-1768.
4. Neri S, Ferlazzo E, Africa E, et al. Novel COL4A2 mutation causing familial malformations of cortical development. Eur Rev Med Pharmacol Sci, 2021, 25(2): 898-905.
5. Shi J, Lin J, Bai J, et al. Phenotype and surgical management of drug-resistant epilepsy in patients with COL4A1 and COL4A2 variants. Epilepsia Open, 2025, 10(3): 725-735.
6. Wang QH, Zou LP, Zhang MN, et al. Phenotypic characterization of COL4A1-related West syndrome. Epilepsy Res, 2020, 164: 106349.
7. Papandreou A, Tisdall MM, Chong WK, et al. COL4A1 mutations should not be a contraindication for epilepsy surgery. Childs Nerv Syst, 2014, 30(8): 1467-1469.
8. Becker LL, Makridis KL, Abad-Perez AT, et al. The importance of routine genetic testing in pediatric epilepsy surgery. Epilepsia Open, 2024, 9(2): 800-807.
9. Nishimura N, Kumaki T, Murakami H, et al. Expanding the phenotype of COL4A1-related disorders—Four novel variants. Brain Dev, 2020, 42(9): 639-645.
10. Nakamura Y, Okanishi T, Yamada H, et al. Progressive cerebral atrophies in three children with COL4A1 mutations. Brain Dev, 2021, 43(10): 1033-1038.
11. Duc NM, Thu NTM, Bui CB, et al. Genotype and phenotype characteristics of West syndrome in 20 Vietnamese children: Two novel variants detected by next-generation sequencing. Epilepsy Res, 2023, 190: 107094.
12. Rim JH, Kim SH, Hwang IS, et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics, 2018, 11(1): 6.
13. Fearns N, Wagner M, Borggr?fe I, et al. Good outcome of resective epilepsy surgery in a 1-year-old child with drug-resistant focal epilepsy with a novel pathogenic COL4A1 mutation. Neuropediatrics, 2024, 55(4): 255-259.
14. Morsi A, Maldonado A, Lal D, et al. Vasospasm following hemispherectomy: a case report of a novel complication. World Neurosurg, 2020, 137: 357-361.
15. Giorgio E, Vaula G, Bosco G, et al. Two families with novel missense mutations in COL4A1: When diagnosis can be missed. J Neurol Sci, 2015, 352(1-2): 99-104.
16. Hino-Fukuyo N, Kikuchi A, Iwasaki M, et al. Dramatic response after functional hemispherectomy in a patient with epileptic encephalopathy carrying a de novo COL4A1 mutation. Brain Dev, 2017, 39(4): 337-340.
17. Salinas V, Martínez N, Maturo JP, et al. Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation. Eur J Med Genet, 2021, 64(12): 104363.
18. 張鵬, 王秋紅, 鄒麗萍, 等. COL4A1/COL4A2基因變異相關嬰兒痙攣癥的臨床特點及預后. 解放軍醫學院學報, 2021, 42(06): 601-607.
19. Tambala D, Vassar R, Snow J, et al. COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management. Genet Med, 2025, 27(9): 101514.
20. Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science, 2005, 308: 1167-1171.
21. Aguglia U, Gambardella A, Breedveld GJ, et al. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Neurology, 2004, 62: 1613-1615.
22. Favor J, Gloeckner CJ, Janik D, et al. Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles. Genetics, 2007, 175: 725-736.
23. Verbeek E, Meuwissen ME, Verheijen FW, et al. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet, 2012, 20: 844-851.
24. Zagaglia S, Selch C, Nisevic JR, et al. Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease. Neurology, 2018, 91: e2078-e2088.
25. Yaramis A, Lochmüller H, T?pf A, et al. COL4A1-related autosomal recessive encephalopathy in 2 Turkish children. Neurology Genetics, 2020, 6: e392.
26. Jeanne M, Gould DB. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Matrix Biol, 2017, 57-58: 29-44.
27. Labelle-Dumais C, Schuitema V, Hayashi G, et al. COL4A1 mutations cause neuromuscular disease with tissue-specific mechanistic heterogeneity. Am J Hum Genet, 2019, 104(5): 847-860.
28. Meuwissen MEC, Halley DJJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med, 2015, 17(11): 843-853.
29. Yoneda Y, Haginoya K, Kato M, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol, 2012, 73: 48-57.
30. Dublin AB, French BN. Diagnostic image evaluation of hydranencephaly and pictorially similar entities, with emphasis on computed tomography. Radiology, 1980, 137: 81-91.
31. K?rber-Rosso I. Epilepsy in patients carrying COL4A1/COL4A2 mutations with focus on neuroimaging, epilepsy surgery and histology: München. Ludwig-Maximilians-Universit?t (Dissertation, LMU München), 2021: 1-109.
32. Marini S, Anderson CD, Rosand J. Genetics of cerebral small vessel disease. Stroke, 2020, 51: 12-20.
33. Hagel C, Groden C, Niemeyer R, et al. Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL. Acta Neuropathol, 2004, 108: 231-240.
34. Ayrignac X, Carra-Dalliere C, Menjot de Champfleur N, et al. Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients. Brain, 2015, 138: 284-292.
35. Nandeesh BN, Bindu PS, Narayanappa G, et al. Cerebral small vessel disease with hemorrhagic stroke related to COL4A1 mutation: A case report. Neuropathology, 2020, 40(1): 93-98.
36. Van Agtmael T, Schlotzer-Schrehardt U, McKie L, et al. Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy. Hum Mol Genet, 2005, 14: 3161-3168.
37. Jones FE, Bailey MA, Murray LS, et al. ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice. Dis Model Mech, 2016, 9: 165-176.
38. Jones FE, Murray LS, McNeilly S, et al. Sodium phenylbutyric acid has both efficacy and counterindicative effects in the treatment of Col4a1 disease. Hum Mol Genet, 2019, 28: 628-638.
39. Shah S, Ellard S, Kneen R, et al. Childhood presentation of COL4A1 mutations. Dev Med Child Neurol, 2012, 54: 569-574.
40. Gould B D, Phalan C F, Breedveld JG , et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science, 2005, 308(5725): 1167-1171.

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COL4A1和COL4A2基因變異相關發育性癲癇性腦病二例并文獻復習

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