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Phenotypic spectrum of COL4A1 mutations: Porencephaly to schizencephaly

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Annals of Neurology

  1. Yuriko Yoneda MSc1,†
  2. Kazuhiro Haginoya MD, PhD2,3,†
  3. Mitsuhiro Kato MD, PhD4,
  4. Hitoshi Osaka MD, PhD5
  5. Kenji Yokochi MD, PhD6
  6. Hiroshi Arai MD7
  7. Akiyoshi Kakita MD, PhD8
  8. Takamichi Yamamoto MD, MS, DMSc9
  9. Yoshiro Otsuki MD, PhD10
  10. Shin-ichi Shimizu DDS, PhD10
  11. Takahito Wada MD PhD5
  12. Norihisa Koyama MD, PhD11,
  13. Yoichi Mino MD12
  14. Noriko Kondo MD13,
  15. Satoru Takahashi MD, PhD14
  16. Shinichi Hirabayashi MD, PhD15
  17. Jun-ichi Takanashi MD, PhD16
  18. Akihisa Okumura MD, PhD17,
  19. Toshiyuki Kumagai MD18
  20. Satori Hirai MD7,
  21. Makoto Nabetani MD19
  22. Shinji Saitoh MD, PhD20
  23. Ayako Hattori MD, PhD20
  24. Mami Yamasaki MD, PhD21
  25. Akira Kumakura MD22
  26. Yoshinobu Sugo MD1
  27. Kiyomi Nishiyama PhD1
  28. Satoko Miyatake MD, PhD1
  29. Yoshinori Tsurusaki PhD1
  30. Hiroshi Doi MD, PhD1
  31. Noriko Miyake MD, PhD1,
  32. Naomichi Matsumoto MD, PhD1
  33. Hirotomo Saitsu MD, PhD1,‡,*

DOI: 10.1002/ana.23736 


Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal and muscular features. In this study, we aimed to clarify phenotypic spectrum and incidence of COL4A1 mutations.


We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult.


COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, hyper-CKnemia, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and three splice site mutations. Five mutations were confirmed as de novo events. One mutation was co-segregated with familial porencephaly, and two mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase PCR analyses in two patients with splice site mutations.


Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the fact that COL4A1mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions. Ann Neurol 2012.

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