Towards a treatment for congenital central hypoventilation syndrome based on the pathophysiology

• Project/Area Number: 17K10171
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Yamagata University
• Principal Investigator: Sasaki Ayako 山形大学, 医学部, 准教授 (60333960)
• Co-Investigator(Kenkyū-buntansha): 早坂 清 山形大学, 医学部, 名誉教授 (20142961)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 先天性中枢性低換気症候群 / PHOX2B遺伝子 / 遺伝子診断

Outline of Final Research Achievements

Congenital central hypoventilation syndrome is characterized by failure of the automatic control of breathing during sleep and impaired autonomic nervous system. We studied PHOX2B in 401 cases showing respiratory symptoms and detected disease-causing mutations in 151 cases.
We analyzed genotype-phenotype relationship and developmental prognosis in 151 cases. The patients carrying long PARMs or most NPARMs presented with severe phenotype. We found mental retardation in 30% of all patients and no significant difference in their genotypes. And we found a favorable prognosis in the patients who received the ventilation support from day 0. We also analyzed two genes in 250 cases with no PHOX2B mutations. However, we didn’t find any mutation. It is very important to promptly make a diagnosis by molecular analysis and provide appropriate ventilator support.

Academic Significance and Societal Importance of the Research Achievements

日本における先天性中枢性低換気症候群の遺伝子型と表現型の関係を検討し発表することで，疾患の認知度を向上させることで、早期診断につながるようになると考えられる．さらに人工呼吸管理法と発達の関連を検討ことにより，患者のよりよいQuality of lifeに貢献できる．

Research Products

• [Journal Article] Adult cases of late-onset congenital central hypoventilation syndrome and paired-like homeobox 2B-mutation carriers: an additional case report and pooled analysis (2020)
  • Author(s): Hino Aoi、Terada Jiro、Kasai Hajime、Shojima Hikaru、Ohgino Keiko、Sasaki Ayako、Hayasaka Kiyoshi、Tatsumi Koichiro
  • Journal Title: Journal of Clinical Sleep Medicine Volume: 16 Issue: 11 Pages: 1891-1900
  • DOI: 10.5664/jcsm.8732
  • Peer Reviewed
• [Journal Article] 呼吸生理学的に軽症と診断した先天性中枢性肺胞低換気症候群 非ポリアラニン伸長変異 (2020)
  • Author(s): 山田恵、大森さゆ、山田洋輔、長谷川久弥、佐々木綾子、早坂清、佐藤清二
  • Journal Title: 日本小児科学会誌 Volume: 124 Pages: 1509-1513
  • Peer Reviewed
• [Journal Article] 難病研究の進歩】呼吸器 先天性中枢性低換気症候群 (2020)
  • Author(s): 佐々木綾子、早坂清
  • Journal Title: 生体の科学 Volume: 71 Pages: 454-455
• [Journal Article] Novel PHOX2B mutation in congenital central hypoventilation syndrome. (2019)
  • Author(s): Sasaki A, Kisikawa Y, Imaji R, Fukushima Y, Nakamura Y, Nishimura Y, Yamada M, Mino Y, Mitsui T, Hayasaka K.
  • Journal Title: Pediatr International Volume: 61 Issue: 4 Pages: 393-396
  • DOI: 10.1111/ped.13812
  • Peer Reviewed
• [Journal Article] Genetic Diagnosis and Characteristics of CCHS in Japan. (2019)
  • Author(s): Sasaki A, Hayasaka K.
  • Journal Title: Pediatric Pulmonology Volume: 54
• [Journal Article] Hirschsprung病類縁疾患を合併した先天性中枢性低換気症候群の新生児例と本邦既報例の比較検討 (2019)
  • Author(s): 藤代定志、大橋 敦、田中裕香、平林雅人、峰 研治、土井 崇、佐々木綾子、金子一成
  • Journal Title: 日本小児科学会雑誌 Volume: 123 Pages: 1248-1254
  • Peer Reviewed
• [Journal Article] A novel PHOX2B gene mutation in an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease (2018)
  • Author(s): Miura Yuichiro、Watanabe Tatsuya、Uchida Toshihiko、Nawa Tatsuro、Endo Naobumi、Fukuzawa Taichi、Ohkubo Ryuji、Takeyama Junji、Sasaki Ayako、Hayasaka Kiyoshi
  • Journal Title: European Journal of Medical Genetics Volume: - Issue: 9 Pages: 103541-103541
  • DOI: 10.1016/j.ejmg.2018.09.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 日本における先天性中枢性低換気症候群の発達予後 (2018)
  • Author(s): 佐々木綾子, 三井哲夫, 早坂清
  • Journal Title: 日本小児呼吸器学会雑誌 Volume: 29 Pages: 146-152
  • NAID: 40021801866
  • Peer Reviewed
• [Journal Article] 先天性中枢性低換気症候群 (CCHS) を合併したmacrocephaly capillary malformation (M-CM) 症候群の1例 (2018)
  • Author(s): 兵頭勇紀, 竹内章人, 山田洋輔, 長谷川久弥, 佐々木綾子, 早坂清, 森本大作, 玉井圭, 森茂弘, 中村和恵, 中村信, 影山操
  • Journal Title: 日本新生児成育医学会雑誌 Volume: 30 Pages: 73-78
  • NAID: 40021505684
  • Peer Reviewed
• [Presentation] CCHSにおける遺伝子診断・症状・合併症 (2021)
  • Author(s): 佐々木綾子
  • Organizer: 日本呼吸ケア・リハビリテーション学会
• [Presentation] Genetic Diagnosis and Characteristics of Congenital Central Hypoventilation Syndrome in Japan (2019)
  • Author(s): Ayako Sasaki, Kiyoshi Hayasaka.
  • Organizer: CIPP ⅩⅧ
  • Int'l Joint Research / Invited
• [Presentation] 出生後に遺伝子検査にて中枢性低換気症候群と診断された羊水過多症の1例 (2018)
  • Author(s): 森美妃, 加藤宏章, 阿南春分, 上野繁, 池田朋子, 阿部恵美子, 近藤裕司, 越智博, 依岡壮一郎, 海老原知博 井上博晴, 長友太郎, 穐吉眞之介, 佐々木綾子
  • Organizer: 第54回日本周産期・新生児医学会総会
• [Presentation] 日本における先天性中枢性低換気症候群の発達予後について. (2017)
  • Author(s): 佐々木綾子
  • Organizer: 第62回日本新生児成育医学会・学術集会