Aldehyde degradation deficiency（ADD）症候群 --アルデヒド代謝酵素欠損によるファンコニ貧血症類似の新たな遺伝性骨髄不全症候群の発見--

Abstract

細胞バンクに保存されていた日本人再生不良性貧血患者サンプルのエクソーム解析を発端に，新たな遺伝性骨髄不全症候群が同定された。本疾患は，もともと姉妹染色分体交換（SCE）が高頻度に認められることから新規疾患として認識されていたが，次世代シーケンサーという新技術開発によって原因遺伝子同定がなされたものである。ADH5とALDH2の2つのアルデヒド代謝酵素の同時欠損により，骨髄における血球分化に伴う内因性ホルムアルデヒドが分解されずDNA修復不能なレベルのゲノム損傷を引き起こし，骨髄不全とMDS白血病発症に至ると考えられる。本稿では，この疾患の存在が広く認知されるよう，日本の血液分野の臨床家にむけて，この疾患発見にいたる経緯と現在判明している特徴，その病態を概説する。

We have recently described the identification of a novel inherited bone marrow failure syndrome. The first set of patients was diagnosed through the exome analysis of cells from Japanese patients with hypoplastic anemia, which have been deposited to the JCRB cell bank for quite some time previously. Originally, these cases were diagnosed with a novel disorder based on increased levels of sister chromatid exchanges in lymphocytes; however, causative genes were clarified only after applying the recently developed next-generation sequencing technology. Aldehyde degradation deficiency syndrome (ADDS) is caused by combined defects in two genes, ADH5 and ALDH2, which are both critical for degrading endogenously generated formaldehyde. Formaldehyde is highly reactive and toxic to biological molecules including DNA, and its endogenous generation in the absence of the degradation system results in DNA damage that overwhelms the DNA repair capacity, leading to the development of BMF with loss of hematopoietic stem cells and progression to MDS/leukemia. In this short review, we would like to summarize what is known today about ADDS for a wide readership of hematology clinicians in Japan.