ALDH5A1のバイアレル変異はコハク性セマルアルデヒドデヒドロゲナーゼ欠損症と重度の知的障害と関連しています

Bi-allelic Mutations in ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability.

• Mahshid Fattahi
• Ata Bushehri
• Afagh Alavi
• Vahid Asghariazar
• Ahoura Nozari
• Saghar Ghasemi Firouzabadi
• Parisa Motamedian Dehkordi
• Marzieh Javid
• Saeed Farajzadeh Valiliou
• Javad Karimian
• Farkhondeh Behjati

抄録

ALDH5A1のホモ接合変異は、γ-アミノ酪酸（GABA）の代謝に影響を及ぼすコハク酸性セマルアルデヒド脱水素酵素欠損症（SSADHD）と関連し、軽度の知的障害から重度の神経変性障害まで幅広い臨床表現型を示すことが報告されている。我々は、重度の知的障害、発達遅延、全身性強直間代発作を呈する2名のLor家の臨床および分子データを報告する。全ゲノム配列決定を含む包括的な遺伝学的研究により、ALDH5A1（アルデヒド脱水素酵素5ファミリーメンバーA1）遺伝子のホモ接合性ミスセンス置換（NM_001080:c.G1321A:p.G441R）が同定され、患者の臨床表現型と一致し、家族内の疾患と共析していた。非同義変異であるp.G441Rは、高度に保存されたアミノ酸残基に影響を与え、酵素の深刻な不安定化を引き起こすことが予想される。タンパク質のモデル化により、コハク酸セマルアルデヒド(SSA)の結合トンネルへのアクセス性の障害が示され、タンパク質のフォールディングの安定性とダイナミクスの予測は、4.02 kcal/molの自由エネルギーの減少であった。これらのインシリコ所見と一致して、過剰なγ-ヒドロキシ酪酸(GHB)がGABA経路の副産物として患者の尿中に検出された。SSADHD, コハク性セミアルデヒド脱水素酵素欠損症; GABA, γ-アミノ酪酸; ALDH5A1, アルデヒド脱水素酵素5ファミリーメンバーA1; GHB, γ-ヒドロキシ酪酸; SSA, コハク性セミアルデヒド; WISC, Wechsler Intelligence Scale for Children; CNS, 中枢神経系 .EEG、脳波計; EEEF、経験的有効エネルギー関数; ASD、自閉症スペクトラム障害; ADHD、注意欠陥多動性障害; IQ、知能指数; EMG、筋電図; NCV、神経伝導速度; CP、脳性麻痺。

Homozygous mutations of ALDH5A1 have been reportedly associated with Succinic semialdehyde dehydrogenase deficiency (SSADHD) that affects gamma-aminobutyric acid (GABA) catabolism and evinces a wide range of clinical phenotype from mild intellectual disability to severe neurodegenerative disorders. We report clinical and molecular data of a Lor family with 2 affected members presenting with severe intellectual disability, developmental delay, and generalized tonic-clonic seizures. A comprehensive genetic study that included whole-exome sequencing identified a homozygous missense substitution (NM_001080:c.G1321A:p.G441R) in ALDH5A1 (Aldehyde Dehydrogenase 5 Family Member A1) gene, consistent with clinical phenotype in the patients and co-segregating with the disease in the family. The non-synonymous mutation, p.G441R, affects a highly conserved amino acid residue, which is expected to cause a severe destabilization of the enzyme. Protein modeling demonstrated an impairment of the succinic semialdehyde (SSA) binding tunnel accessibility, and the anticipation of the protein folding stability and dynamics was a decrease in the free energy by 4.02 kcal/mol. Consistent with these in silico findings, excessive γ -hydroxybutyrate (GHB) could be detected in patients' urine as the byproduct of the GABA pathway. SSADHD, Succinic semialdehyde dehydrogenase deficiency; GABA, gamma-aminobutyric acid; ALDH5A1, Aldehyde Dehydrogenase 5 Family Member A1; GHB, γ -hydroxybutyrate; SSA, succinic semi aldehyde; WISC, Wechsler Intelligence Scale for Children; CNS, central nervous system ; EEG, electroencephalography; EEEF, empirical effective energy functions; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; IQ, intelligence quotient; EMG, electromyography; NCV, nerve conduction velocity; CP, cerebral palsy.

Copyright © 2020. Published by Elsevier B.V.