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

• Published in: Gene 2020-07, p.144918-144918, Article 144918
• Main Authors: Fattahi, Mahshid, Bushehri, Ata, Alavi, Afagh, Asghariazar, Vahid, Nozari, Ahoura, Ghasemi Firouzabadi, Saghar, Motamedian Dehkordi, Parisa, Javid, Marzieh, Farajzadeh Valiliou, Saeed, Karimian, Javad, Behjati, Farkhondeh
• Format: Article
• Language: English
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2020.144918

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.