SSADH deficiency in an Italian family: a novel ALDH5A1 gene mutation affecting the succinic semialdehyde substrate binding site

Metab Brain Dis. 2017 Oct;32(5):1383-1388. doi: 10.1007/s11011-017-0058-5. Epub 2017 Jun 29.


SSADH deficiency (SSADHD) is a rare autosomal recessively inherited metabolic disorder. It is associated with mutations of ALDH5A1 gene, coding for the homotetrameric enzyme SSADH. This enzyme is involved in γ-aminobutyric acid (GABA) catabolism, since it oxidizes succinic semialdehyde (SSA) to succinate. Mutations in ALDH5A1 gene result in the abnormal accumulation of γ-hydroxybutyrate (GHB), which is pathognomonic of SSADHD. In the present report, diagnosis of SSADHD in a three-month-old female was achieved by detection of high levels of GHB in urine. Sequence analysis of ALDH5A1 gene showed that the patient was a compound heterozygote for c.1226G > A (p.G409D) and the novel missense mutation, c.1498G > C (p.V500 L). By ALDH5A1 gene expression in transiently transfected HEK293 cells and enzyme activity assays, we demonstrate that the p.V500 L mutation, despite being conservative, produces complete loss of enzyme activity. In silico protein modelling analysis and evaluation of tetramer destabilizing energies suggest that structural impairment and partial occlusion of the access channel to the active site affect enzyme activity. These findings add further knowledge on the missense mutations associated with SSADHD and the molecular mechanisms underlying the loss of the enzyme activity.

Keywords: ALDH5A1 gene; GABA (γ-aminobutyric acid); GHB (γ-hydroxybutyric acid); SSADH; SSADHD (succinic semialdehyde dehydrogenase deficiency).

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Binding Sites
  • Computer Simulation
  • DNA / genetics
  • Developmental Disabilities / genetics*
  • Female
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Infant
  • Models, Molecular
  • Mutation / genetics
  • Mutation, Missense
  • Pedigree
  • Sodium Oxybate / urine
  • Succinate-Semialdehyde Dehydrogenase / deficiency*
  • Succinate-Semialdehyde Dehydrogenase / genetics
  • gamma-Aminobutyric Acid / analogs & derivatives*
  • gamma-Aminobutyric Acid / metabolism


  • gamma-Aminobutyric Acid
  • Sodium Oxybate
  • DNA
  • ALDH5A1 protein, human
  • Succinate-Semialdehyde Dehydrogenase
  • succinic semialdehyde

Supplementary concepts

  • succinic semialdehyde dehydrogenase deficiency