Conflict of interest: None
A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family
Article first published online: 4 JUL 2013
Copyright © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 8, pages 1915–1922, August 2013
How to Cite
2013. A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family. Am J Med Genet Part A. 161A:1915–1922., , , , , , , , , , , .
- Issue published online: 24 JUL 2013
- Article first published online: 4 JUL 2013
- Manuscript Accepted: 15 APR 2013
- Manuscript Received: 18 JUL 2012
- Iranian National Science Foundation and the Max Planck Innovation Fund
- SSADH deficiency;
- intellectual disability;
- autosomal recessive
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a disorder of the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA) with a very variable clinical phenotype ranging from mild intellectual disability to severe neurological defects. We report here on a large Iranian family with four affected patients presenting with severe intellectual disability, developmental delay and generalized tonic–clonic seizures. Molecular genetic analysis revealed a missense mutation c.901A>G (p.K301E, RefSeq number NM_001080) in ALDH5A1 co-segregating with the disease in the family. The missense mutation affects an amino acid residue that is highly conserved across the animal kingdom. Protein modeling showed that p.K301E most likely leads to a loss of NAD+ binding and a predicted decrease in the free energy by 6.67 kcal/mol furthermore suggests a severe destabilization of the protein. In line with these in silico observations, no SSADH enzyme activity could be detected in patient lymphoblasts. © 2013 Wiley Periodicals, Inc.