Journal of Inherited Metabolic Disease

, Volume 33, Issue 5, pp 571–581 | Cite as

The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1

  • Gunter Scharer
  • Chad Brocker
  • Vasilis Vasiliou
  • Geralyn Creadon-Swindell
  • Renata C. Gallagher
  • Elaine Spector
  • Johan L. K. Van Hove
Rapid Communication


Pyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of α-aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyridoxal-phosphate, explaining the effective treatment with pyridoxine. We report the clinical phenotype of three patients, their mutations and those of 12 additional patients identified in our clinical molecular laboratory. There were six missense, one nonsense, and five splice-site mutations, and two small deletions. Mutations c.1217_1218delAT, I431F, IVS-1(+2)T > G, IVS-2(+1)G > A, and IVS-12(+1)G > A are novel. Some disease alleles were recurring: E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). A systematic review of mutations from the literature indicates that missense mutations cluster around exons 14, 15, and 16. Nine mutations represent 61% of alleles. Molecular modeling of missense mutations allows classification into three groups: those that affect NAD+ binding or catalysis, those that affect the substrate binding site, and those that affect multimerization. There are three clinical phenotypes: patients with complete seizure control with pyridoxine and normal developmental outcome (group 1) including our first patient; patients with complete seizure control with pyridoxine but with developmental delay (group 2), including our other two patients; and patients with persistent seizures despite pyridoxine treatment and with developmental delay (group 3). There is preliminary evidence for a genotype-phenotype correlation with patients from group 1 having mutations with residual activity. There is evidence from patients with similar genotypes for nongenetic factors contributing to the phenotypic spectrum.


Missense Mutation Pyridoxine Splice Mutation Pipecolic Acid Cofactor Binding Site 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Dr. Philip Reigan at the University of Colorado Denver School of Pharmacy Computational Chemistry and Biology Core for help with molecular modeling and simulations, and David Banjavic for technical support on mutation analysis. Financial support: This work was supported by National Institutes of Health grants (R01 EY011490-13 and R01 EY017963-04). The authors confirm independence from the sponsor; the content of the article has not been influenced by the sponsor.


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Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Gunter Scharer
    • 1
  • Chad Brocker
    • 2
  • Vasilis Vasiliou
    • 2
  • Geralyn Creadon-Swindell
    • 1
  • Renata C. Gallagher
    • 1
  • Elaine Spector
    • 1
  • Johan L. K. Van Hove
    • 1
    • 3
  1. 1.Section of Clinical Genetics and Metabolism, Department of PediatricsUniversity of Colorado DenverAuroraUSA
  2. 2.Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical SciencesUniversity of Colorado DenverAuroraUSA
  3. 3.Section of Clinical Genetics and Metabolism, Department of PediatricsUniversity of Colorado DenverAuroraUSA

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