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J Inherit Metab Dis. 2019 Mar;42(2):353-361. doi: 10.1002/jimd.12045. Epub 2019 Feb 22.

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy.

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Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Molecular Genetics Laboratory, Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, Colorado, 80045, USA.
School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Department of Pediatrics and Clinical Genetics, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands.
Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z4H4, Canada.
Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington, Seattle, Washington, USA.
Seattle Children's Research Institute, Seattle, Washington, USA.
Fulgent Genetics, Temple City, California, 91780, USA.
Medical Neurogenetics Laboratories, LLC, Atlanta, Georgia, USA.
Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center & Amsterdam Neuroscience, Amsterdam, The Netherlands.


Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over-expressed in an E.coli-based expression system to measure α-aminoadipic semialdehyde dehydrogenase activity and production of α-aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.


ALDH7A1; PDE; alpha aminoadipic semialdehyde; pyridoxine dependent epilepsy

[Available on 2020-03-01]

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