Abstract
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.
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Acknowledgements
The authors thank Dr. Coulter-Mackie and colleagues for providing the ALDH7A1 gene construct in a pET15b expression vector, colleagues in the International PDE Consortium and Ms. Aisha Ghani and Mr. Sravan Jaggumantri for management of the PDE patient registry. We are grateful for the support of the ‘Rare Diseases Foundation’ in Vancouver, and the US-based patient organization: ‘Pyridoxine Dependent Epilepsy Foundation.’ This work was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR001082 and the research endowments of the Division of Neurology, Seattle Children’s Hospital. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views.
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This work was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR001082 and the research endowments of the Division of Neurology, Seattle Children’s Hospital.
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C. Coughlin II, M.A. Swanson, E. Spector, NJL Meeks, KE Kronquist, M Aslamy, MF Wempe, CDM van Karnebeek, SM Gospe Jr., VG Aziz, PL Nagy, K Hyland, SJM van Dooren, GS Salomons and JLK Van Hove declare that they have no conflict of interest. H Gao and B Tsai are both employees and stockholders of Fulgent Genetics, a DNA sequencing laboratory. There is no apparent financial gain or loss expected as a result of this study.
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Communicated by: John Christodoulou
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Suppl. Fig. 1:
Frequency of ALDH7A1 variants. Legend: Pathogenic variants from 185 subjects are presented by mutation type and frequency. All variants are reported by predicted protein consequence and frequency is represented as percentage of all disease alleles. (PNG 464 kb)
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Coughlin, C.R., Swanson, M.A., Spector, E. et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis (2018). https://doi.org/10.1007/s10545-018-0219-7
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DOI: https://doi.org/10.1007/s10545-018-0219-7