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

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.

Keywords: ALDH7A1; PDE; alpha aminoadipic semialdehyde; pyridoxine dependent epilepsy.

Conflict of interest statement

A competing interest statement: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.

© 2018 SSIEM.

Figures

Figure 1:. AASADH activity of ALDH7A1 variants

The human ALDH7A1 open reading frame was cloned into an E.coli-based expression vector. The enzyme activity of 10 expressed variants is shown for α-AASA dehydrogenase activity as reduction of NAD (dotted bar) and as AAA production (lined bar), each represented as % of the wild type, with standard deviation provided. The variants expressed included negative and positive controls (Controls), variants previously reported in the literature (Previously Reported), variants identified in subjects within this report (This report), rare variants identified in gnomAD and predicted to be pathogenic (Predicted Deleterious) and rare variants identified in gnomAD and not predicted to be pathogenic (Not Predicted Deleterious).

Figure 2:. ALDH7A1 pathogenic variants

The ALDH7A1 gene is represented as a schematic with exons to scale and introns at 1/10th scale. Placement of predicted protein changes are denoted by solid black line. CNVs are denoted by rectangular boxes.