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.

Structural analysis of pathogenic mutations targeting Glu427 of ALDH7A1, the hot spot residue of pyridoxine‐dependent epilepsy

“…The three ALDH7A1 Glu427 variants studied display negligible catalytic activity, consistent with clinical studies implicating them in the pathology of PDE . We note that PDE patients who are biallelic for E427Q generally experience relatively early disease onset, which is consistent with the lack of activity of this mutant …”

Disorders affecting vitamin B6 metabolism

“…Serine racemase, a PLP-dependent enzyme, is involved in neuronal migration. 73 Coughlin et al 74 have recently published a comprehensive overview of 165 known ALDH7A1 pathogenic variants which includes the genotypes of 185 individuals. It is estimated that the carrier frequency of ALDH7A1 mutations is 1:127 and that the estimated incidence of ALDH7A1 deficiency is 1:64 352 live births.…”

“…It is estimated that the carrier frequency of ALDH7A1 mutations is 1:127 and that the estimated incidence of ALDH7A1 deficiency is 1:64 352 live births. 74 Seizures of patients with ALDH7A1 deficiency are well controlled on pyridoxine monotherapy in about 90% of cases, however, at least 75% of children have intellectual disability (ID) and developmental delay (DD). The degree to which they have ID/DD does not correlate with treatment delay, pretreatment symptomatic interval, or duration taken to achieve seizure control.…”

“…The degree to which they have ID/DD does not correlate with treatment delay, pretreatment symptomatic interval, or duration taken to achieve seizure control. 74 Two add-on treatment options have been trialed in relatively small numbers of patients. The first approach is the lysine-restricted diet to lower potentially toxic AASA concentrations.…”

Identification of a novel biomarker for pyridoxine‐dependent epilepsy: Implications for newborn screening

“…Recent estimates suggest a disease incidence of approximately 1:60 000 live births . This is similar to other diseases that currently undergo newborn screening such as galactosemia (1:50 000 live births) and biotinidase deficiency (1:60 000 live births) .…”