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.

Clinical and genetic features in pyridoxine‐dependent epilepsy: a Chinese cohort study

“…Among them, 15 ALDH7A1 variants and three PLPBP variants were unreported previously. In a review of the literature, p. E427Q was the most common mutation presenting in 26 per cent of all alleles . This ‘hot spots’ mutation accounted for only 5 per cent in our study, but p. Y516C (16%), IVS11+1G>A (15%), and p. Y345C (13%) had high frequency.…”

“…van Karnebeek et al focused on six cases with atypical manifestations among 266 cases reported in 49 articles. Coughlin et al reviewed the genetics of 185 cases from previous reports. Therefore, this study involved the largest cohort of patients with PDE in a single centre reported to date, with analysis of both clinical and genetic features.…”

Disorders affecting vitamin B6 metabolism

“…Coughlin et al 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 …”

“…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 . Two add‐on treatment options have been trialed in relatively small numbers of patients.…”

Structural and biochemical consequences of pyridoxine‐dependent epilepsy mutations that target the aldehyde binding site of aldehyde dehydrogenase ALDH7A1

“…Certain mutations in the ALDH7A1 gene cause pyridoxine‐dependent epilepsy (PDE), an autosomal recessive metabolic disease characterized by seizures and in some cases intellectual disability . The estimated carrier frequency of ALDH7A1 mutations is 1 : 127, and the estimated incidence of ALDH7A1 deficiency is 1 : 64 352 births . The molecular basis of PDE is a decrease in the ubiquitous enzyme cofactor pyridoxal 5′‐phosphate (PLP) caused by Knoevenagel condensation of PLP with Δ 1 ‐piperideine‐6‐carboxylic acid (P6C), the cyclized form of AASAL (Fig.…”