Submission Details

Autosomal recessive

02/13/2019

The ALDH7A1 gene is located on chromosome 5 at 5q23.2 and encodes the aldehyde dehydrogenase 7 family member A1 protein. This enzyme plays a key role in lysine metabolism and may indirectly regulate inhibitory neurotransmission in the brain by affecting pyridoxal 5’-phosphate-dependent synthesis. The ALDH7A1 gene was first reported in relation to autosomal recessive pyridoxine-dependent epilepsy in 2006 (16491085: Mills et al. 2006). Evidence supporting this gene-disease relationship includes case level data and experimental data. From a selection of the literature, at least eight variants, including missense, splicing, stop-gained, and one synonymous with a splicing effect, have been reported in either a homozygous or compound heterozygous state in seven individuals with pyridoxine dependent epilepsy (16491085 Mills et al. 2006; 17721876: Salomons et al. 2007). Considerably more case-level evidence is available in the literature (30043187: Coughlin et al. 2018), but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of disease is homozygous loss of function; missense variants demonstrate an absent or reduced recombinant enzyme activity (22784480: Coulter-Mackie et al. 2012). A zebrafish Aldh7A1 knock out model recapitulates the biochemical deficiency, seizure phenotype, and mechanism of disease, as well as amelioration of disease features with pyridoxine treatment (29061647: Pena et al. 2017). In summary, the ALDH7A1 gene is definitively associated with autosomal recessive pyridoxine dependent epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

16491085 17721876 22784480 29061647