Novel <i>ALDH5A1</i> variants and genotype: Phenotype correlation in SSADH deficiency.

Abstract

To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency. <i>ALDH5A1</i> variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study. Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 <i>ALDH5A1</i> variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (<i>p</i> = 0.003) and severity (<i>p</i> = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (<i>p</i> = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype. Seven novel pathogenic and one previously unpublished benign <i>ALDH5A1</i> variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.