Clinical features and ALDH5A1 gene findings in 13 Chinese cases with succinic semialdehyde dehydrogenase deficiency

Abstract

Background and aims: To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency.

Materials and methods: This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023.

Results: Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction.

Conclusions: A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.

Keywords: ALDH5A1 gene; 4-hydroxybutyric acid; Novel variants; Succinic semialdehyde dehydrogenase deficiency; Γ-aminobutyric acid.

Fig. 1

Brain MRI of Patient 4 (10 months old) showed symmetric T2 and T2-FLAIR long abnormal signals in both sides of the pallidus (A, B, C, the white arrow) and cerebellar hemispheres (D, E, F, the white arrow)

Fig. 2

Exon and domain structure of ALDH5A1, and localization of ALDH5A1 variants in this study. The human ALDH5A1 gene exhibits 535 amino acids. The orange box shows the exons, joined by the dark blue lines representing introns. Colored blocks refer to the protein domains as indicated. Dashed lines connect the reported disease-causing variants with the respective exons and protein domains. The variants identified in our study are shown in red color