Reader Response: Novel ALDH5A1 Variants and Genotype: Phenotype Correlation in SSADH Deficiency

In a recent article by DiBacco et al.,1 the authors reported novel pathologic ALDH5A1 variants in patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. The novel pathologic variants caused clinical phenotyping disease in the participants. In these patients, the neurologic and psychiatric disorders were induced by a dysfunction of the GABAergic system, induced by an increase in gamma hydroxybutyric acid (GHB) levels. In these phenotype correlations of patients with novel genotype SSADH deficiency, the authors found an overall correlation between age and severity of epilepsy and presence of obsessive-compulsive disorder (OCD). They elegantly illustrated that epilepsy and OCD were more significantly prevalent in the adolescent/adult than in pediatric participants. This observation could derive from different expression of GHB receptors over the years.2 Furthermore, the GHB—involved in GABAergic and dopaminergic neurotransmissions2—could have an effect not only at the neuron level but also at the astrocyte level.2,3 Prolonged exposure to GHD caused an alteration of activity of astrocytes.3 Astroglial dysfunctions contribute to the pathogenesis of several neurologic and psychiatric disorders.4,5 These conditions—in particular an alteration of gliotransmission—could explain the different pathologic expressiveness of neuropsychiatric disorders over the years in these patients.