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

We thank Dr. Siniscalchi for his interest in our characterization of the phenotype of SSADH deficiency (SSADHD; ALDH5A1)1 and for highlighting the putative role of elevated gamma hydroxybutyric acid (GHB) in abnormal gliotransmission. In vivo exposure of the brain to GHB triggers intracellular calcium spikes, which has long-term impacts on astrocyte function and might contribute to the well-known epileptogenic activity of GHB.2 Other studies3—including our own—underscore the role of activated glial cells (reactive astrogliosis) and ensuing GABA-glutamine-glutamate cycle dysfunction in the phenotype of experimental ADLH5A1 deficiency (aldh5a1-deficient mice). Earlier studies in this model presented evidence for glial dysfunction and reduced glutamate/glutamine cycling.4 Recent studies using stable isotopes revealed that astrocytes extensively metabolize GABA for maintenance of glutamine.5 Metabolic analyses in multiple brain regions of an autopsied patient (age 37 years) with SSADHD verified not only highly elevated GABA and GHB, but strikingly low glutamine.6 As a short chain alcohol, elevated GHB in SSADHD may also affect astrocyte/oligodendrocyte function in a fashion analogous to that of ethanol, which can trigger seizures during withdrawal.7 Targeted knockout of aldh5a1 in mammalian astrocytes may provide additional insight into the role of GHB in astrocyte pathology in SSADHD.

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