Response to Stove and colleagues concerning newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency in dried blood spots

Abstract

Reply: We appreciate the interest in our report on newborn screening for succinic semialdehyde dehydrogenase (SSADH) deficiency by Drs. Stove, Ingels, and Lambert [1]. We are also grateful for their highlighting of excellent GCMS methods for determining gamma-hydroxybutyric acid (GHB) in dried blood spots (DBS) for use in toxicology or forensics [2,3]. Our method was developed to screen DBS of newborns for the very high elevations of GHB found in the blood of patients with the inherited disorder, SSADH deficiency [4]. It utilized LC-MS/MS which is currently available in most newborn screening laboratories. Our method was not intended for toxicology use, or for the accurate determination of low endogenous levels in DBS of newborns not affected with SSADH deficiency. Nevertheless it does permit establishing a screening cut-off for GHB above which a deficiency of SSADH is likely. As with most newborn screening tests, elevations of GHB in DBS above the cut-off would need to be followed up with diagnostic tests to determine the final diagnosis, which could include accurate tests for GHB levels in blood or urine, urine organic acid analysis for GHB levels in biochemical genetics laboratories, or sequencing DNA for mutations in the ALDH5A1 gene. With this report our goal was to demonstrate the feasibility of this approach, the manuscript was not intended as a detailed method development and/or validation paper; accordingly, only a brief description of the validation was summarized in the results. The letter to the editor correctly points out that the GHB concentrations were μM, which was an oversight on our part. We believe our report is an important contribution to the prospect of widespread newborn screening for SSADH deficiency, for which potential specific therapy is currently in clinical trials.