Study ObjectivesSSADHD is an autosomal‐recessive disorder of GABA metabolism featuring a non‐specific neurological phenotype, which precludes clinical diagnosis. The latter is achieved through identification of elevated g‐hydroxybutyric acid (GHB) or GABA in patient physiological fluids and/or mutations in the ALDH5A1 (aldehyde dehydrogenase 5A1) gene encoding SSADH. Targeted therapeutics are lacking, as is an understanding of the natural history of the disorder. To further the latter, we continue the pursuit of novel biomarkers that might help guide natural history studies. Because BDNF (brain derived neurotrophic factor) and GABAergic signaling are closely linked (Brady, 2017) and there is evidence that miR‐29a regulates ALDH5A1 expression in vitro (Yu, 2015), we measured the expression of BDNF and miR‐29a genes in both human and murine SSADHD.MethodsRNA was isolated from patient, obligate heterozygote (parents) and control red blood cell (RBCs) (n=9), and from brain cortex samples obtained from wild‐type and SSADH‐deficient mice (Hogema, 2001). cDNA was synthesized employing miScript II RT Kits (Qiagen) and gene expression studies performed using pre‐validated miScript Sybr Green and QuantiTect Primer Assays (Qiagen). Data analysis employed the CT method with significance (t test) set to 0.05.ResultsIn patient samples, BDNF demonstrated a 4‐fold down‐regulation (p=0.0335) and miR29a a 5‐fold down‐regulation (p=0.0191). In SSADH‐deficient mouse cortex, BDNF was 6.4 (p=0.0446)‐fold down regulated and 8.5‐fold (p=0.0115) down‐regulated in heterozygous SSADH‐deficient mice. Similarly, miR29a was 2‐fold down regulated in SSADH‐deficient mice in comparison to wild‐type mice.Discussion/ConclusionThe established role of BDNF in neuropsychiatric disorders (e.g. depression, anxiety, epilepsy; Cataneo, 2016) suggest exciting new directions in understanding SSADHD pathogenesis, as well as novel treatment paradigms in the form of SSRI (selective serotonin reuptake inhibitors) (Li, 2017) known to target CNS BDNF levels. The potential in vivo molecular feedback between ALDH5A1 and miR29a may inform inter‐individual phenotypic heterogeneity in patients in relation to residual enzyme levels. Moreover, miR‐29a regulates multiple gene products (Slusarz, 2015), and thus may be a secondary contributor to SSADHD pathophysiology. We conclude that longitudinal evaluation of BDNF and miR29a in a natural history study of SSADHD may provide new insights into disease pathogenesis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.