Dissertation
Metabolomic approaches to the detection and treatment of succinic semialdehyde dehydrogenase deficiency, a heritable disorder of GABA catabolism
Doctor of Philosophy (PhD), Washington State University
01/2020
Handle:
https://hdl.handle.net/2376/110926
Abstract
Patients with succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD) manifest extensive neurological morbidity, including developmental delays, movement and speech disorders, neurobehavioral abnormalities, and variable epilepsy, all associated with various mutations in the ALDH5A1 (aldehyde dehydrogenase 5A1=SSADH) gene, which ablate SSADH enzyme activity. The biochemical hallmarks include accumulation of GABA (-aminobutyric acid; the major inhibitory neurotransmitter) and the GABA derivative -hydroxybutyrate (GHB; a neuromodulator with undefined pharmacological effects) in physiological fluids. Neither GABA nor GHB measurements are currently included in newborn screening (NBS) panels. Hence, SSADHD is not screened for at birth, leading to delayed diagnosis and treatment. A novel screening approach was investigated and tested using archival dried newborn bloodspots (DBS). Such screening relies on the comprehensive analysis of amino acid, acylcarnitine and guanidino- species (guanidinoacetic acid, creatine, creatinine) concentrations provided by routine NBS protocols. These investigations revealed SSADHD patients display a unique metabolic profile consisting of low ornithine, short-chain acylcarnitines, and creatine, a profile found similarly in the murine model of the disease, aldh5a1-/- mouse. Such biosignature holds promise as a 1st tier screening method for SSADHD. To corroborate positive 1st tier screens, a 2nd tier screen was developed and validated, demonstrating that GHB content in the same archival newborn DBS from patients exceeded the GHB cutoff value in control DBS established previously, predicating significant translational impact for the accurate identification of SSADHD in newborns. This GHB methodology was used to identify SSADHD in a patient concomitantly affected with Rett syndrome, a separate heritable neurologic disorder, confirming the diagnostic utility of the DBS GHB methodology. Lastly, previously identified glutamine deficiency in both patients and the animal model prompted investigations of the potential for phenotypic rescue using dietary glutamine supplementation. Comprehensive studies were performed with 4% glutamine-enriched diet in the aldh5a1-/- mouse with a focus on disease-specific molecular, metabolic and cellular markers. Although rescue was not achieved, results of glutamine supplementation yielded new insight into glutamine cycling in SSADHD. In sum, this translational research significantly improved our understanding of SSADHD pathogenesis while highlighting the complexity of validating disease-identification methods suitable for newborn screening and the challenge to develop novel effective therapies.
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Details
- Title
- Metabolomic approaches to the detection and treatment of succinic semialdehyde dehydrogenase deficiency, a heritable disorder of GABA catabolism
- Creators
- Madalyn Brown
- Contributors
- K. Michael Gibson (Advisor)Jean-Baptiste Roullet (Committee Member)Shobhan Gaddameedhi (Committee Member)Senthil Natesan (Committee Member)Nancy Potter (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 163
- Identifiers
- 99900581500201842
- Language
- English
- Resource Type
- Dissertation