Human succinic semialdehyde dehydrogenase (SSADH;aldehyde dehydrogenase 5a1 (Aldh5a1)) deficiency is a rare neurogenetic disorder affecting the GABA neurotransmitter system. Aldh5a1-/- mice manifest early absence seizures which evolve into lethal generalized convulsive epilepsy, similar to seizure phenotypes observed in the human disease. The investigators'long-term goals are to define an effective treatment strategy for patients and springboard that treatment into expanded newborn screening for SSADH deficiency. The investigators will work toward these goals via the following hypotheses and aims: Hypothesis 1 is that chronic application of SGS-742, an orally active GABAB receptor (GABABR) antagonist, to Aldh5a1-/- mice will prevent early lethality and normalize neuropharmacological abnormalities.
Specific Aim 1 will characterize anthropormorphics, neuropharmacology, seizure threshold, and GABABR structure in Aldh5a1-/- mice treated with SGS-742. Hypothesis 2 is that SGS-742 intervention in adult SSADH-deficient patients will improve neuropsychological deficits and restore GABABR function downregulated by chronic exposure to supraphysiological GABA levels.
Specific Aim 2 will be a pilot trial of SGS-742 in six adult SSADH-deficient patients using neuropsychiatric evaluations and transcranial magnetic stimulation (TMS;estimating GABABR function) as outcome measures. Hypothesis 3 is that guanidinobutyrate (GB), a GABA analogue elevated in SSADH-deficient physiological fluids, represents a reliable biomarker to identify SSADH deficiency in newborn bloodspots.
Specific Aim 3 implements a pilot evaluation of newborn screening for SSADH deficiency that will establish normative ranges and sensitivity/specificity correlations. The design is cohort-control except for Aim 2, where each patient will serve as their own control. Accepted methodology is applied throughout (neuropharmacology, tandem mass spectrometry, neuropsychological batteries), although the use of noninvasive TMS in this disorder is novel.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD058553-06
Application #
8390456
Study Section
Special Emphasis Panel (ZHD1-MRG-C (07))
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2013
Total Cost
$259,430
Indirect Cost
$37,659
Name
Washington State University
Department
Type
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Vogel, Kara R; Kennedy, Andrew A; Whitehouse, Luke A et al. (2014) Therapeutic hepatocyte transplant for inherited metabolic disorders: functional considerations, recent outcomes and future prospects. J Inherit Metab Dis 37:165-76
Vogel, Kara R; Arning, Erland; Wasek, Brandi L et al. (2014) Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease. Orphanet J Rare Dis 9:73
Lakhani, Ronak; Vogel, Kara R; Till, Andreas et al. (2014) Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition. EMBO Mol Med 6:551-66
Forni, Sabrina; Pearl, Phillip L; Gibson, K Michael et al. (2013) Quantitation of gamma-hydroxybutyric acid in dried blood spots: feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency. Mol Genet Metab 109:255-9
Skvorak, Kristen J; Dorko, Kenneth; Marongiu, Fabio et al. (2013) Placental stem cell correction of murine intermediate maple syrup urine disease. Hepatology 57:1017-23
Vogel, Kara R; Arning, Erland; Wasek, Brandi L et al. (2013) Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAHENU2 mice. J Inherit Metab Dis 36:513-23
Vogel, Kara R; Pearl, Phillip L; Theodore, William H et al. (2013) Thirty years beyond discovery--clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. J Inherit Metab Dis 36:401-10
Siggberg, Linda; Mustonen, Aki; Schuit, Robert et al. (2011) Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity. Am J Med Genet B Neuropsychiatr Genet 156B:448-53
Errington, Adam C; Gibson, K Michael; Crunelli, Vincenzo et al. (2011) Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice. PLoS One 6:e19021
Kim, Kyung-Jin; Pearl, Phillip L; Jensen, Kimmo et al. (2011) Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance. Antioxid Redox Signal 15:691-718

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