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.
|Malaspina, P; Roullet, J-B; Pearl, P L et al. (2016) Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem Int 99:72-84|
|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|
|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|
|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. (2013) Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAHENU2 mice. J Inherit Metab Dis 36:513-23|
|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|
|Vogel, Kara R; Arning, Erland; Wasek, Brandi L et al. (2013) Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood-brain phenylalanine transport in Pah enu2 mice: preliminary findings. Mol Genet Metab 110 Suppl:S71-8|
|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|
|Goodwin, Amy K; Gibson, K Michael; Weerts, Elise M (2013) Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): time course and severity of withdrawal in baboons. Drug Alcohol Depend 132:427-33|
|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|
Showing the most recent 10 out of 29 publications