Abstracts

Rationale:
Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a rare autosomal recessive disorder due to pathogenic variants in ALDH5A1. Loss of function in SSADH results in reduced gamma-aminobutyric acid (GABA) catabolism, leading to elevated levels of GABA and gamma-hydroxybutyric acid (GHB). Preliminary animal work in the SSADH mutant model has suggested benefit from treatment with SGS-742 (3-aminopropyl-n-butyl phosphinic acid), a GABA-B receptor antagonist. We examined safety, tolerability, and efficacy of SGS-742 on the neuropsychological function and cortical excitability in a small group of patients with SSADH deficiency.
Method:
This was a single-center randomized, double-blind cross-over phase II clinical trial of SGS-742 versus placebo in patients with SSADH-D. SGS-742 was titrated up to the target dose of 10 mg/kg/dose (up to 600 mg) tid. Assessments were conducted at baseline, end of first treatment arm (phase 1), and end of second treatment arm (phase 2). Procedures included transcranial magnetic stimulation (TMS) and the Adaptive Behavior Assessment Scale (ABAS).
Results:
Nineteen subjects were consented and enrolled at the NIH. Mean age was 14.0 +/- 7.5 years at enrollment (range 5 to 34.5) and 11 (58%) were female. We did not find a significant effect of SGS-742 on the ABAS score (baseline-adjusted treatment effect = -0.69, p = 0.80), motor threshold (baseline-adjusted treatment effect = 1.22%, p = 0.47), and paired-pulse stimulation – baseline-adjusted treatment effect was -49.4% (p = 0.13) for short interval intracortical inhibition, -10.5% (p = 0.53) for intracortical facilitation, and -41.2% (p = 0.27) for long interval intracortical inhibition. The difference in recruitment curve slopes between treatment groups was 0.003 (p = 0.09). There was no relation of patient age to outcome; younger patients were not more likely to show improvement on active drug. Five patients had a well-documented history of seizures and were taking anti-seizure medications. Three of the five had seizures during the study; there was no difference in frequency or severity between active drug and placebo periods. Adverse effects were generally mild, requiring either no intervention, over-the-counter, or transient medical outpatient treatment.  There was no clinically significant difference in incidence of adverse effects between drug and placebo arms for any body system.
Conclusion:
The GABA-B receptor antagonist, SGS-742, failed to produce improved cognition and normalization of cortical excitability, as measured by the ABAS and TMS. Our data do not support the current use of SGS-742 in SSADH-D.
Funding:
:The monetary and logistical support of the SSADH Association for this study is gratefully acknowledged. Supported in part by R01 NS082286 (KMG), NINDS, NIH.