Abstracts

Rationale: SSADH deficiency is a metabolic epilepsy associated with chronically high endogenous GABA and GHB levels. Taurine intervention for SSADH is rational due to partial GABA(A&B) receptor agonist effects and rescue in the null mouse from status epilepticus and premature lethality. Methods: Subjects were titrated weekly from 50 to a target 200mg/kg/day, and assessed for safety, tolerability, and adaptive functioning using age-normalized ABAS scales. Selected individuals consented to additional outcome and biomarker studies utilizing neuropsychological testing, CSF metabolites and amino acids including free and total GABA levels, transcranial magnetic stimulation, and flumazenil-PET. Results: Twenty-five patients (14M/11F, age 0.5-33yrs, mean 11yrs) were recruited. Sixteen unique subjects (8M/8F) provided follow-up data (mean time elapsed 13mo); two re-enrolled after a 3-year hiatus. Adaptive domains remained unchanged with taurine (p=ns). Three subjects withdrew due to perceived lack of efficacy, and data from one was invalidated due to an error in administering the ABAS. One serious AE occurred (hospitalization for hypersomnia) on 16 grams/day (200mg/kg/day), leading to a dose-lowering paradigm with a maximum dose of 10 grams/D. Results did not show statistically significant improvement in the adaptive domains (p>0.18). Eight patients (6M/2F; age range 12-33 yrs) enrolled into the biomarker arm; preliminary neuropsychological results indicate baseline average Full Scale IQ (Wechsler Nonverbal Scale of Ability) of 44.1 (range 34-55), 3.6 SD < mean. Of 6 who returned at 6-month follow-up, 5 completed testing (3M/2F) on therapy; average FS IQ = 43.4 (range 33-51), an insignificant difference. CSF biomarkers were (n=4 subjects): taurine: 9 1 M SEM); 26 6 (n=4, p<0.05 off/on): free GABA (ref range, 32-170 nM): 394 88; 403 62 (p=ns, off/on): total GABA (ref range 3.3-12.1 M): 14.3 1; 14.9 2.4 (p=ns, off/on). CSF -alanine and carnosine (histidine: -alanine dipeptide) were increased (10-30; nl, undetected). Conclusions: Feasibility and safety of a clinical trial of taurine in SSADH deficiency were demonstrated. CSF indicated compliance with therapy and no change in free or total GABA levels on therapy. Adaptive behavior did not improve with taurine. CSF amino acid data support the concept that GABA and -alanine share identical transamination reactions. This study provides the first report of formal IQ scores in a series of SSADH patients and baseline biomarker data for upcoming trials of novel therapeutics including the GABA