Abstracts

Rationale: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic condition that results in impaired GABA catabolism. This leads to excess synaptic GABA, downregulation of postsynaptic GABA-A and GABA-B receptors, and epilepsy in approximately 50% of patients. Biomarkers that measure cortical excitability and GABAergic tone in SSADHD are thus highly desirable. We measured cortical excitation:inhibition ratio by transcranial magnetic stimulation (TMS) as a step toward developing physiologic biomarkers that may be used as measures of target engagement in future SSADHD treatments.

Methods: In this single-center observational study, 19 patients with SSADHD and 15 healthy sibling controls underwent motor cortex TMS. Resting motor threshold (rMT) and long interval intracortical inhibition (LICI) were measured in both groups by motor evoked potential (MEP) recording from the right abductor pollicis brevis (ABP) muscle.

Results: TMS was tolerated by all participants (N=19). TMS was not associated with any seizures during data collection. rMT was successfully measured in all 19 patients and LICI was measured in 17/19. rMT decreased with age in all patients with SSADHD at the same rate as in healthy participants, with declining values until age ~14 years, and steady values thereafter. Test-retest reliability for MT measures was calculated for the 15 patients who had been followed for two years. This revealed a significantly higher absolute change in %MO used from one test to the next in patients younger than 14 years of age (t-test p=0.03) Patients with SSADHD without epilepsy (N=9) had a higher rMT than healthy controls (N=15; t-test p=0.001), and patients with SSADHD who also had epilepsy (N=10) trended strongly toward a higher rMT (t-test p=0.06). The LICI ratio revealed paradoxical MEP facilitation in the patients with SSADHD (9/17 Chi sq p=0.03), and such facilitation was more likely in patients with SSADHD with epilepsy (6/9; chi sq relative to control p=0.02) than patients with SSADHD without epilepsy (3/8; Chi sq p=0.12).

Conclusions: We find abnormal corticospinal tract (CST) physiology in SSADHD, though with preserved developmental trajectory for CST maturation. Facilitation with a LICI protocol indicates GABAergic circuit dysfunction and raises the potential of a qualitative TMS-derived biomarker of target engagement by future SSADHD treatments.

Funding: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number: R01HD091142. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.