Abstract Details

Title Pathophysiology of Epilepsy in Inherited Metabolic Disorders of GABA Metabolism

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S35 - Epilepsy/Clinical Neurophysiology (EEG): Clinical Epilepsy (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Background The pathologic cerebral accumulation of GABA in GABA transaminase deficiency (GABATD) and Succinic semialdehyde dehydrogenase deficiency (SSADHD), and of GHB in SSADHD, results in a broad spectrum of encephalopathic manifestations, including seizures.

Objective To investigate the excitatory and inhibitory components associated with epilepsy in inherited metabolic disorders of γ-aminobutyrate (GABA) metabolism.

Design/Methods This was a prospective multinational, 5-year longitudinal study of individuals with two rare disorders of GABA metabolism: SSADHD and GABATD. GABA-related neurotransmission was evaluated by electroencephalography, magnetic resonance imaging and spectroscopy (MRI/MRS), transcranial magnetic stimulation (TMS), and serum measurements of GABA, GHB, guanidinobutyrate (GBA), glutamate, and related metabolites.

Results

A total of 106 participants were included; 61 individuals with SSADHD, 3 with GABATD, and 42 healthy controls. Epilepsy was significantly more common with age (p=.001), and lower plasma [GABA] (p=.002), [GBA] (p=.003), and [GHB] (p=.02), and drug-resistant epilepsy was significantly associated with lower plasma [GABA] (p=.002) and [GHB] (p=.003) levels. Decreased resting motor threshold (rMT) on TMS correlated with [GABA] (R = .343, p=.05) and [GHB] (R = .518, p=.01). The decline in GABA, GHB, and TMS measured rMT were inversely correlated with age [(R = -0.714, p = <.001), (R = -.768, p = <.001), (R = -.552, p = .003), respectively], reaching a plateau around 10-15 years of age.

Conclusions

The longitudinal decrease in inhibitory neurotransmitter levels, reflecting compensatory downregulation of GABA_A and GABA_Breceptors in response to chronic hyperGABAergic states, results in hyperexcitation and epileptogenesis. Knowledge of the age at which quantitative biochemical and neurophysiological GABA-related metrics decline may aid in determining the appropriate timing of enzyme replacement therapy and sheds light on the pathophysiology of epileptogenesis in hyperGABAergic states.

Authors/Disclosures
Itay Tokatly Latzer, MD (Boston Children's Hospital) PRESENTER	Dr. Tokatly Latzer has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Alexander Rotenberg, MD, PhD (Childrens Hospital)	Dr. Rotenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Rotenberg has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Clinical Neurophysiology. Dr. Rotenberg has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for multiple. Dr. Rotenberg has stock in PrevEp. Dr. Rotenberg has stock in Neuromotion Labs. The institution of Dr. Rotenberg has received research support from Encoded. The institution of Dr. Rotenberg has received research support from Roche. The institution of Dr. Rotenberg has received research support from Biomarin. The institution of Dr. Rotenberg has received research support from CRE Medical. The institution of Dr. Rotenberg has received research support from Neuroelectrics. The institution of Dr. Rotenberg has received research support from SSADH Foundation. The institution of Dr. Rotenberg has received research support from Loulou Foundation. Dr. Rotenberg has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
Phillip L. Pearl, MD, FAAN (Boston Children'S Hospital)	Dr. Pearl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Dr. Pearl has received publishing royalties from a publication relating to health care. Dr. Pearl has received publishing royalties from a publication relating to health care. Dr. Pearl has received publishing royalties from a publication relating to health care. Dr. Pearl has received publishing royalties from a publication relating to health care.