Pathophysiology of Epilepsy in Inherited Metabolic Disorders of GABA Metabolism
Itay Tokatly Latzer1, Melissa DiBacco1, Thomas Opladen2, Kathrin Jeltsch3, Angels Garcia-Cazorla4, Deniz Aygun1, Alexander Rotenberg1, Jean-Baptiste Roullet5, Michael Gibson5, Phillip Pearl1
1Department of Neurology, Boston Children's Hospital, 2Division of Inborn Metabolic Diseases, University Children’s Hospital Heidelberg, 3Department of Pediatrics I, University Children's Hospital Heidelberg, 4Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, 5Department of Pharmacotherapy, Washington State University
Objective:
To investigate the excitatory and inhibitory components associated with epilepsy in inherited metabolic disorders of γ-aminobutyrate (GABA) metabolism.
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.
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 GABAA and GABAB receptors 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.