The presence and severity of epilepsy coincide with reduced ?-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency
Por:
Tokatly Latzer I, Bertoldi M, DiBacco ML, Arning E, Tsuboyama M, MacMullin P, Sachee D, Rotenberg A, Lee HHC, Aygun D, Opladen T, Jeltsch K, Garcia-Cazorla A, Roullet JB, Gibson KM and Pearl PL
Publicada:
1 jun 2023
Ahead of Print:
1 abr 2023
Resumen:
Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of gamma-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation.
Methods: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements.
Results: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), gamma-hydroxybutyrate (GHB; p = .004), and ?-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 mu mol.L-1 (p = .002), GHB < 143.6 mu mol.L-1 (p = .004), and GBA < .075 mu mol.L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008).
Significance: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.
Filiaciones:
Tokatly Latzer I:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
Bertoldi M:
Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Italy
DiBacco ML:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Arning E:
Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, Texas, USA
Tsuboyama M:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
MacMullin P:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Sachee D:
Harvard College, Harvard University, Cambridge, MA, 02138, USA
Rotenberg A:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA
Lee HHC:
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA
Rosamund Stone Zander Translational Neuroscience Center, Boston, Children's Hospital, MA, 02115, USA
Aygun D:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Opladen T:
Division of Neuropediatrics & Metabolic Medicine, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
Jeltsch K:
Division of Neuropediatrics & Metabolic Medicine, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
Garcia-Cazorla A:
Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain
Roullet JB:
Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
Gibson KM:
Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
Pearl PL:
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Green Submitted
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