TY - JOUR
T1 - The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency
AU - Tokatly Latzer, Itay
AU - Bertoldi, Mariarita
AU - DiBacco, Melissa L.
AU - Arning, Erland
AU - Tsuboyama, Melissa
AU - MacMullin, Paul
AU - Sachee, Daniyal
AU - Rotenberg, Alexander
AU - Lee, Henry H.C.
AU - Aygun, Deniz
AU - Opladen, Thomas
AU - Jeltsch, Kathrin
AU - García-Cazorla, Àngels
AU - Roullet, Jean Baptiste
AU - Gibson, K. Michael
AU - Pearl, Phillip L.
N1 - Publisher Copyright:
© 2023 International League Against Epilepsy.
PY - 2023/6
Y1 - 2023/6
N2 - Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-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), γ-hydroxybutyrate (GHB; p =.004), and γ-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 μmol·L−1 (p =.002), GHB < 143.6 μmol·L−1 (p =.004), and GBA <.075 μmol·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.
AB - Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-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), γ-hydroxybutyrate (GHB; p =.004), and γ-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 μmol·L−1 (p =.002), GHB < 143.6 μmol·L−1 (p =.004), and GBA <.075 μmol·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.
KW - epileptogenesis
KW - excitation
KW - inhibition
KW - pathomechanism
KW - seizures
UR - http://www.scopus.com/inward/record.url?scp=85151999731&partnerID=8YFLogxK
U2 - 10.1111/epi.17592
DO - 10.1111/epi.17592
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C2 - 36961285
AN - SCOPUS:85151999731
SN - 0013-9580
VL - 64
SP - 1516
EP - 1526
JO - Epilepsia
JF - Epilepsia
IS - 6
ER -