Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of ɣ-aminobutyrate (GABA) catabolism. Despite the resultant hyperGABAergic 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/NAA 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=0.001) and lower levels of GABA (p=0.002), γ-hydroxybutyrate (GHB) (p=0.004), and γ-guanidinobutyrate (GBA) (p=0.003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (rMT) (p=0.04). The cut-off values with the highest discriminative ability to predict seizures were age >9.2 years (p=0.001), GABA<2.57μM/L (p=0.002), GHB<143.6 (p=0.004), and GBA<0.075 (p=0.007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age, lower plasma GABA, GHB, and GBA (area under the ROC of 0.798, p=0.008). 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 hyperGABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

The presence and severity of epilepsy coincide with reduced GABA and cortical excitatory markers in SSADH deficiency

Bertoldi, Mariarita;
2023-01-01

Abstract

Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of ɣ-aminobutyrate (GABA) catabolism. Despite the resultant hyperGABAergic 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/NAA 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=0.001) and lower levels of GABA (p=0.002), γ-hydroxybutyrate (GHB) (p=0.004), and γ-guanidinobutyrate (GBA) (p=0.003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (rMT) (p=0.04). The cut-off values with the highest discriminative ability to predict seizures were age >9.2 years (p=0.001), GABA<2.57μM/L (p=0.002), GHB<143.6 (p=0.004), and GBA<0.075 (p=0.007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age, lower plasma GABA, GHB, and GBA (area under the ROC of 0.798, p=0.008). 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 hyperGABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.
2023
Epileptogenesis
Excitation
Inhibition
Pathomechanism
Seizures
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1089729
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