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The presence and severity of epilepsy coincide with reduced γ‐aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.

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Title: The presence and severity of epilepsy coincide with reduced γ‐aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.
Authors: Tokatly Latzer, Itay (AUTHOR), Bertoldi, Mariarita (AUTHOR), DiBacco, Melissa L. (AUTHOR), Arning, Erland (AUTHOR), Tsuboyama, Melissa (AUTHOR), MacMullin, Paul (AUTHOR), Sachee, Daniyal (AUTHOR), Rotenberg, Alexander (AUTHOR), Lee, Henry H. C. (AUTHOR), Aygun, Deniz (AUTHOR), Opladen, Thomas (AUTHOR), Jeltsch, Kathrin (AUTHOR), García‐Cazorla, Àngels (AUTHOR), Roullet, Jean‐Baptiste (AUTHOR), Gibson, K. Michael (AUTHOR), Pearl, Phillip L. (AUTHOR)
Source: Epilepsia (Series 4). Jun2023, Vol. 64 Issue 6, p1516-1526. 11p.
Subjects: Epilepsy, Succinate dehydrogenase, Nuclear magnetic resonance spectroscopy, Receiver operating characteristic curves, Transcranial magnetic stimulation
Abstract: 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. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: The presence and severity of epilepsy coincide with reduced γ‐aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.
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  Data: &lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Tokatly&#160;Latzer%2C+Itay%22&quot;&gt;Tokatly&#160;Latzer, Itay&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Bertoldi%2C+Mariarita%22&quot;&gt;Bertoldi, Mariarita&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22DiBacco%2C+Melissa+L%2E%22&quot;&gt;DiBacco, Melissa L.&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Arning%2C+Erland%22&quot;&gt;Arning, Erland&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Tsuboyama%2C+Melissa%22&quot;&gt;Tsuboyama, Melissa&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22MacMullin%2C+Paul%22&quot;&gt;MacMullin, Paul&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Sachee%2C+Daniyal%22&quot;&gt;Sachee, Daniyal&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Rotenberg%2C+Alexander%22&quot;&gt;Rotenberg, Alexander&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Lee%2C+Henry+H%2E+C%2E%22&quot;&gt;Lee, Henry H. C.&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Aygun%2C+Deniz%22&quot;&gt;Aygun, Deniz&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Opladen%2C+Thomas%22&quot;&gt;Opladen, Thomas&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Jeltsch%2C+Kathrin%22&quot;&gt;Jeltsch, Kathrin&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Garc&#237;a‐Cazorla%2C+&#192;ngels%22&quot;&gt;Garc&#237;a‐Cazorla, &#192;ngels&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Roullet%2C+Jean‐Baptiste%22&quot;&gt;Roullet, Jean‐Baptiste&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Gibson%2C+K%2E+Michael%22&quot;&gt;Gibson, K. Michael&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Pearl%2C+Phillip+L%2E%22&quot;&gt;Pearl, Phillip L.&lt;/searchLink&gt; (AUTHOR)
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22Epilepsia+%28Series+4%29%22&quot;&gt;Epilepsia (Series 4)&lt;/searchLink&gt;. Jun2023, Vol. 64 Issue 6, p1516-1526. 11p.
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  Data: 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 &gt; 9.2 years (p =.001), GABA &lt; 2.57 μmol&#183;L−1 (p =.002), GHB &lt; 143.6 μmol&#183;L−1 (p =.004), and GBA &lt;.075 μmol&#183;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. [ABSTRACT FROM AUTHOR]
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  Data: &lt;i&gt;Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
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        Value: 10.1111/epi.17592
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        Text: English
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