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Aim: To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ‐aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. Method: In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. Results: Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months–18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = −0.67, p < 0.001) and γ‐hydroxybutyrate levels (r = −0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = −0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 μM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. Interpretation: ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA‐related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD. [ABSTRACT FROM AUTHOR]

Objective: To describe quantitative EEG (electroencephalography) suppression ratio in children with increased intracranial pressure comparing acute suppression ratio changes to imaging and/or examination findings. Methods: We retrospectively reviewed the suppression ratio from patients with neuroimaging and /or examination findings of increased intracranial pressure while on continuous EEG. The time of the first change in the suppression ratio was compared to the time of the first image and/or examination change confirming increased intracranial pressure. Results: Thirteen patients with a median age of 3.1 years(interquartile range 1.8-6.3) had a rise in the suppression ratio with median time from identification to acute neuroimaging or examination of increased intracranial pressure of 3.12 hours (interquartile range 2.2-33.5) after the first increase in the suppression ratio. Conclusions: Acute suppression ratio increase is seen prior to imaging and/or examination findings of increased intracranial pressure. With further study, the suppression ratio can be targeted with intracranial pressure–lowering agents to prevent morbidity and mortality associated with increased intracranial pressure. [ABSTRACT FROM AUTHOR]

Objective: Succinic Semialdehyde Dehydrogenase (SSADH) deficiency is a disorder of elevated gamma‐amino butyric acid (GABA) and gamma hydroxybutyric acid (GHB) and a complex neuropsychiatric profile. Adult reports suggest worsening epilepsy and high SUDEP risk. Methods: Subjects with confirmed SSADH deficiency were recruited into a longitudinal study. Plasma thyroid hormone and total GABA/GHB were quantified by standard clinical chemistry methodologies and mass spectrometry, respectively. Results: A total of 133 subjects with SSADH deficiency are enrolled in the registry; 49 participated in the longitudinal study. The age range of the population is 8 weeks to 63 years (median 7.75 year; 44% male). There is a significant difference in proportions among the age groups in subjects affected with hypotonia, compulsive behavior, sleep disturbances, and seizures. Epilepsy is present in 50% of the total population, and more prevalent in subjects 12 years and older (P = 0.001). The median age of onset for absence seizures was 2 years, and 12 years for generalized tonic‐clonic seizures (P < 0.01). The SUDEP rate in adults was 12% (4/33). There was a significant age‐dependent negative correlation between GABA and T3 levels. Interpretation: There is an age‐dependent association with worsening of epilepsy, behavioral disturbances including obsessive‐compulsive behavior, and sleep disturbances with age in SSADH deficiency. There is a high risk of SUDEP. We have observed more absence seizures in younger patients, compared to tonic‐clonic in the older cohort, which correlates with age‐related changes in GABA and GHB concentration and thyroid function, as well as the natural history of seizures in the murine model. [ABSTRACT FROM AUTHOR]

Introduction: To assess the alpha-delta ratio (ADR) as a biomarker for cerebral injury and stroke in pediatric extracorporeal membrane oxygenation (ECMO)., Methods: Retrospective study of children aged >44 weeks gestation to 21 years monitored with continuous electroencephalography during ECMO. The interhemispheric ADR difference between the left and right hemisphere was calculated per hour. A t -test was performed comparing the mean interhemispheric difference between controls and patients with cerebral injury at set intervals (i.e., 1, 3, 6, 9, 12, and 24 hours) from the start of continuous electroencephalography. Injury was established if confirmed by imaging on the same day as ECMO cannulation and acquired if confirmed the day after ECMO or later. Analysis of variance was performed to compare the mean interhemispheric difference in the ADR among control patients to those with early-acquired and late-acquired injury at 24 hours., Results: We included 49 patients with a median age of 3.4 years (interquartile range [1-10.4]), 47% (23/49) were male, and 73% (36/49) had cardiac arrest. Cerebrovascular injury was detected in 45% (22/49), with focal stroke in 82% (18/22). A significant difference was seen between control patients compared with cerebrovascular injury after 6 hours of continuous electroencephalography (0.016 vs. 0.042) (mean interhemispheric ADR difference) ( P = 0.03). Analysis of variance of control patients to early- and late-acquired injury at 24 hours showed a significant difference ( P = 0.03)., Conclusions: The ADR is a reliable metric to detect in-ECMO cerebral injury and stroke. Further study is needed to automate and assess this metric for real-time detection of stroke in ECMO., Competing Interests: M. L. DiBacco is now employed by Agios pharmaceuticals, however, was not employed by this company at the time of data collection or preparation of this manuscript. A. J. Sansevere receives royalties from Springer Publishing Company, LLC for: A. J. Sansevere, Harrar DB, eds. Atlas of pediatric and neonatal ICU EEG, New York: Demos Medical Publishing. Copyright Springer Publishing Company, LLC.; 2021. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessively inherited metabolic disorder of γ-aminobutyric acid catabolism manifested by intellectual disability, expressive aphasia, movement disorders, psychiatric ailments and epilepsy. Subjects with succinic semialdehyde dehydrogenase deficiency are characterized by elevated γ-aminobutyric acid and related metabolites, such as γ-guanidinobutyric acid, and an age-dependent downregulation of cerebral γ-aminobutyric acid receptors. These findings indicate impaired γ-aminobutyric acid and γ-aminobutyric acid sub-type A (GABA A ) receptor signalling as major factors underlying the pathophysiology of this neurometabolic disorder. We studied the cortical oscillation patterns and their relationship with γ-aminobutyric acid metabolism in 18 children affected by this condition and 10 healthy controls. Using high-density EEG, we recorded somatosensory cortical responses and resting-state activity. Using electrical source imaging, we estimated the relative power changes (compared with baseline) in both stimulus-evoked and stimulus-induced responses for physiologically relevant frequency bands and resting-state power. Stimulus-evoked oscillations are phase locked to the stimulus, whereas induced oscillations are not. Power changes for both evoked and induced responses as well as resting-state power were correlated with plasma γ-aminobutyric acid and γ-guanidinobutyric acid concentrations and with cortical γ-aminobutyric acid measured by proton magnetic resonance spectroscopy. Plasma γ-aminobutyric acid, γ-guanidinobutyric acid and cortical γ-aminobutyric acid were higher in patients than in controls ( P < 0.001 for both). Beta and gamma relative power were suppressed for evoked responses in patients versus controls ( P < 0.01). No group differences were observed for induced activity ( P > 0.05). The mean gamma frequency of evoked responses was lower in patients versus controls ( P = 0.002). Resting-state activity was suppressed in patients for theta ( P = 0.011) and gamma ( P < 0.001) bands. Evoked power changes were inversely correlated with plasma γ-aminobutyric acid and with γ-guanidinobutyric acid for beta ( P < 0.001) and gamma ( P < 0.001) bands. Similar relationships were observed between the evoked power changes and cortical γ-aminobutyric acid for all tested areas in the beta band ( P < 0.001) and for the posterior cingulate gyrus in the gamma band ( P < 0.001). We also observed a negative correlation between resting-state activity and plasma γ-aminobutyric acid and γ-guanidinobutyric acid for theta ( P < 0.001; P = 0.003), alpha ( P = 0.003; P = 0.02) and gamma ( P = 0.02; P = 0.01) bands. Our findings indicate that increased γ-aminobutyric acid concentration is associated with reduced sensory-evoked beta and gamma activity and impaired neuronal synchronization in patients with succinic semialdehyde dehydrogenase deficiency. This further elucidates the pathophysiology of this neurometabolic disorder and serves as a potential biomarker for therapeutic trials., Competing Interests: The authors report no competing interests., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

Objective: To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism., Methods: Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics., Results: A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 ( p = 0.001), worse overall clinical outcomes ( p = 0.008) and specifically more severe cognitive deficits ( p = 0.01), epilepsy ( p = 0.04) and psychiatric morbidity ( p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome ( p = 0.02) and adaptive skills ( p = 0.04)., Conclusions: The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders., Competing Interests: Competing Interests The authors I.T.L, J.B.R., M.B., S.C., M.L.D., E.A., T.O., K.J., À.G.C., N.J.P., K.M.G. have no relevant financial or non- financial interests to discolose. The authors A.R. and H.H.C.L. are co-founders and have equity in Galibra Neuroscience, Inc., which develops treatments for SSADH deficiency, including gene replacement therapy mentioned in this study. The authors A.R., H.C.C.L., and P.L.P. are inventors of a filed SSADH deficiency gene therapy patent.