Succinic Semialdehyde Dehydrogenase Deficiency Research Articles

Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests as hypotonia, autism, and epilepsy. SSADH deficiency patients usually have family-specific gene variants. Here, we describe a family exhibiting four different SSADH variants: Val90Ala, Cys93Phe, and His180Tyr/Asn255Asp (a double variant). We provide a structural and functional characterization of these variants and show that Cys93Phe and Asn255Asp are pathogenic variants that affect the stability of the SSADH protein. Due to the impairment of the cofactor NAD+ binding, these variants show a highly reduced enzyme activity. However, Val90Ala and His180Tyr exhibit normal activity and expression. The His180Tyr/Asn255Asp variant exhibits a highly reduced activity as a recombinant species, is inactive, and shows a very low expression in eukaryotic cells. A treatment with substances that support protein folding by either increasing chaperone protein expression or by chemical means did not increase the expression of the pathogenic variants of the SSADH deficiency patient. However, stabilization of the folding of pathogenic SSADH variants by other substances may provide a treatment option for this disease.

Generation and characterization of six human induced pluripotent stem cell lines (hiPSCs) from three individuals with SSADH Deficiency and CRISPR-corrected isogenic controls

Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) is an ultra-rare autosomal recessive neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. Here, we report the generation and characterization of human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of three unrelated SSADHD patients – one female and two males with the CRISPR-corrected isogenic controls. These individuals are clinically diagnosed and are being followed in a longitudinal clinical study.

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

Delays in latencies of median-nerve evoked magnetic fields in patients with succinic semialdehyde dehydrogenase deficiency

ObjectiveSuccinic semialdehyde dehydrogenase deficiency (SSADHD) is a genetic disorder resulting in abnormal regulation of γ-aminobutyric acid, lipid metabolism, and myelin biogenesis, leading to ataxia, seizures, and cognitive impairment. Since the myelin sheath is thinner in a murine model of SSADHD compared to a wild type, we hypothesized that this also holds for human brain. We tested whether the conduction velocity in the somatosensory pathway is accordingly delayed. MethodsSomatosensory evoked magnetic fields (SEF) produced by transcutaneous electrical stimulation of the median nerve were measured in 13 SSADHD patients, 11 healthy and 14 disease controls with focal epilepsy. The peak latencies of the initial four components (M1, M2, M3 and M4) were measured. ResultsThe SEF waveforms and scalp topographies were comparable across the groups. The latencies were statistically significantly longer in the SSADHD group compared to the two controls. We found these latencies for the SSADHD, healthy and disease controls respectively to be: M1: (21.9 ± 0.8 ms [mean ± standard error of the mean], 20.4 ± 0.6 ms, and 21.0 ± 0.4 ms) (p < 0.05); M2: (36.1 ± 1.0 ms, 33.1 ± 0.6 ms, and 32.1 ± 1.1 ms) (p < 0.005); M3: (62.5 ± 2.4 ms, 54.7 ± 2.0 ms, and 49.9 ± 1.8 ms) (p < 0.005); M4: (86.2 ± 2.3 ms, 78.8 ± 2.8 ms, and 73.5 ± 2.9 ms) (p < 0.005). ConclusionsThe SEF latencies are delayed in patients with SSADHD compared with healthy controls and disease controls. SignificanceThis is the first study that compares conduction velocities in the somatosensory pathway in SSADHD, an inherited disorder of GABA metabolism. The longer peak latency implying slower conduction velocity supports the hypothesis that myelin sheath thickness is decreased in SSADHD.

Inherited Pediatric Neurotransmitter Disorders: Case Studies and Long-Term Outcomes

AbstractPrimary pediatric neurotransmitter disorders include genetic defects of neurotransmitter metabolism that may mimic common neurological conditions in children. Our objective was to evaluate the clinical experience and outcomes of affected patients. Five patients with primary neurotransmitter defects were identified in the neurometabolic database between 2004 and 2022. Two patients with 6-pyruvoyltetrahydropterin synthase deficiency and one with pyridoxine-dependent epilepsy (PDE) presented in the neonatal period. One patient with succinic semialdehyde dehydrogenase (SSADH) deficiency and one with aromatic l-amino acid decarboxylase (AADC) deficiency presented in later life. A diagnosis of cerebral palsy was revised following biochemical confirmation of SSADH deficiency. AADC deficiency was confirmed via exome sequencing and reduced activity on enzyme assay. Late diagnosis in the latter two cases was likely due to a low index of suspicion and lack of access to diagnostic tests in the country of origin. In two children with tetrahydrobiopterin deficiency, newborn screening results and atypical clinical features prompted investigations. An early diagnosis of PDE was established based on presenting features, a high index of suspicion, the presence of an identifiable biochemical marker and molecular genetic testing. Pediatric neurotransmitter disorders can be diagnosed based on a high clinical index of suspicion, availability of biochemical markers, and molecular genetic testing. These disorders, though rare, need to be included in the differential diagnosis of common neurological presentations in children as they may be potentially treatable. Outcomes and influencing factors in the present series are discussed in comparison to published data.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.

Reduced evoked cortical beta and gamma activity and neuronal synchronization in succinic semialdehyde dehydrogenase deficiency, a disorder of γ-aminobutyric acid metabolism.

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 (GABAA) 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.

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma-aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma-hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next-generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4-guanidinobutanoic acid, and 2-hydroxyglutaric acid, and prominent elevations of GHB and 4,5-dihydroxyhexanoic acid (4,5-DHHA) in SSADHD samples. Remarkably, the intensities of 4,5-DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5-DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5-DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5-dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology.

Succinic semialdehyde dehydrogenase deficiency: A model of neurocircuit imbalances in autism and potential insight into new biomarkers.

This commentary is on the original article by Latzer et al on pages 1596–1606 of this issue.

Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder with a variable phenotype and rate of progression. We aimed to develop and validate a clinical severity scoring (CSS) system applicable to the clinical setting and composed of five domains reflecting the principal manifestations of this disorder: cognitive, communication, motor, epilepsy, and psychiatry. A prospectively characterized cohort of 27 SSADHD subjects (55% females, median [IQR] age 9.2 [4.6-16.2] years) who enrolled in the SSADHD Natural History Study were included. The CSS was validated by comparison to an objective severity scoring (OSS) system based on comprehensive neuropsychologic and neurophysiologic assessments, which mirror and complement the domains of the CSS. The total CSS was sex and age-independent, and 80% of its domains lacked interdependence. With increasing age, there was a significant improvement in communication abilities (p = 0.05) and a worsening of epilepsy and psychiatric manifestations (p = 0.004 and p = 0.02, respectively). There was a significant correlation between all the CSS and OSS domain scores, as well as between the total CSS and OSS (R = 0.855, p < 0.001). Additionally, there were no significant demographic or clinical differences in the ratio of individuals in the upper quartile to the lower three quartiles of the CSS and OSS. The SSADHD CSS is validated using objective measures and offers a reliable condition-specific instrument universally applicable in clinical settings. This severity score may be utilized for family and patient counseling, genotype-phenotype correlations, biomarker development, clinical trials, and objective descriptions of the natural history of SSADHD.

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

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. In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. 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. 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.

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

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. 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. 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). 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.

Human iPSC-derived neural stem cells with ALDH5A1 mutation as a model of succinic semialdehyde dehydrogenase deficiency

BackgroundSuccinic semialdehyde dehydrogenase deficiency (SSADH-D) is an autosomal recessive gamma-aminobutyric acid (GABA) metabolism disorder that can arise due to ALDH5A1 mutations, resulting in severe, progressive, untreatable neurodegeneration. SSADH-D is primarily studied using simplified models, such as HEK293 cells overexpressing genes of interest, but such overexpression can result in protein aggregation or pathway saturation that may not be representative of actual underlying disease phenotypes.MethodsWe used a CRISPR/Cas9 approach to generate human iPSC cell lines bearing ALDH5A1 mutations. Through screening, two different mutant cell lines, NM_001080.3: c.727_735del (p.L243_S245del) and NM_001080.3: c.730_738del (p.A244_Q246del), were obtained. We induced iPSCs to neural stem cells and analyzed the characteristics of ALDH5A1 mutations in stem cells.ResultsThe human iPSC and NSC cell lines presented typical stem cell–like morphology. We found changes in ALDH5A1 expression and GABA accumulation in the different cell lines. In addition, by analyzing the cDNA between the wild-type and the mutant cell lines, we found that the mutant cell lines had a splicing variant.ConclusionsiPSCs represent a promising in vitro model for SSADH-D that can be used to study early central nervous system developmental alterations and pathogenic mechanisms.

Succinic semialdehyde dehydrogenase deficiency – a rare cause of metabolic stroke

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare neurometabolic disorder characterized by defective degradation of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the brain. Children with SSADH deficiency present with motor mental delay, intractable seizures, infantile onset hypotonia, speech disturbances, extrapyramidal symptoms and ataxia. This wide spectrum results from increased accumulation of 4hydroxy butyric acid (4HBA) leading to down regulation of GABA receptors, which likely explain epileptogenesis but the pathophysiology of stroke in SSADH deficiency is not much elucidated. Here, we report an infant aged 11 months, product of consanguineous marriage with significant family history of motor delay and intellectual disability, presented with sudden onset focal neurological deficit preceded by diarrheal illness. Examination revealed an infant with age-appropriate milestones having left uncrossed hemiplegia along with neuroradiological evidence of right globus pallidus ischemic infarct. Urinary organic acid profile by chromatography was suggestive of 4 hydroxybutyric aciduria.

Volumetric study of brain MRI in a cohort of patients with neurotransmitter disorders.

Inborn errors of neurotransmitters are rare monogenic diseases. In general, conventional neuroimaging is not useful for diagnosis. Nevertheless, advanced neuroimaging techniques could provide novel diagnosis and prognosis biomarkers. We aim to describe cerebral volumetric findings in a group of Spanish patients with neurotransmitter disorders. Fifteen 3D T1-weighted brain images from the International Working Group on Neurotransmitter related Disorders Spanish cohort were assessed (eight with monoamine and seven with amino acid disorders). Volumes of cortical and subcortical brain structures were obtained for each patient and then compared with those of two healthy individuals matched by sex and age. Regardless of the underlying disease, patients showed a smaller total cerebral tissue volume, which was apparently associated with clinical severity. A characteristic volumetric deficit pattern, including the right Heschl gyrus and the bilateral occipital gyrus, was identified. In severe cases, a distinctive pattern comprised the middle and posterior portions of the right cingulate, the left superior motor area and the cerebellum. In succinate semialdehyde dehydrogenase deficiency, volumetric affection seems to worsen over life. Despite the heterogeneity and limited size of our cohort, we found novel and relevant data. Total volume deficit appears to be a marker of severity, regardless of the specific neurotransmitter disease and irrespective of the information obtained from conventional neuroimaging. Volumetric assessment of individual brain structures could provide a deeper knowledge about pathophysiology, disease severity and specific clinical traits.

EP013: Novel biomarkers of succinic semialdehyde dehydrogenase deficiency highlight opportunities for screening and detection of GABA catabolism pathway abnormalities

GABA (gamma-aminobutyric acid) is catabolized in the mitochondrial matrix via the GABA shunt, a 2-step enzymatic pathway which encompasses the transamination of GABA to succinic semialdehyde by GABA-transaminase (GABA-T), followed by oxidation to succinate by succinic semialdehyde dehydrogenase (SSADH). Deficiency of SSADH results in accumulation of GABA and reduction of succinic semialdehyde to gamma-hydroxybutyrate (GHB), the principal neurotoxin in SSADH deficiency (SSADHD). SSADHD is an autosomal recessive disorder associated with biallelic pathogenic variants in ALDH5A1, typically characterized by developmental delay, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances.

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSADHD therapies. We conclude with a description of a novel SSADHD mouse model that enables ‘on-demand’ SSADH restoration, allowing proof-of-concept studies to fine-tune SSADH restoration in preparation for eventual human trials.