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Succinic Semialdehyde Dehydrogenase Deficiency

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency. Core disease mechanisms, m...

2026-05-11
Asta MONDO:0010083 Model: Asta Scientific Corpus Retrieval 16 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency. Core disease mechanisms, m...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 16
  • Snippets retrieved: 20

Relevant Papers

[1] Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder

  • Authors: Itay Tokatly Latzer, J. Roullet, Wardiya Afshar-Saber, Henry H. C. Lee, M. Bertoldi et al.
  • Year: 2024
  • Venue: Journal of Neurodevelopmental Disorders
  • URL: https://www.semanticscholar.org/paper/e7c08a57fe45fd8fdf4db00d75ce5e933865ab66
  • DOI: 10.1186/s11689-024-09538-9
  • PMID: 38658850
  • PMCID: 11044349
  • Citations: 10
  • Summary: While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve, and this further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.696) > Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271,980) is an autosomal recessive inherited metabolic disorder of γ-aminobutyric acid (GABA) catabolism with an estimated pan-ethnic prevalence of ∼ 1/460,000 [1]. It was first postulated that SSADH deficiency leads to increased excretion of γ-hydroxybutyrate (GHB) and the associated neurological and developmental abnormalities in 1981 [2]. During the following decades, multiple case reports and laboratory-based studies established the evidence that the primary metabolic defect of SSADHD involves the GABA degradation pathway [3][4][5][6][7][8][9][10][11][12][13]. Deficiency or absence of SSADH, a mitochondrial enzyme, ensues in the accumulation of GABA and other metabolites such as GHB (Fig. 1). The genetic basis of SSADHD was first reported in 1998 [14], and since then, a number of case series and cohort studies have described the clinical and biochemical phenotypes of SSADHD resulting from biallelic pathogenic variants in ALDH5A1 [15][16][17][18][19][20]. Since different combinations of ALDH5A1 variants may ensue in variable structural and functional impairments of the resultant SSADH enzyme, the clinical presentation of SSADHD is broad in the degree of severity [21,22]. Considering the dominant presence of GABA in the basal ganglia, neuropathological findings of striking discoloration of the globus pallidi [23] and neuroimaging findings of (MRI)-derived T2-weighted hyperintensity in the globus pallidi and subthalamic nuclei, along with magnetic resonance spectroscopy (MRS)-derived increased GABA/N-acetylaspartate (NAA) ratios [24], suggest this is one of the primary areas involved in the clinical manifestations of the disorder.
  • Snippet 2 (score: 0.504) > Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4–14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder’s clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in

[2] Evidence of redox imbalance in a patient with succinic semialdehyde dehydrogenase deficiency

  • Authors: A. Niemi, C. Brown, T. Moore, G. Enns, T. Cowan
  • Year: 2014
  • Venue: Molecular Genetics and Metabolism Reports
  • URL: https://www.semanticscholar.org/paper/e55849581ee59c657a0c26681c8c0bbceb4d0855
  • DOI: 10.1016/j.ymgmr.2014.02.005
  • PMID: 27896081
  • PMCID: 5121295
  • Citations: 10
  • Summary: A patient with SSADH deficiency is reported on, in whom low levels of blood reduced glutathione (GSH), and elevations of dicarboxylic acids in urine are found, suggestive of possible redox imbalance and/or mitochondrial dysfunction.
  • Evidence snippets:
  • Snippet 1 (score: 0.686) > Succinic semialdehyde dehydrogenase (SSADH; EC 1.2.1.24) deficiency is a rare disorder (OMIM 271980) of γ-aminobutyric acid (GABA) degradation caused by mutations in ALDH5A1 [1,2]. In this disorder, succinic semialdehyde, the transamination product of GABA, is not converted to succinic acid but instead into 4-hydroxybutyric acid (γ-hydroxybutyric acid, GHB) and other related metabolites including 4,5-dihydroxyhexanoic acids [3]. The diagnosis of SSADH deficiency is based on detecting elevated levels of 4-hydroxybutyric and related metabolites in body fluids including urine [3,4]. The clinical picture of SSADH deficiency is variable, with the most common manifestations being intellectual disability, expressive language deficits, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances [1,5,6]. Therapeutic interventions attempted in humans or murine models have included vigabatrin [7], phenobarbital [8], and taurine [9], but no treatment has shown consistent significant efficacy. Thus, novel therapeutic approaches are needed. > The pathophysiology of SSADH deficiency is not completely understood. It is unclear whether elevated GABA, GHB, or a secondary deficiency of tricarboxylic acid (TCA) cycle, or Krebs cycle, intermediates due to lack of conversion of succinic semialdehyde to succinic acid, or some another mechanism contributes to the clinical phenotype of these patients. Mitochondrial dysfunction and oxidative stress have been suggested to play a role by both in vitro and murine model studies [10][11][12][13][14][15][16]. Decreased total radical-trapping potential (TRAP), increased lipid peroxidation and altered antioxidant enzyme activities have been demonstrated in SSADH deficient mice [10,[13][14][15]17].

[3] An Unusual Presentation of Succinic Semialdehyde Dehydrogenase Deficiency: A Fatal Case of Severe Progressive Seizures in a Four-Month-Old Infant

  • Authors: Sara Idkaidak, Lila H. Abu-Hilal, Duha I Barghouthi, Osama M. Atawneh, Abdelrazzaq Abumayaleh et al.
  • Year: 2024
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/e676a85552293bb172d0a497ca410090c0827b4b
  • DOI: 10.7759/cureus.58326
  • PMID: 38752093
  • PMCID: 11095822
  • Citations: 1
  • Summary: A fetal case of a four-month-old female infant presenting with severe, progressive seizures leading to fatality is reported, highlighting the difficulties in controlling SSADH deficiency and the necessity for additional studies on successful therapy approaches.
  • Evidence snippets:
  • Snippet 1 (score: 0.684) > Succinic semialdehyde dehydrogenase (SSADH) deficiency is an uncommon genetic condition characterized by disrupting the normal processing of gamma-aminobutyric acid (GABA), a crucial inhibitory neurotransmitter in the brain. This condition follows an autosomal recessive pattern of inheritance [1]. The condition is caused by mutations in the ALDH5A1 gene, which is a member of the aldehyde dehydrogenase 5 family located on chromosome 6p22. Although the pathophysiology of this disease is not fully understood, part of the mechanism of the disease is related to the abnormal accumulation of the compound succinic semialdehyde caused by SSADH deficiency, which in turn is converted to gamma-hydroxybutyric acid (GHB) [2]. Also, the impairment of the function of the SSADH enzyme leads to a disruption of the metabolism of GABA. Both GABA and GHB contribute to pathophysiology. > The clinical features of SSADH deficiency are widely variable. SSADH deficiency can present at various ages, including late infancy and early childhood. The clinical presentation is marked by developmental delay and intellectual disability, along with notable delays in expressive language, low muscle tone, lack of coordination, movement abnormalities, and seizures [3,4]. Seizures can be seen in this disease and usually, the patient presents with generalized seizures and can be managed with appropriate medications. > Here we describe an unusual presentation of a four-month-old female patient diagnosed with SSADH deficiency who presented with severe progressive seizure leading to the death of the patient.

[4] Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

  • Authors: T. Peters, U. Engelke, S. Boer, Joris T. G. Reintjes, J. Roullet et al.
  • Year: 2023
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/3bfb400717f8bd5fd000fd3838412c5628619685
  • DOI: 10.1002/jimd.12657
  • PMID: 37455357
  • Citations: 7
  • Summary: 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.
  • Evidence snippets:
  • Snippet 1 (score: 0.683) > Succinic semialdehyde dehydrogenase deficiency (SSADHD; MIM #271980) is a rare neurometabolic disorder, with $450 patients described worldwide. 1It is caused by disruption of the gamma-aminobutyric acid (GABA) pathway (Figure 1).GABA-transaminase converts GABA into succinic semialdehyde (SSA), which is further metabolized by SSADH into succinic acid.In case of SSADHD, SSA is mainly converted into the alternative product gamma-(or 4-) hydroxybutyric acid (GHB).This metabolite can be found in urine, blood, and CSF of patients and is a hallmark of the disease, which is therefore also known as 4-hydroxybutyric aciduria. 2nother biomarker that is considered pathognomonic for SSADHD is 4,5-dihydroxyhexanoic acid (4,5-DHHA).It is thought to be formed from a reaction between SSA and pyruvate, catalyzed by pyruvate dehydrogenase, but this remains to be proven. 3he clinical symptoms of SSADHD are diverse, including motor and mental delay, hypotonia, speech delay, and epilepsy. 4This nonspecific clinical phenotype warrants biochemical and genetic confirmation when SSADHD is suspected.This is usually done by analysis of GHB in urine and by sequencing for variants of ALDH5A1, the gene encoding SSADH. 5The connection between the clinical symptoms and the metabolic disruptions is still largely unclear.An effective (curative) treatment is not yet available. 6Several new therapies based on the SSADHD disease mechanism are currently under development, mostly in the preclinical stage.Some clinical trials (phase I or II) have been performed, but without beneficial outcomes.For example, the only phase II clinical trial to date, which tested the GABA B receptor antagonist SGS-742, neither showed any improvement of cognition nor of cortical excitability. 7

[5] Clinical diagnosis and mutation analysis of four Chinese families with succinic semialdehyde dehydrogenase deficiency

  • Authors: Ping Wang, Fengying Cai, Lirong Cao, Yizheng Wang, Qianqian Zou et al.
  • Year: 2019
  • Venue: BMC Medical Genetics
  • URL: https://www.semanticscholar.org/paper/0398392b950970490f2b7e31054acd4dd93a252e
  • DOI: 10.1186/s12881-019-0821-z
  • PMID: 31117962
  • PMCID: 6532217
  • Citations: 12
  • Influential citations: 1
  • Summary: A novel mutation p.V267G located in the NAD binding domain, which is possibly crucial for this disease’s severity is described, which expands the mutation spectrum of ALDH5A1 and highlights the importance of molecular genetic evaluation in patients with SSADH deficiency.
  • Evidence snippets:
  • Snippet 1 (score: 0.660) > Succinic semialdehyde dehydrogenase (SSADH, OMIM: 271980) deficiency, also known as 4-hydroxybutyric aciduria, is a rare autosomal recessive genetic disorder that affects the degradation of γ-aminobutyric acid [1]. SSADH catalyzes succinic semialdehyde (SSA) to succinic acid (SA) in the final step of γ-aminobutyric acid (GABA) catabolism. In the absence of SSADH, SSA is converted into γ-hydroxybutyric acid (GHB) and other related metabolites. GHB can be converted to 3-deoxytetronic acid (3DT) or 2-deoxytetronic acid (2DT) via α or β oxidation. GABA and GHB accumulate in the brain, blood, urine, and cerebral spinal fluid. The clinical features of this disease are various and non-specific, including developmental delay, intellectual deficit, hypotonia, ataxia and seizures, and especially language delays [2][3][4]. Severity ranges from mild impairment to a relentlessly progressive neurodegenerative course with intractable seizures in infancy [5]. GABA A receptor down regulation was previously reported as one of the pathophysiological mechanisms [2], but current data reveal a surprisingly complex pattern of pathophysiology including oxidative stress parameters and dysregulation of autophagy and mitophagy [1]. > The gene of ALDH5A1 with a full length of 1605 bp containing 10 exons, located in chromosome 6p22.3, and codes 535 amino acids with the first 47 residues representing the mitochondrial targeting peptide [4,6]. The monomeric SSADH consisted of three domains: an oligomerization domain (174-195 and 525-535), a catalytic domain (308-508), and an N-terminal NAD-binding domain (residues 48-173, 196-307, and 509-524) that is responsible for the binding of NAD + to the enzyme [7].

[6] Succinic Semialdehyde Dehydrogenase Deficiency: An Update

  • Authors: M. Didiášová, A. Banning, H. Brennenstuhl, S. Jung-Klawitter, C. Cinquemani et al.
  • Year: 2020
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/4e97fb0d65ee1803b2f0a03cfe1bf7dcefb3392a
  • DOI: 10.3390/cells9020477
  • PMID: 32093054
  • PMCID: 7072817
  • Citations: 42
  • Influential citations: 3
  • Summary: The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.642) > Succinic semialdehyde dehydrogenase deficiency (SSADH-D, also called 4-hydroxybutyric aciduria, OMIM #271980) is an ultra-rare monogenic disorder of the γ-amino butyric acid (GABA) metabolism, with approximately 450 patients known to the literature (reviewed in [1,2]).The first case of SSADH-D was identified in 1981 in a patient excreting γ-hydroxybutyric acid (GHB) in the urine, and only two years later, the deficiency of succinic semialdehyde dehydrogenase (SSADH) activity was demonstrated to be the underlying cause [3,4].Variants of the ALDH5A1 gene have later been shown to be the cause of SSADH-D [5], which is inherited in an autosomal recessive fashion.Heterozygous carriers of one defective allele show no clinical signs of the disease, whereas the patients who are either homozygous or compound heterozygous for disease-causing variants are affected to a varying degree.Enzymatic dysfunction of SSADH leads to an accumulation of potentially neurotoxic metabolites, including GABA and GHB, as well as numerous other substances (see Table 1).Despite ambitious scientific effort, detailed knowledge about many aspects of the pathophysiology of the underlying enzyme defect is still lacking, and at present, no curative treatment that would directly target the enzyme deficiency is available for SSADH-D.As with many other rare disorders affecting the central nervous system (CNS), several symptomatic treatments have been and are currently investigated [6,7]. > Table 1.Accumulation of potentially harmful GABA metabolites in the body fluids of SSADH-D patients.Modified from [8].The clinical picture of SSADH-D is highly heterogeneous, and in many cases, the somewhat nonspecific nature of the symptoms may delay the diagnosis of patients without prior family history of the disease [1,9].
  • Snippet 2 (score: 0.631) > Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.
  • Snippet 3 (score: 0.495) > 1. Succinic Semialdehyde Dehydrogenase Deficiency: Clinical Phenotype, Genetics, and Standard Care

[7] Gene therapy for neurotransmitter‐related disorders

  • Authors: W. Chu, J. Ng, S. Waddington, M. Kurian
  • Year: 2024
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/c1b04457d92fbdfccfdbff1c35524f1e42a02e71
  • DOI: 10.1002/jimd.12697
  • PMID: 38221762
  • PMCID: 11108624
  • Citations: 9
  • Summary: Preclinical and clinical advances to address NT‐related diseases are presented, potential challenges that require careful considerations for NT gene therapy studies are summarized, and potential challenges that require careful considerations are summarised.
  • Evidence snippets:
  • Snippet 1 (score: 0.623) > Succinic semialdehyde dehydrogenase (SSADH) is a systemically expressed mitochondrial enzyme, with major expression in the brain and liver. 125In healthy individuals, synaptic GABA is transported into astrocytes by GAT, converted to succinic semialdehyde by GABA transaminase (GABA-T), then oxidised in tandem by SSADH to succinate, a substrate of the TCA cycle. 125In SSADHD (OMIM #271980), biallelic loss-of-function mutations in the encoding ALDH5A1 (6p22.3)gene result in the cytosolic conversion of succinic semialdehyde to γ-hydroxybutyrate (GHB), a neuromodulator with neurotoxic properties, instead. 126Excess accumulations of GABA, GHB and other GABA metabolites are found in brain and body fluids, but the exact pathophysiology remains to be elucidated. 125Clinical symptoms, including hypotonia, developmental delay, epilepsy, and behavioural and sleep disturbances, manifest in early childhood 126 ; age-dependent association in symptom severity and seizure types have been described. 127Post-mortem study of one patient also found amino acid, phospholipid, and NT disturbances. 128No effective treatment currently exists to address the underlying deficiency and downstream metabolic sequelae. > As the liver also expresses high levels of SSADH, and central and peripheral GHB rapidly equilibrates, 125 a liver-directed adenoviral approach was evaluated in a mouse SSADH-KO model. 129These mice recapitulate metabolic features observed in humans but have more severe phenotypes, with reduced survival up to P26 due to status epilepticus. 130

[8] A crucial active site network of titratable residues guides catalysis and NAD + binding in human succinic semialdehyde dehydrogenase

  • Authors: Samuele Cesaro, Marco Orlando, Ilaria Bettin, C. Longo, G. Spagnoli et al.
  • Year: 2024
  • Venue: Protein Science : A Publication of the Protein Society
  • URL: https://www.semanticscholar.org/paper/a288a30dabd43d3f42f175f6a4935e8c7bad91b6
  • DOI: 10.1002/pro.70024
  • PMID: 39731543
  • PMCID: 11681614
  • Summary: The identification of this weak bond network essential for cofactor binding and catalysis represents a first step to tackling the molecular basis for the molecular basis for this enzyme deficiency.
  • Evidence snippets:
  • Snippet 1 (score: 0.605) > Human succinic semialdehyde dehydrogenase is a mitochondrial enzyme fundamental in the neurotransmitter γ‐aminobutyric acid catabolism. It catalyzes the NAD+‐dependent oxidative degradation of its derivative, succinic semialdehyde, to succinic acid. Mutations in its gene lead to an inherited neurometabolic rare disease, succinic semialdehyde dehydrogenase deficiency, characterized by mental and developmental delay. Due to the poor characterization of this enzyme, we carried out evolutionary and kinetic investigations to contribute to its functional behavior, a prerequisite to interpreting pathogenic variants. An in silico analysis shows that succinic semialdehyde dehydrogenases belong to two families, one human‐like and the other of bacterial origin, differing in the oligomeric state and in a network of active site residues. This information is coupled to the biophysical–biochemical characterization of the human recombinant enzyme uncovering that (i) catalysis proceeds by an ordered bi–bi mechanism with NAD+ binding before the aldehyde that exerts a partial non‐competitive inhibition; (ii) a stabilizing complex between the catalytic Cys340 and NAD+ is observed and interpreted as a protective mechanism; and (iii) a concerted non‐covalent network assists the action of the catalytic residues Cys340 and Glu306. Through mutational analyses of Lys214, Glu306, Cys340, and Glu515 associated with pH studies, we showed that NAD+ binding is controlled by the dyad Lys214‐Glu515. Moreover, catalysis is assured by proton transfer exerted by the same dyad networked with the catalytic Glu306, involved in catalytic Cys340 deprotonation/reprotonation. The identification of this weak bond network essential for cofactor binding and catalysis represents a first step to tackling the molecular basis for its deficiency.

[9] The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

  • Authors: N. Juliá-Palacios, Oya Kuseyri Hübschmann, M. Olivella, Roser Pons, Gabriella Horvath et al.
  • Year: 2024
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/4e19bbf0e8cbdeb4eee833162c7038072d77b2ba
  • DOI: 10.1002/jimd.12723
  • PMID: 38499966
  • Citations: 9
  • Summary: 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.
  • Evidence snippets:
  • Snippet 1 (score: 0.604) > Succinic semialdehyde dehydrogenase deficiency (SSADHD; OMIM #271980) is the most frequent inherited disorder of γ-aminobutyric acid (GABA) metabolism and is caused by homozygous or compound heterozygous variants in the ALDH5A1 gene (610045) on chromosome 6p22.Its impairment leads to the accumulation of large quantities of GABA and γ-hydroxybutyric acid (GHB; 4-hydroxybutyric), especially in the central nervous system (CNS). > GABA, the CNS major inhibitory neurotransmitter, is formed from glutamate by pyridoxal-5-phosphatedependent glutamate decarboxylase.It is catabolized into succinic acid through the sequential action of two mitochondrial enzymes, GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH).Succinic acid enters the Krebs cycle and is converted to 2-oxoglutarate, which further leads to the synthesis of glutamate.In the absence of SSADH, the accumulation of succinic semialdehyde results in its conversion to GHB. > High concentrations of GABA and GHB, are detectable in cerebrospinal fluid (CSF) and urine of individuals with SSADHD and are related to the neurological manifestation of the disease, but this is not a known pathophysiological explanation as far as the literature states, and there still is need of further study.In addition, recent evidence suggests that multiple metabolic perturbations may be associated with the pathophysiology including involvement of the mitogen-activated protein kinases (MAPK) pathway affecting the myelination, 1 dysregulation of autophagy and oxidative stress via mTOR pathway 2 and astrogliosis and myelin-related phospholipid reduction. 3n SSADHD, the first symptoms appear at an average age of 11 months (range 0-44 months).However, the mean age at diagnosis was reported as 6.6 years. 4,5

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

  • Authors: M. Didiášová, Samuele Cesaro, S. Feldhoff, Ilaria Bettin, Nana Tiegel et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/867a88fcf42cd64945d27484cdac30b45471df5b
  • DOI: 10.3390/ijms25105237
  • PMID: 38791277
  • PMCID: 11121183
  • Citations: 2
  • Summary: 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.
  • Evidence snippets:
  • Snippet 1 (score: 0.598) > The catabolic pathway of the neurotransmitter γ-amino butyric acid (GABA) leads to the production of succinic semialdehyde (SSA), which is normally converted into succinate by a mitochondrial enzyme, succinic semialdehyde dehydrogenase (SSADH, reviewed in [1,2]).In the absence of SSADH activity, SSA and GABA accumulate in the cells and in the extracellular fluids [3,4].In addition, a large fraction of SSA is converted into a toxic metabolite, γ-hydroxy butyric acid (GHB; reviewed in [1,2]). > Impairment of SSADH activity is caused by mutations in the ALDH5A1 gene, which resides on chromosome 6p22 and encodes the SSADH enzyme, the deficiency of which results in a rare genetic disease, SSADH deficiency (SSADH-D) [5,6].The disease prevalence has been estimated to be about 1 in 460,000 [7].The patients usually suffer from a varying degree of mental retardation, behavioral problems with autistic features, muscle hypotonia, and lack of speech.Some SSADH-D patients also have epileptic seizures that can be very severe and may result in sudden unexpected death from epilepsy [8][9][10][11][12].Accumulation of the GABA metabolites is observed in the tissues and body fluids of the patients and can be used as a diagnostic tool.Recent years have brought about several interesting hypotheses on the molecular mechanisms of SSADH-D, with novel ideas for treatment options.The current understanding of SSADH-D and the molecular mechanism of this disease have recently been discussed in review articles that the readers should consider for more detailed information on this disease [2,[12][13][14]. > SSADH-D is a recessively inherited disease in which a large spectrum of pathogenic ALDH5A1 gene variants have been described, and the sequencing of the ALDH5A1 gene is usually performed to verify the diagnosis [1,[15][16][17].

[11] Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency

  • Authors: Trevor O. Kirby, Dana C. Walters, Xutong Shi, Coleman T. Turgeon, P. Rinaldo et al.
  • Year: 2020
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/6ea99377dfb49d27d455c61a8c49653296c7a14c
  • DOI: 10.1186/s13023-020-01522-5
  • PMID: 32967698
  • PMCID: 7510106
  • Citations: 5
  • Summary: Age-dependent acylcarnitine correlations may represent metabolic compensation responsive to age-related changes in GHB and GABA and are highlighted in a study highlights novel biomarkers in SSADHD and expands the metabolic pathophysiology of this rare disorder of GABA metabolism.
  • Evidence snippets:
  • Snippet 1 (score: 0.579) > Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD) is a rare disorder on the GABA metabolic pathway. The product of glutamate decarboxylation, GABA is catabolized to succinic acid in a two-enzyme sequence, including generation of succinic semialdehyde (SSA) catalyzed by GABA-aminotransferase and the further oxidation of SSA to succinic acid catalyzed by SSADH [10]. The backbone of GABA thus enters the tricarboxylic acid cycle for further metabolism. SSADHD is frequently referred to as γ-hydroxybutyric aciduria. This is due to the fact that accumulated SSA, in the absence of functional SSADH activity, is converted to γ-hydroxybutyrate (GHB), the latter being a compound with diverse and still poorly understood neuromodulatory roles [13]. In addition to increased GABA and GHB, patients manifest a broad variety of additional metabolic abnormalities, which have recently been summarized [2,11]. > The phenotype of SSADHD encompasses developmental and speech delays, hypotonia, neuropsychiatric morbidity (attention deficit disorder, obsessive compulsive behavior), and seizures in ~50% of patients. The metabolic signature includes elevated GHB and GABA in physiological fluids, among other metabolites [11]. The incidence of SSADHD is estimated to be 1:10 6 , but expanding molecular genetic studies are likely to reveal a higher prevalence. To explore the clinical and metabolic evolution of SSADHD, we have recently embarked on an NIHfunded natural history study. Enrolling up to 55 patients (any age), this study encompasses multiple neuroimaging and electrophysiological evaluations over a 5-year period. An important ancillary component of clinical evaluation is the collection of biospecimens yearly, including plasma, white and red cells, DNA and RNA, hair, saliva, stool, urine, fibroblasts, and others.

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

  • Authors: H. Lee, Gabrielle E. McGinty, P. Pearl, A. Rotenberg
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/bfe2b6f01467505a287f076fdc85969443625568
  • DOI: 10.3390/ijms23052606
  • PMID: 35269750
  • PMCID: 8910003
  • Citations: 23
  • Influential citations: 1
  • Summary: 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.
  • Evidence snippets:
  • Snippet 1 (score: 0.571) > 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.
  • Snippet 2 (score: 0.558) > Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic metabolic disorder caused by loss-of-function mutations of the ALDH5A1 gene. ALDH5A1 encodes SSADH which is essential for the mitochondrial breakdown of succinic semialdehyde (SSA), a γ-aminobutyric acid (GABA) downstream metabolite, into succinate. In the absence of SSADH, SSA conversion to succinate is prohibited, leading to SSA conversion to γ-hydroxybutyrate (GHB). Both GABA and GHB are accumulated in the brain and body fluids (cerebrospinal fluid, blood) up to pathologic levels, resulting in numerous downstream neurological and metabolic abnormalities. > To date, SSADHD treatments remain symptomatic and only minimally effective. A fundamentally different approach is targeted SSADH restoration, which may be accomplished via gene therapy or enzyme replacement therapy (ERT). While gene and enzyme replacement therapies are still in their infancy, we envision that the current technology and research environment enable a quick transition from basic bench side research to clinical trials (Figure 1A). We therefore describe our ongoing work aimed to develop SSADH-targeted treatments. By generating a novel SSADHD mouse model which allows 'on-demand' SSADH restoration, we aim to understand the impact of SSADH restoration from molecular level to animal behaviors. The ongoing SSADHD Natural History Study provides correlating clinical data for relevant biomarkers development. These combined efforts will accelerate the transition from bench to bedside development of the eventual safe and effective therapeutic products. > Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 2 of 15 and research environment enable a quick transition from basic bench side research to clinical trials (Figure 1A). We therefore describe our ongoing work aimed to develop SSADHtargeted treatments. By generating a novel SSADHD mouse model which allows 'on-demand' SSADH restoration, we aim to understand the impact of SSADH restoration from molecular level to animal behaviors. The ongoing SSADHD Natural History Study provides correlating clinical data for relevant biomarkers development.

[13] Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1

  • Authors: H. Brennenstuhl, M. Didiášová, B. Assmann, M. Bertoldi, G. Molla et al.
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/b03a6095722d5f7729750941e91b4c7377932074
  • DOI: 10.3390/ijms21228578
  • PMID: 33203024
  • PMCID: 7696157
  • Citations: 7
  • Summary: A patient is presented with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain ofSSADH.
  • Evidence snippets:
  • Snippet 1 (score: 0.562) > Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.

[14] Sensorineural Hearing Loss in a Child with Succinic Semialdehyde Dehydrogenase Deficiency

  • Authors: M. Parezanović, N. Ilić, S. Ostojic, G. Stevanović, J. Jecmenica et al.
  • Year: 2023
  • Venue: Balkan Journal of Medical Genetics : BJMG
  • URL: https://www.semanticscholar.org/paper/d7a837ce93c4cc347de8bfe1971982fb6d37354e
  • DOI: 10.2478/bjmg-2023-0008
  • PMID: 37576789
  • PMCID: 10413887
  • Citations: 2
  • Summary: A five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL) is reported, hoping that this case will contribute to the understanding of phenotypic complexity of SSadH deficiency.
  • Evidence snippets:
  • Snippet 1 (score: 0.529) > The first description of succinic semialdehyde dehydrogenase deficiency is found in Jakobs et al. from 1981, followed by the elucidation of its genetic basis and aggregation of significant amount of data reflecting its clinical spectrum. 1,4,12 Numerous pathogenic variants in ALDH5A1 associated with SSADH deficiency have been reported, but precise genotype-phenotype correlation was not yet established. 2,13 Additionally, the relationship between the genetic change and residual succinic semialdehyde dehydrogenase activities lacked consistency. 2 ue to its heterogeneous and often non-specific clinical presentation, SSADH deficiency may be significantly underdiagnosed. 5][16] In the case of our patient, hypotonia was noticeable in early infancy. The course of the disease remained non-progressive, despite the notion that some SSADH deficiency patients with early onset have severe complications including extrapyramidal signs, seizures, regression and even death in infancy. In the case of our patient, hypotonia and global developmental delay are the hallmarks of the disease from the beginning. Up to the age of five years, our patient has remained seizure free. > Quality of life for SSADH deficiency patients could be significantly reduced in cases of pronounced neuropsychiatric problems, among which a lack of attention and aggressive behavior begin in early childhood while disabling obsessive-compulsive disorder occur mostly in adolescence and adulthood. 7-9 Similar manifestations have not been encountered yet in the boy we present, apart from a single visit to the pediatric emergency department at the age of four years due to unexplained agitation lasting for several hours. Given moderate sleeping difficulties, our patient is using melatonin with good results. A clinical severity scoring (CSS) system was recently proposed for evaluating SSADH patients, based on cognitive aspects, communication skills, motor function, epilepsy, and psychiatric aspect of the disease. 17 The CSS ranges from 5-25 (average (17.3), with higher scores correlating with milder presentation. Our patient's score of 17 at 5 years of age is almost the exact average of the SSADH patients group involved in study that established the CSS.

[15] Metabolic Stroke: A Novel Presentation in a Child with Succinic Semialdehyde Dehydrogenase Deficiency

  • Authors: S. Yoganathan, Gautham Arunachal, L. Kratz, Mugil Varman, Maya Thomas et al.
  • Year: 2020
  • Venue: Annals of Indian Academy of Neurology
  • URL: https://www.semanticscholar.org/paper/1194fabd46eb74779bfa11c723054ac12306e5b1
  • DOI: 10.4103/aian.AIAN_213_18
  • PMID: 32055132
  • PMCID: 7001443
  • Citations: 8
  • Influential citations: 1
  • Summary: A 15-month-old girl with SSADH deficiency presenting with developmental delay, language deficits, and acute-onset right hemiparesis, following recovery from a diarrheal illness is described.
  • Evidence snippets:
  • Snippet 1 (score: 0.510) > SSADH deficiency is a rare under-recognized disorder of GABA metabolism, although the exact incidence is not known. In our case, developmental delay, language deficit, hypotonia, hyporeflexia, and autistic traits were identified as described in the literature. To the best of our knowledge, this is the first report of a child with SSADH deficiency presenting as stroke mimic. The biochemical defect in SSADH deficiency is a failure to oxidize succinic semialdehyde to succinic acid. GABA transamination to succinic semialdehyde in the metabolic pathway is followed by its conversion to succinic acid which enters the Krebs cycle. [2] However, in the absence of SSADH, succinic semialdehyde is reduced to 4-hydroxybutyric acid which is a neurotoxic agent. [2] Predominant right-sided weakness in our case could be explained by the asymmetric involvement of the basal ganglia. > Metabolic stroke has been reported in patients with homocystinuria, methylmalonic aciduria, glutaric aciduria Type I and II, isovaleric aciduria, propionic aciduria, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and urea cycle disorders. [3,4] The exact pathophysiology of stroke in patients with SSADH is unclear. It is possible that 4-hydroxybutyric acid, a toxic metabolite that accumulates endogenously in children with SSADH deficiency, is neurotoxic as seen in our patient, leading onto the clinical manifestations. Although the exact reason behind such a presentation is unclear, we can derive at an indirect explanation through the murine models of SSADH. It is postulated that hyperGABAergic state and elevated 4-hydroxybutyric acid affect neurotransmission and also cause escalation of various parameters of oxidative stress. [5] The catabolic process induced by infection as seen in our case might have worsened the underlying oxidative stress, followed by recovery with the cessation of the catabolic process.

[16] Succinic semialdehyde dehydrogenase deficiency: a metabolic and genomic approach to diagnosis

  • Authors: Kevin E. Glinton, C. Gijavanekar, Abbhirami Rajagopal, Laura Mackay, Kirt A. Martin et al.
  • Year: 2024
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/4f1b260e19af51f9fd804fc64959c9f7f1d6749c
  • DOI: 10.3389/fgene.2024.1405468
  • PMID: 39011401
  • PMCID: 11247174
  • Citations: 5
  • Summary: This study utilized an integrated approach to diagnosis of SSADHD by examining molecular, clinical, and metabolomic data from a single large commercial laboratory and showed that patients with this disorder have a clear metabolomic signature that, along with molecular and clinical findings, may allow for more rapid and efficient diagnosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.503) > Genomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed. Succinic semialdehyde dehydrogenase deficiency (SSADHD, OMIM #271980) is a neurometabolic disorder in the GABA catabolism pathway. The disorder is due to bi-allelic pathogenic variants in ALDH5A1 and is usually characterized by moderate-to-severe developmental delays, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances. In this study, we utilized an integrated approach to diagnosis of SSADHD by examining molecular, clinical, and metabolomic data from a single large commercial laboratory. Our analysis led to the identification of 16 patients with likely SSADHD along with three novel variants. We also showed that patients with this disorder have a clear metabolomic signature that, along with molecular and clinical findings, may allow for more rapid and efficient diagnosis. We further surveyed all available pathogenic/likely pathogenic variants and used this information to estimate the global prevalence of this disease. Taken together, our comprehensive analysis allows for a global approach to the diagnosis of SSADHD and provides a pathway to improved diagnosis and potential incorporation into newborn screening programs. Furthermore, early diagnosis facilitates referral to genetic counseling, family support, and access to targeted treatments–taken together, these provide the best outcomes for individuals living with either GABA-TD or SSADHD, as well as other rare conditions.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.