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

Background: 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.

Methods: 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.

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.

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

Objective: Succinic 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.

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.

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.

Farnesol brain transcriptomics in CNS inflammatory demyelination.

Background: Farnesol (FOL) prevents the onset of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS).

Objective: We examined the transcriptomic profile of the brains of EAE mice treated with daily oral FOL using next-generation sequencing (RNA-seq).

Methods: Transcriptomics from whole brains of treated and untreated EAE mice at the peak of EAE was performed.

Phenotypic Correlates of Structural and Functional Protein Impairments Resultant from ALDH5A1 Variants.

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.

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).

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.

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

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.

Allosteric modulation of α1β3γ2 GABA receptors by farnesol through the neurosteroid sites.

In mammalian cells, all-trans farnesol, a 15-carbon isoprenol, is a product of the mevalonate pathway. It is the natural substrate of alcohol dehydrogenase and a substrate for CYP2E1, two enzymes implicated in ethanol metabolism. Studies have shown that farnesol is present in the human brain and inhibits voltage-gated Ca channels at much lower concentrations than ethanol.

Intestinal Dysbiosis as a component of pathophysiology in succinic semialdehyde dehydrogenase deficiency (SSADHD).

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited inborn error of the γ-aminobutyric acid (GABA) metabolism pathway. It results from mutations in the ALDH5A1 gene leading to elevated GABA, γ-hydroxybutyric acid (GHB), succinic semialdehyde (SSA), decreased glutamine and alterations in several other metabolites. The phenotype includes developmental and cognitive delays, hypotonia, seizures, neuropsychiatric morbidity and other nervous system pathologies.

Development of a Quality-of-Life Survey for Patients With Succinic Semialdehyde Dehydrogenase Deficiency, a Rare Disorder of GABA Metabolism.

Succinic semialdehyde dehydrogenase deficiency (SSADHD), a rare disorder of GABA metabolism, presents with significant neurodevelopmental morbidity. Although there is a growing interest in the concept of quality of life through patient reports as a meaningful outcome in rare disease clinical trials, little is known about the overall impact of SSADHD from the patient/family perspective. The purpose of this study was to determine issues related to quality of life and patient/family experience through a focus group discussion with family caregivers of patients with SSADHD.

Farnesol induces protection against murine CNS inflammatory demyelination and modifies gut microbiome.

Farnesol is a 15‑carbon organic isoprenol synthesized by plants and mammals with anti-oxidant, anti-inflammatory, and neuroprotective activities. We sought to determine whether farnesol treatment would result in protection against murine experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis (MS). We compared disease progression and severity in C57BL/6 mice treated orally with 100 mg/kg/day farnesol solubilized in corn oil to corn-oil treated and untreated EAE mice.

Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue.

This study has extended previous metabolic measures in postmortem tissues (frontal and parietal lobes, pons, cerebellum, hippocampus, and cerebral cortex) obtained from a 37-year-old male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) who expired from SUDEP (sudden unexplained death in epilepsy). Histopathologic characterization of fixed cortex and hippocampus revealed mild to moderate astrogliosis, especially in white matter. Analysis of total phospholipid mass in all sections of the patient revealed a 61% increase in cortex and 51% decrease in hippocampus as compared to (n = 2-4) approximately age-matched controls.

Succinic Semialdehyde Dehydrogenase Deficiency: Review of the Natural History Study.

Objective: The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity.

Methods: The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort.

Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity.

((S)-(+)/(R)-(-)) vigabatrin (Sabril; γ-vinyl GABA), an antiepileptic irreversibly inactivating GABA-transaminase, was administered to male C57Bl6 J mice via continuous infusion (0, 40, 80 mg/kg/d) for 12 days. Our study design pooled retina, eye (minus retina), whole brain and plasma from n = 24 animals for each dose to provide n = 8 triplicates per treatment group. Hypothesizing that (S)-(+) VGB (active isomer) would preferentially accumulate in retina, we determined VGB isomers, comprehensive amino acids, and pharmacokinetic parameters.

Dysbiosis of the intestinal microbiome as a component of pathophysiology in the inborn errors of metabolism.

Inborn errors of metabolism (IEMs) represent monogenic disorders in which specific enzyme deficiencies, or a group of enzyme deficiencies (e.g., peroxisomal biogenesis disorders) result in either toxic accumulation of metabolic intermediates or deficiency in the production of key end-products (e.

Zellweger spectrum disorder: A cross-sectional study of symptom prevalence using input from family caregivers.

Zellweger spectrum disorders (ZSD) are rare, debilitating genetic diseases of peroxisome biogenesis that affect multiple organ systems and present with broad clinical heterogeneity. Although many case studies have characterized the multitude of signs and symptoms associated with ZSD, there are few reports on the prevalence of symptoms to help inform the development of meaningful endpoints for future clinical trials in ZSD. In the present study, we used an online survey tool completed by family caregivers to study the occurrence, frequency and severity of symptoms in individuals diagnosed with ZSD.