Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA

Pl, Pearl; Schreiber, John M.; Theodore, W. H.; McCarter, Robert C.; Es, Barrios; J, Yu; Wiggs, Edythe; He, Jia; Gibson, Kevin J.

doi:10.1212/wnl.0000000000000210

Cited by 32 publications

(23 citation statements)

References 17 publications

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“…However, a borderline lower score was observed on the conceptual (p=0.1) index during taurine use. Our open-label pilot trial of taurine in patients with SSADH deficiency did not reveal demonstrable improvement in adaptive neurobehavioral functioning (Pearl et al 2012). Nonetheless, additional biomarker studies during taurine intervention are in progress.…”

Section: Treatment Strategies For Ssadh Deficiencymentioning

confidence: 74%

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Vogel

Pearl

Theodore

et al. 2012

J of Inher Metab Disea

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Summary This review summarizes a presentation made at the retirement Symposium of Prof. dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.

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Section: Treatment Strategies For Ssadh Deficiencymentioning

confidence: 74%

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Vogel

Pearl

Theodore

et al. 2012

J of Inher Metab Disea

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“…Early reports of uncontrolled trials suggested a potential benefit of taurine intervention in patients (Saronwala et al 2008), although we were unable to document significant changes using an adaptive behavior scale in an open-label study (Pearl et al 2014). Here, we report the effects of taurine on TMS measures of cortical excitability and inhibition, CSF biomarkers, and cognitive testing in a group of these patients participating in the open-label taurine trial.…”

mentioning

confidence: 68%

“…One subject was already taking taurine and completed the "on" assessment first. All subjects were titrated to 10 g daily, the maximum dose based on hypersomnolence noted on higher doses as reported in the open-label trial (Pearl et al 2014). No adverse events were reported during TMS.…”

Section: Resultsmentioning

confidence: 99%

Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency

et al. 2015

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Aim: We tested the hypothesis that patients with succinic semialdehyde dehydrogenase (SSADH) deficiency on taurine would have decreased cortical excitability as measured by transcranial magnetic stimulation (TMS) and improved cognition, due to taurine's partial GABA(A and B) receptor agonist effects and rescue in the null mouse model from status epilepticus and premature lethality.Method: Biomarkers including neuropsychological testing, TMS, and CSF metabolites were studied in a cohort of patients on and off three months' taurine treatment.Results: Seven patients (5M/2F; age range 12-33 years) were enrolled in this open-label crossover study. Baseline average full-scale IQ (FSIQ) was 44.1 (range 34-55). Of six who returned at 6-month follow-up, five completed cognitive testing (3M/2F) on therapy; average FSIQ ¼ 43.4 (range 33-51). CSF biomarkers (n ¼ 4 subjects) revealed elevation in taurine levels but no change in free or total GABA. Baseline cortical excitability measured with TMS agreed with previous findings in this population, with a short cortical silent period and lack of long-interval intracortical inhibition. Patients on taurine showed a decrease in cortical silent period and short-interval intracortical inhibition compared to their off taurine study.Interpretation: TMS demonstrated decreased inhibition in patients on taurine, in contrast to the study hypothesis, but consistent with its failure to produce clinical or cognitive improvement. TMS may be a useful biomarker for therapy in pediatric neurotransmitter disorders.Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive defect in the catabolic pathway of GABA (gamma-aminobutyric acid), leading to elevated levels of GABA and gamma-hydroxybutyric acid (GHB) in body fluids and brain parenchyma (Pearl et al. 2003a, b). The typical clinical phenotype has been described as a slowly progressive or static encephalopathy. Most patients present with developmental delay noted in the first 2 years of life, as well as hypotonia, hyporeflexia, ataxia, speech disturbance, and intellectual disability, and at least half have seizures.Several lines of evidence indicate that SSADH deficiency results in chronic, overuse-dependent downregulation of GABA(A) and GABA(B) receptors. In the mouse model, decreased binding of the selective GABA(A) receptor antagonist tert-butylbicyclophosphorothionate ([35S]TBPS) was observed in the cerebral cortex, hippocampus, and thalamus of the mutant strain compared to wild type, and reduced GABA(A)-mediated inhibitory postsynaptic potentials and enhanced postsynaptic population spikes were recorded from hippocampal slices of the mutant strain ). There was also significantly decreased binding of a specific GABA(B) receptor antagonist in the mutant strain and attenuated GABA(B)-mediated synaptic potentials . We demonstrated

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“…Further, long-term treatment with VGB is contraindicated due to marked and permanent visual-field impairments (Singh et al 2013; Froger et al 2014; Good et al 2011; Pellock 2011; Escalera et al 2010; Casarano et al 2011; Matern et al 1996; Al-Essa et al 2000). Of further concern is the predicted expectation that VGB will augment brain GABA (Ergezinger et al 2003; Pearl et al 2014a; 2014b), which is a relevant observation in light of recent studies (described above) highlighting GABA-induced impairment of autophagic processes (Vogel et al 2015). The potential use of mTOR inhibitors (e.g., rapamycin, Torin 1 or 2) along with VGB might be an effective intervention, since this would both decrease production of GHB and clear the oxidative-damaging effects of further-enhanced GABA levels.…”

Section: Treatment Of Ssadhdmentioning

confidence: 99%

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

Malaspina

Roullet

Pearl

et al. 2016

Neurochemistry International

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Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.

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Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA

Cited by 32 publications

References 17 publications

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

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