Baylor Scott and White Research Institute

Walters, D. C., E. Arning, T. Bottiglieri, E. E. W. Jansen, G. S. Salomons, M. N. Brown, M. A. Schmidt, G. R. Ainslie, J. B. Roullet and K. M. Gibson (2019). “Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues.” Neurochem Int 125: 151-162.

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The anticonvulsant vigabatrin (VGB; Sabril(R)) irreversibly inhibits GABA transaminase to increase neural GABA, yet its mechanism of retinal toxicity remains unclear. VGB is suggested to alter several amino acids, including homocarnosine, beta-alanine, ornithine, glycine, taurine, and 2-aminoadipic acid (AADA), the latter a homologue of glutamic acid. Here, we evaluate the effect of VGB on amino acid concentrations in mice, employing a continuous VGB infusion (subcutaneously implanted osmotic minipumps), dose-escalation paradigm (35-140mg/kg/d, 12 days), and amino acid quantitation in eye, visual and prefrontal cortex, total brain, liver and plasma. We hypothesized that continuous VGB dosing would reveal numerous hitherto undescribed amino acid disturbances. Consistent amino acid elevations across tissues included GABA, beta-alanine, carnosine, ornithine and AADA, as well as neuroactive aspartic and glutamic acids, serine and glycine. Maximal increase of AADA in eye occurred at 35mg/kg/d (41+/-2nmol/g (n=21, vehicle) to 60+/-8.5 (n=8)), and at 70mg/kg/d for brain (97+/-6 (n=21) to 145+/-6 (n=6)), visual cortex (128+/-6 to 215+/-19) and prefrontal cortex (124+/-11 to 200+/-13; mean+/-SEM; p<0.05), the first demonstration of tissue AADA accumulation with VGB in mammal. VGB effects on basic amino acids, including guanidino-species, suggested the capacity of VGB to alter urea cycle function and nitrogen disposal. The known toxicity of AADA in retinal glial cells highlights new avenues for assessing VGB retinal toxicity and other off-target effects.

Brown, M. N., D. C. Walters, M. A. Schmidt, J. Hill, A. McConnell, E. Jansen, G. S. Salomons, E. Arning, T. Bottiglieri, K. M. Gibson and J. B. Roullet (2019). “Maternal Glutamine Supplementation in Murine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD), a Disorder of GABA Metabolism.” J Inherit Metab Dis Apr 29. [Epub ahead of print].

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Murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of gamma-aminobutyric acid (GABA) and gamma-hydroxybutyrate (GHB) and low glutamine in the brain. To understand the pathogenic contribution of central glutamine deficiency, we exposed aldh5a1(-/-) (SSADHD) mice and their genetic controls (aldh5a1(+/+) ) to either a 4% (w/w) glutamine-containing diet or a glutamine-free diet from conception until post-natal day 30. Endpoints included brain, liver and blood amino acids, brain GHB, ataxia scores and open field testing. Glutamine supplementation did not improve aldh5a1(-/-) brain glutamine deficiency nor brain GABA and GHB. It decreased brain glutamate but did not change the ratio of excitatory (glutamate) to inhibitory (GABA) neurotransmitters. In contrast, glutamine supplementation significantly increased brain arginine (30% for aldh5a1(+/+) and 18% for aldh5a1(-/-) mice), and leucine (12% and 18%). Glutamine deficiency was confirmed in the liver. The test diet increased hepatic glutamate in both genotypes, decreased glutamine in aldh5a1(+/+) but not in aldh5a1(-/-) , but had no effect on GABA. Dried bloodspot analyses showed significantly elevated GABA in mutants (~800% above controls) and decreased glutamate (~25%), but no glutamine difference with controls. Glutamine supplementation did not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity were observed in aldh5a1(-/-) mice but remained unchanged by the diet intervention. The study suggests that glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Future studies are needed to fully understand the pathogenic role of brain glutamine deficiency in SSADHD.

Brown, M., P. Ashcraft, E. Arning, T. Bottiglieri, W. McClintock, F. Giancola, D. Lieberman, N. S. Hauser, R. Miller, J. B. Roullet, P. Pearl and K. M. Gibson (2019). “Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female.” Mol Genet Genomic Med 7(5): e629.

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BACKGROUND: We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies). METHODS: gamma-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing. RESULTS: The biochemical hallmark of SSADHD, GHB was increased in the proband’s dried bloodspot (DBS; 673 microM; previous SSADHD DBSs (n = 7), range 124-4851 microM); control range (n = 2,831), 0-78 microM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*). CONCLUSION: The major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.

Snyder, P., K. Dunbar, D. J. Cipher, R. F. Souza, S. J. Spechler and V. J. A. Konda (2019). “Aberrant p53 Immunostaining in Barrett’s Esophagus Predicts Neoplastic Progression: Systematic Review and Meta-Analyses.” Dig Dis Sci Mar 26. [Epub ahead of print].

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Risk stratification of patients with Barrett’s esophagus (BE) presently relies on the histopathologic grade of dysplasia found in esophageal biopsies, which is limited by sampling error and inter-pathologist variability. p53 immunostaining of BE biopsies has shown promise as an adjunct tool but is not recommended by American gastroenterology societies, who cite insufficient evidence of its prognostic value. We have conducted a systematic review and meta-analyses to clarify this value. We searched for studies that: (1) used immunohistochemistry to assess p53 expression in esophageal biopsies of BE patients and (2) reported subsequent neoplastic progression. We performed separate meta-analyses of case-control studies and cohort studies. We identified 14 relevant reports describing 8 case-control studies comprising 1435 patients and 7 cohort studies comprising 582 patients. In the case-control study meta-analysis of the risk of neoplasia with aberrant p53 expression, the fixed- and random-effect estimates of average effect size with aberrant p53 expression were OR 3.84, p < .001 (95% CI 2.79-5.27) and OR 5.95, p < .001 (95% CI 2.68-13.22), respectively. In the cohort study meta-analysis, the fixed- and random-effect estimates of average effect size were RR = 17.31, p < .001 (95% CI 9.35-32.08) and RR = 14.25, p < .001 (95% CI 6.76-30.02), respectively. Separate meta-analyses of case-control and cohort studies of BE patients who had baseline biopsies with p53 immunostaining revealed consistent, strong, and significant associations between aberrant p53 immunostaining and progression to high-grade dysplasia or esophageal adenocarcinoma. These findings support the use of p53 immunostaining as an adjunct to routine clinical diagnosis for dysplasia in BE patients.

Schiattarella, G. G., A. Sannino, G. Esposito and C. Perrino (2019). “Diagnostics and therapeutic implications of gut microbiota alterations in cardiometabolic diseases.” Trends Cardiovasc Med 29(3): 141-147.

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Alterations in gut microbiota composition and its metabolic activity are emerging as one of the most powerful determinants of cardiovascular disease. Although our knowledge of the precise molecular mechanisms by which gut microbiota influences cardiometabolic homeostasis is still limited, a growing body of knowledge has recently been uncovered about the potential modulation of microbiome for cardiovascular diagnostic and therapeutic aspects. The multitude of interactions between the microorganisms inhabiting the digestive tract and the host has been recognized crucial in the development and progression of atherosclerosis, obesity, diabetes and hypertension. Here, we summarize the role of gut microbiota in host physiology as well as in the pathophysiology of the most common cardio-metabolic disorders, discussing the potential therapeutic opportunities offered by interventions aimed at modifying microbiome composition and activity.