Baylor Scott and White Research Institute

Posted March 15th 2019

Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

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 Mar 4: e629. [Epub ahead of print]: 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.


Posted February 15th 2019

Can targeted metabolomics predict depression recovery? Results from the CO-MED trial

Erland Arning Ph.D.

Erland Arning Ph.D.

Czysz, A. H., C. South, B. S. Gadad, E. Arning, A. Soyombo, T. Bottiglieri and M. H. Trivedi (2019). “Can targeted metabolomics predict depression recovery? Results from the CO-MED trial.” Transl Psychiatry 9(1): 11.

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Metabolomics is a developing and promising tool for exploring molecular pathways underlying symptoms of depression and predicting depression recovery. The AbsoluteIDQ p180 kit was used to investigate whether plasma metabolites (sphingomyelins, lysophosphatidylcholines, phosphatidylcholines, and acylcarnitines) from a subset of participants in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial could act as predictors or biologic correlates of depression recovery. Participants in this trial were assigned to one of three pharmacological treatment arms: escitalopram monotherapy, bupropion-escitalopram combination, or venlafaxine-mirtazapine combination. Plasma was collected at baseline in 159 participants and again 12 weeks later at study exit in 83 of these participants. Metabolite concentrations were measured and combined with clinical and sociodemographic variables using the hierarchical lasso to simultaneously model whether specific metabolites are particularly informative of depressive recovery. Increased baseline concentrations of phosphatidylcholine C38:1 showed poorer outcome based on change in the Quick Inventory of Depressive Symptoms (QIDS). In contrast, an increased ratio of hydroxylated sphingomyelins relative to non-hydroxylated sphingomyelins at baseline and a change from baseline to exit suggested a better reduction of symptoms as measured by QIDS score. All metabolite-based models performed superior to models only using clinical and sociodemographic variables, suggesting that metabolomics may be a valuable tool for predicting antidepressant outcomes.


Posted February 15th 2019

Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Arora, K., J. M. Sequeira, J. M. Alarcon, B. Wasek, E. Arning, T. Bottiglieri and E. V. Quadros (2019). “Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.” FASEB J 33(2): 2563-2573.

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In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320(-/-)) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320(-/-) mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cbl deficiency remain unresolved, the Cd320(-/-) mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency. -Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.


Posted February 15th 2019

The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.

Binu Tharakan, Ph.D.

Binu Tharakan, Ph.D.

Anasooya Shaji, C., B. D. Robinson, A. Yeager, M. R. Beeram, M. L. Davis, C. L. Isbell, J. H. Huang and B. Tharakan (2019). “The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.” Sci Rep 9(1): 133.

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Hydrogen peroxide (H2O2) plays an important role physiologically as the second messenger and pathologically as an inducer of oxidative stress in injury, ischemia and other conditions. However, it is unclear how H2O2 influences various cellular functions in health and disease differentially, particularly in the blood-brain barrier (BBB). We hypothesized that the change in cellular concentrations of H2O2 is a major contributor in regulation of angiogenesis, barrier integrity/permeability and cell death/apoptosis in BBB endothelial cells. Rat brain microvascular endothelial cells were exposed to various concentrations of H2O2 (1 nM to 25 mM). BBB tight junction protein (zonula ocludens-1; ZO-1) localization and expression, cytoskeletal organization, monolayer permeability, angiogenesis, cell viability and apoptosis were evaluated. H2O2 at low concentrations (0.001 muM to 1 muM) increased endothelial cell tube formation indicating enhanced angiogenesis. H2O2 at 100 muM and above induced monolayer hyperpermeability significantly (p < 0.05). H2O2 at 10 mM and above decreased cell viability and induced apoptosis (p < 0.05). There was a decrease of ZO-1 tight junction localization with 100 mum H2O2, but had no effect on protein expression. Cytoskeletal disorganizations were observed starting at 1 mum. In conclusion H2O2 influences angiogenesis, permeability, and cell death/apoptosis in a tri-phasic and concentration-dependent manner in microvascular endothelial cells of the blood-brain barrier.


Posted January 15th 2019

Targeted metabolomics to understand the association between arsenic metabolism and diabetes-related outcomes: Preliminary evidence from the Strong Heart Family Study.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Spratlen, M. J., M. Grau-Perez, J. G. Umans, J. Yracheta, L. G. Best, K. Francesconi, W. Goessler, T. Bottiglieri, M. V. Gamble, S. A. Cole, J. Zhao and A. Navas-Acien (2019). “Targeted metabolomics to understand the association between arsenic metabolism and diabetes-related outcomes: Preliminary evidence from the Strong Heart Family Study.” Environ Res 168: 146-157.

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BACKGROUND: Inorganic arsenic exposure is ubiquitous and both exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes. This profile, however, has also been associated with increased risk for diabetes-related outcomes. OBJECTIVES: The mechanism behind these conflicting associations is unclear; we hypothesized the one-carbon metabolism (OCM) pathway may play a role. METHODS: We evaluated the influence of OCM on the relationship between arsenic metabolism and diabetes-related outcomes (HOMA2-IR, waist circumference, fasting plasma glucose) using metabolomic data from an OCM-specific and P180 metabolite panel measured in plasma, arsenic metabolism measured in urine, and HOMA2-IR and FPG measured in fasting plasma. Samples were drawn from baseline visits (2001-2003) in 59 participants from the Strong Heart Family Study, a family-based cohort study of American Indians aged >/=14 years from Arizona, Oklahoma, and North/South Dakota. RESULTS: In unadjusted analyses, a 5% increase in DMA% was associated with higher HOMA2-IR (geometric mean ratio (GMR)= 1.13 (95% CI: 1.03, 1.25)) and waist circumference (mean difference=3.66 (0.95, 6.38). MMA% was significantly associated with lower HOMA2-IR and waist circumference. After adjustment for OCM-related metabolites (SAM, SAH, cysteine, glutamate, lysophosphatidylcholine 18.2, and three phosphatidlycholines), associations were attenuated and no longer significant. CONCLUSIONS: These preliminary results indicate that the association of lower MMA% and higher DMA% with diabetes-related outcomes may be influenced by OCM status, either through confounding, reverse causality, or mediation.