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 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.

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.

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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/kd/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., 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.

Full text of this article.

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.

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.

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.