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Saadet Mercimek-mahmutoglu - One of the best experts on this subject based on the ideXlab platform.

  • A Prospective Case Study of the Safety and Efficacy of Lysine-Restricted Diet and Arginine Supplementation Therapy in a Patient With Pyridoxine-Dependent Epilepsy Caused by Mutations in ALDH7A1
    Pediatric neurology, 2016
    Co-Authors: Muhammad Mahajnah, Dawn Corderio, Carly Mutch, Melissa T. Carter, Valerie Austin, Sarah Herd, Saadet Mercimek-mahmutoglu
    Abstract:

    Abstract Background Pyridoxine-dependent epilepsy (PDE) is caused by mutations in ALDH7A1 (PDE- ALDH7A1 ), which encodes α-aminoadipic semialdehyde dehydrogenase in the lysine catabolic pathway, resulting in accumulation of α-aminoadipic-acid-semialdehyde. Patient Description and Results We present a three-year treatment outcome of a child with PDE- ALDH7A1 on pyridoxine (started at age three weeks of age), lysine-restricted diet (started at age seven months), and arginine supplementation therapy (started at age 26 months). He had a markedly elevated urinary α-aminoadipic-acid-semialdehyde (39.6 mmol/mol of creatinine; reference range = 0 to 2) and compound heterozygous mutations in ALDH7A1 (c.446C>A and c.919C>T). He has been seizure free since the age three weeks. He achieved normal cognitive function at age 3.5 years. He exhibited gross motor delay after the age 13 months. Tryptophan supplementation was added for the mild cerebral serotonin deficiency at the thirteenth month of therapy. Arginine supplementation was added to achieve further decrease in the cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels at the 26th month of therapy. His cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels were markedly decreased on this combined therapy. Conclusions This treatment was well tolerated. Mild cerebral serotonin deficiency was the only biochemical effect with no clinical features. Despite excellent compliance and strict treatment regimen, cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels did not normalize.

  • Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet.
    European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2014
    Co-Authors: Saadet Mercimek-mahmutoglu, Keith Hyland, Dawn Cordeiro, Lianna Kyriakopoulou, Vivian Cruz, Eva Mamak
    Abstract:

    Abstract Background and hypothesis Pyridoxine dependent epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE- ALDH7A1 ) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that l -arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE- ALDH7A1. Methods A 12-year-old male with PDE- ALDH7A1 was treated with l -arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. Results l -arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. Conclusion The short-term treatment outcome of this novel l -arginine supplementation therapy for PDE- ALDH7A1 was successful for biochemical and neurocognitive improvements.

  • Fetal Onset Ventriculomegaly and Subependymal Cysts in a Pyridoxine Dependent Epilepsy Patient
    Pediatrics, 2014
    Co-Authors: Shailly Jain-ghai, Cecil D Hahn, Navin Mishra, Susan Blaser, Saadet Mercimek-mahmutoglu
    Abstract:

    Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene encoding α-aminoadipic semialdehyde dehydrogenase. The classic clinical presentation is neonatal seizures responsive only to pyridoxine therapy. White matter abnormalities, corpus callosum agenesis or hypoplasia, megacisterna magna, cortical dysplasia, neuronal heterotopias, intracerebral hemorrhage, and hydrocephalus in neuroimaging have been reported in patients with PDE. We report a new patient with asymmetric progressive ventriculomegaly noted on fetal sonography at 22 weeks’ gestation. Postnatal brain sonography on day 1 and MRI on day 5 confirmed bilateral asymmetric ventriculomegaly caused by bilateral subependymal cysts. Intractable seizures at age 7 days initially responded to phenobarbital. Markedly elevated urinary α-aminoadipic acid semialdehyde levels and compound heterozygous mutations in the ALDH7A1 gene (c.446C>A/c.919C>T) confirmed the diagnosis of PDE caused by ALDH7A1 genetic defect. Despite the presence of structural brain malformations and subependymal cysts, PDE should always be included in the differential diagnosis of neonatal seizures that are refractory to treatment with antiepileptic drugs.

  • Profound Neonatal Hypoglycemia and Lactic Acidosis Caused by Pyridoxine-Dependent Epilepsy
    Pediatrics, 2012
    Co-Authors: Saadet Mercimek-mahmutoglu, Paula J Waters, Sylvia Stockler-ipsiroglu, Cornelis Jakobs, Gabriella Horvath, Marion B. Coulter-mackie, Tanya N. Nelson, Michael A. Sargent, Mary B. Connolly
    Abstract:

    Pyridoxine-dependent epilepsy (PDE) was first described in 1954. The ALDH7A1 gene mutations resulting in α-aminoadipic semialdehyde dehydrogenase deficiency as a cause of PDE was identified only in 2005. Neonatal epileptic encephalopathy is the presenting feature in >50% of patients with classic PDE. We report the case of a 13-month-old girl with profound neonatal hypoglycemia (0.6 mmol/L; reference range >2.4), lactic acidosis (11 mmol/L; reference range A (p.Val278Val), and a novel putative pathogenic missense mutation c.1192G>C (p.Gly398Arg) in the ALDH7A1 gene. She has been seizure-free since 1.5 months of age on treatment with pyridoxine alone. She has motor delay and central hypotonia but normal language and social development at the age of 13 months. This case is the first description of a patient with PDE due to mutations in the ALDH7A1 gene who presented with profound neonatal hypoglycemia and lactic acidosis masquerading as a neonatal-onset gluconeogenesis defect. PDE should be included in the differential diagnosis of hypoglycemia and lactic acidosis in addition to medically refractory neonatal seizures.

Donald Kufe - One of the best experts on this subject based on the ideXlab platform.

  • muc1 c oncoprotein activates erk c ebpβ signaling and induction of aldehyde dehydrogenase 1a1 in breast cancer cells
    Journal of Biological Chemistry, 2013
    Co-Authors: Maroof Alam, Rehan Ahmad, Hasan Rajabi, Akriti Kharbanda, Donald Kufe
    Abstract:

    Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is used as a marker of breast cancer stem cells; however, little is known about the regulation of ALDH1A1 expression. Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed in most human breast cancers. In studies of breast cancer cells stably silenced for MUC1 or overexpressing the oncogenic MUC1-C subunit, we demonstrate that MUC1-C is sufficient for induction of MEK→ERK signaling and that treatment with a MUC1-C inhibitor suppresses ERK activation. In turn, MUC1-C induces ERK-mediated phosphorylation and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor. The results further show that MUC1-C and C/EBPβ form a complex on the ALDH1A1 gene promoter and activate ALDH1A1 gene transcription. MUC1-C-induced up-regulation of ALDH1A1 expression is associated with increases in ALDH activity and is detectable in stem-like cells when expanded as mammospheres. These findings demonstrate that MUC1-C (i) activates a previously unrecognized ERK→C/EBPβ→ALDH1A1 pathway, and (ii) promotes the induction of ALDH activity in breast cancer cells. Background: Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is up-regulated in breast cancer cells by mechanisms that are unclear. Results: The MUC1-C oncoprotein induces ERK-mediated activation of the C/EBPβ transcription factor and, thereby, ALDH1A1 expression. Conclusion: MUC1-C activates a novel ERK→C/EBPβ→ALDH1A1 pathway that up-regulates ALDH activity. Significance: Overexpression of MUC1-C in breast cancer cells contributes to an ALDH+ phenotype that is linked to stemness.

  • muc1 c oncoprotein activates erk c ebpβ signaling and induction of aldehyde dehydrogenase 1a1 in breast cancer cells
    Journal of Biological Chemistry, 2013
    Co-Authors: Maroof Alam, Rehan Ahmad, Hasan Rajabi, Akriti Kharbanda, Donald Kufe
    Abstract:

    Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is used as a marker of breast cancer stem cells; however, little is known about the regulation of ALDH1A1 expression. Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed in most human breast cancers. In studies of breast cancer cells stably silenced for MUC1 or overexpressing the oncogenic MUC1-C subunit, we demonstrate that MUC1-C is sufficient for induction of MEK → ERK signaling and that treatment with a MUC1-C inhibitor suppresses ERK activation. In turn, MUC1-C induces ERK-mediated phosphorylation and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor. The results further show that MUC1-C and C/EBPβ form a complex on the ALDH1A1 gene promoter and activate ALDH1A1 gene transcription. MUC1-C-induced up-regulation of ALDH1A1 expression is associated with increases in ALDH activity and is detectable in stem-like cells when expanded as mammospheres. These findings demonstrate that MUC1-C (i) activates a previously unrecognized ERK→C/EBPβ→ALDH1A1 pathway, and (ii) promotes the induction of ALDH activity in breast cancer cells.

Baiyun Wang - One of the best experts on this subject based on the ideXlab platform.

  • aldehyde dehydrogenase 1a1 increases nadh levels and promotes tumor growth via glutathione dihydrolipoic acid dependent nad reduction
    Oncotarget, 2017
    Co-Authors: Baiyun Wang, Xue Chen, Zixi Wang, Wei Xiong, Xinyuan Zhao, Yang Cao, Yanru Guo, She Chen, Song Huang
    Abstract:

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.

Song Huang - One of the best experts on this subject based on the ideXlab platform.

  • aldehyde dehydrogenase 1a1 increases nadh levels and promotes tumor growth via glutathione dihydrolipoic acid dependent nad reduction
    Oncotarget, 2017
    Co-Authors: Baiyun Wang, Xue Chen, Zixi Wang, Wei Xiong, Xinyuan Zhao, Yang Cao, Yanru Guo, She Chen, Song Huang
    Abstract:

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.

Chen She - One of the best experts on this subject based on the ideXlab platform.

  • Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD(+) reduction
    ONCOTARGET, 2017
    Co-Authors: Wang Baiyun, Chen Xue, Wang Zixi, Xiong Wei, Xu Tao, Zhao Xinyuan, Cao Yang, Guo Yanru, Li Lin, Chen She
    Abstract:

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD(+) to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD(+) to NADH. The GSH/DHLA-dependent NAD(+)-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD(+)/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD(+) reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD(+)/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD(+)-reduction activity of ALDH1A1 can decrease cellular NAD(+)/NADH ratio and promote tumor growth.National Basic Program of China 973 Program [2013CB910104]; National Science Foundation of China [31271524]; start-up foundation from the Joint Center for Life Sciences in Peking University; Joint Center for Life Sciences in Peking UniversitySCI(E)ARTICLE4067043-67055