Abnormally High Plasma Levels of Vitamin B<sub>6</sub> in Children with Autism Not Taking Supplements Compared to Controls Not Taking Supplements

Adams, James B.; George, Frank R.; Audhya, Tapan

doi:10.1089/acm.2006.12.59

Cited by 74 publications

(58 citation statements)

References 15 publications

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“…Therapy with vitamin B 6 reduces homocysteine levels and appears to improve the symptoms experienced by chronic schizophrenic patients (18,42). Another study found that children with the autism spectrum show consistently higher concentrations of primary B 6 vitamers and significantly lower levels of PLP as compared with normal subjects (15). This study concluded that the autistic patients probably have defective PL kinase that was unable to metabolize the primary vitamers into PLP.…”

Section: The Pnp Oxidase R229w Mutation Alters the Conformation Of Kementioning

confidence: 84%

Molecular Basis of Reduced Pyridoxine 5′-Phosphate Oxidase Catalytic Activity in Neonatal Epileptic Encephalopathy Disorder

Musayev

Salvo

Saavedra-Torres

et al. 2009

Journal of Biological Chemistry

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Mutations in pyridoxine 5-phosphate oxidase are known to cause neonatal epileptic encephalopathy. This disorder has no cure or effective treatment and is often fatal. Pyridoxine 5-phosphate oxidase catalyzes the oxidation of pyridoxine 5-phosphate to pyridoxal 5-phosphate, the active cofactor form of vitamin B 6 required by more than 140 different catalytic activities, including enzymes involved in amino acid metabolism and biosynthesis of neurotransmitters. Our aim is to elucidate the mechanism by which a homozygous missense mutation (R229W) in the oxidase, linked to neonatal epileptic encephalopathy, leads to reduced oxidase activity. The R229W variant is ϳ850-fold less efficient than the wild-type enzyme due to an ϳ192-fold decrease in pyridoxine 5-phosphate affinity and an ϳ4.5-fold decrease in catalytic activity. There is also an ϳ50-fold reduction in the affinity of the R229W variant for the FMN cofactor. A 2.5 Å crystal structure of the R229W variant shows that the substitution of Arg-229 at the FMN binding site has led to a loss of hydrogen-bond and/or salt-bridge interactions between FMN and Arg-229 and Ser-175. Additionally, the mutation has led to an alteration of the configuration of a ␤-strand-loop-␤-strand structure at the active site, resulting in loss of two critical hydrogen-bond interactions involving residues His-227 and Arg-225, which are important for substrate binding and orientation for catalysis. These results provide a molecular basis for the phenotype associated with the R229W mutation, as well as providing a foundation for understanding the pathophysiological consequences of pyridoxine 5-phosphate oxidase mutations.

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Section: The Pnp Oxidase R229w Mutation Alters the Conformation Of Kementioning

confidence: 84%

Molecular Basis of Reduced Pyridoxine 5′-Phosphate Oxidase Catalytic Activity in Neonatal Epileptic Encephalopathy Disorder

Musayev

Salvo

Saavedra-Torres

et al. 2009

Journal of Biological Chemistry

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“…Increased glutamate levels in autism could be explained by presence of low levels of Pyridoxal Phosphate (PLP) in children with autism due to very low activity of pyridoxal kinase leading to blockage of glutamate utilization [32]. Also, alterations in the glutamate transporter or in glutaminase or glutamine synthetase activity would potentially affect glutamate levels [33].…”

Section: Discussionmentioning

confidence: 99%

Autism and Fragile X: Is There a Neurochemical Link?

Meguid

Atta

Rashed

et al. 2014

Open Access Maced J Med Sci

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“…Like NEE, several other neurological disorders, including seizures, autism, attention deficit hyperactive disorder, Alzheimer's, Down Syndrome, schizophrenia, Parkinson's, learning disability, anxiety disorders have also been associated with PLP deficiency [45,[84][85][86][87][88][89]. This has inspired considerable interest in treating the symptoms of some of these disorders with vitamin B 6 .…”

Section: Discussionmentioning

confidence: 99%

Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

Ghatge¹,

Salvo²,

Contestabile³

et al. 2012

Miscellanea on Encephalopathies - A Second Look

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Abnormally High Plasma Levels of Vitamin B₆ in Children with Autism Not Taking Supplements Compared to Controls Not Taking Supplements

Cited by 74 publications

References 15 publications

Molecular Basis of Reduced Pyridoxine 5′-Phosphate Oxidase Catalytic Activity in Neonatal Epileptic Encephalopathy Disorder

Molecular Basis of Reduced Pyridoxine 5′-Phosphate Oxidase Catalytic Activity in Neonatal Epileptic Encephalopathy Disorder

Autism and Fragile X: Is There a Neurochemical Link?

Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

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Abnormally High Plasma Levels of Vitamin B6 in Children with Autism Not Taking Supplements Compared to Controls Not Taking Supplements

Cited by 74 publications

References 15 publications

Molecular Basis of Reduced Pyridoxine 5′-Phosphate Oxidase Catalytic Activity in Neonatal Epileptic Encephalopathy Disorder

Molecular Basis of Reduced Pyridoxine 5′-Phosphate Oxidase Catalytic Activity in Neonatal Epileptic Encephalopathy Disorder

Autism and Fragile X: Is There a Neurochemical Link?

Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

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Abnormally High Plasma Levels of Vitamin B₆ in Children with Autism Not Taking Supplements Compared to Controls Not Taking Supplements