Folate Pathway Genetic Polymorphisms are Related to Attention Disorders in Childhood Leukemia Survivors

Krull, Kevin R.; Brouwers, Pim; Jain, Neelam; Zhang, Linna; Bomgaars, Lisa; Dreyer, ZoAnn E.; Mahoney, Donald H.; Bottomley, Sarah; Okcu, M. Fatih

doi:10.1016/j.jpeds.2007.05.047

Cited by 90 publications

(65 citation statements)

References 29 publications

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“…Consistent with our previous reports, 6,7 we hypothesized that polymorphisms in the folate pathway would be associated with attention problems.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Osupporting

confidence: 82%

“…We recently reported a link between polymorphisms associated with the folate pathway and parent-reported attention problems and neurocognitive measures in long-term survivors of childhood ALL. 6,7 Among these survivors treated with chemotherapy only, those who had germline polymorphisms of 10-methylenetetrahydrofolate reductase (MTHFR) demonstrated elevated ratings on parent-reported attention problems, whereas children with polymorphisms in either MTHFR or the methionine synthase (MS) gene demonstrated reduced performance on direct measures of attention and processing speed.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

Krull

Bhojwani

Conklin

et al. 2013

JCO

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A B S T R A C T PurposeSurvivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome. Patients and MethodsNeurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity. ResultsCompared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P ϭ .01) and on parent ratings of attention problems (P ϭ .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P ϭ .03) and response speed (P ϭ .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P ϭ .01) and reduced attentiveness (P ϭ .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P ϭ .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P ϭ .01). ConclusionThese results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.

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“…Consistent with our previous reports, 6,7 we hypothesized that polymorphisms in the folate pathway would be associated with attention problems.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Osupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

Krull

Bhojwani

Conklin

et al. 2013

JCO

Self Cite

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“…Other, currently unknown moderators of treatment effects may emerge over time, and it is crucial for researchers to provide adequate details of study participants, including genetic and biochemical variables. For example, Krull et al [2008] documented a relationship between folate pathway genetic polymorphisms and development of attention-deficit/ hyperactivity disorder (ADHD) after ALL therapy. Moore et al [2008] found a relationship between methotrexate-induced alterations in beta-oxidation and intellectual and academic abilities.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Neurodevelopmental sequelae of pediatric acute lymphoblastic leukemia and its treatment

Janzen

Spiegler

2008

Dev Disabil Res Revs

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This review will describe the neurocognitive outcomes associated with pediatric acute lymphoblastic leukemia (ALL) and its treatment. The literature is reviewed with the aim of addressing methodological issues, treatment factors, risks and moderators, special populations, relationship to neuroimaging findings, and directions for future research. It is concluded that neurocognitive outcomes for the majority of children with standard-risk ALL treated according to current chemotherapy protocols is relatively good, but subgroups of children are more significantly compromised. As medical treatments advance and survival rates continue to improve, neurocognitive outcomes and other quality of life indicators will become increasingly important. Preventing or ameliorating treatment-related neuropsychological sequelae represents the next major challenge in pediatric ALL.

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“…Survivors of the ALL type of leukemia may develop ADHD. Linkage was found between the polymorphisms in the gene for methylene tetrahydrofolate reductase and inattentive symptoms in these subjects, indicating a link between the folic acid metabolism and ADHD [49] . It would therefore be interesting to compare the incidences of ADHD between societies with fortified cereals and those without.…”

Section: Use Of Nutrients In Epigenetic Treatmentmentioning

confidence: 87%

Epigenetic Manifestations in Diet-Related Disorders

Mariman

2008

Lifestyle Genomics

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Epigenetic phenomena are changes in phenotype that are due to resetting of gene expression under the influence of the environment or genetic factors without changing the DNA sequence. Usually this resetting occurs at a certain stage in life and remains fixed thereafter. In humans, evidence for epigenetic involvement in diet-related complex traits and disorders is accumulating. The fetal origins theory indicates that nutrition can influence the later life risk for certain common disorders like the metabolic syndrome. In parent-of-origin effects, the risk for a common disorder like type I diabetes depends on the sex of the parent who transmits genetic risk factors. Interestingly, both dietary and genetic factors can exert their epigenetic influence over several generations. Imprinting, i.e. silencing of one copy of an autosomal pair of genes, can be part of the mechanism pointing to the importance of DNA methylation. In addition, chromatin modifications have been shown to be involved in epigenetic manifestations. The intriguing possibility that diet may influence the direction and extent of epigenetic changes opens new ways for prevention or treatment of common disorders. At the same time, maternal nutrition might be used to actively direct fetal development with consequences for later life performance such as cognitive abilities. More knowledge on those novel applications is needed. This will in part come from novel strategies to map the epigenomic regions, allowing the identification of more genes involved in epigenetics and allowing the study of their response to nutrition.

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Folate Pathway Genetic Polymorphisms are Related to Attention Disorders in Childhood Leukemia Survivors

Cited by 90 publications

References 29 publications

Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

Neurodevelopmental sequelae of pediatric acute lymphoblastic leukemia and its treatment

Epigenetic Manifestations in Diet-Related Disorders

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