Folate Pathway Polymorphisms Predict Deficits in Attention and Processing Speed After Childhood Leukemia Therapy

Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 09/2011; 57(3):454-60. DOI: 10.1002/pbc.23162
Source: PubMed


Neurocognitive impairment occurs in 20-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.
Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), serine hydroxymethyltransferase (SHMT 1420C>T), methionine synthase (MS 2756 A>G), methionine synthase reductase (MTRR 66A>G), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype.
General impairment on the neurocognitive battery was related to MTHFR 1298A>C (P = 0.03) and MS 2756A>G (P = 0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (P = 0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (P = 0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (P = 0.03). Survivors with ≥6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (P = 0.06) and 14.5 point lower TMTB score (P = 0.002) than survivors with <6 risk alleles.
Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy.

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    • "Krull and colleagues (2008) demonstrated that MTHFR variants (C677T and A1298C [rs1801131]) are associated with an increased likelihood of inattention problems following chemotherapy. Other polymorphisms of genes involved in OCM, such as methionine synthase (A2756G; rs1805087) and thymidylate synthase (1494del6; rs34489327) (see Figure 1), also increase the risk of functional impairments in ALL survivors (Kamdar et al., 2011; Krull et al., 2013). In other words, chemotherapeutic agents may have a differential impact on neurocognitive outcomes due to underlying genetic variation. "
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    ABSTRACT: Childhood cancer survivors frequently experience long-lasting consequences of chemotherapy on health outcomes. Neurocognitive late effects of chemotherapy occur in 40 - 60% of acute lymphoblastic leukemia (ALL) survivors. These deficits affect mental health, school performance, job success, and are associated with poor quality of life, therefore presenting a clinical challenge for psychiatrists. However, not all cancer survivors are impacted by treatment in the same manner and emerging evidence suggests that genetic variation may modulate neurocognitive outcomes. Much like other complex psychopathologies, neurocognitive deficits in cancer survivors are the result of complex interactions between genetic and environmental variables. This review describes adverse neurocognitive outcomes observed in survivors of acute lymphoblastic leukemia (ALL) and discusses genetic variability in biochemical pathways targeted by chemotherapeutic agents as a possible mechanism contributing to psychopathology in ALL survivors.
    Full-text · Article · Feb 2015 · Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent
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    • "To date, there have been no studies evaluating methylation status in ADHD, although the presence of oxidative stress strongly suggests that impaired methylation may occur. In a related recent study, Kamdar et al. (2011) found that the level of impaired attention and cognitive processing speed after childhood chemotherapy for leukemia was related to the prevalence of single-nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR) and MTR. MTHFR provides methyl groups to MTR, which supports both SAM synthesis and dopaminestimulated PLM (Sharma et al., 1999). "
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    • "Individuals homozygous for the low activity T allele of MTHFR have higher overall plasma levels of homocysteine (Jacques et al., 1996; Rozen, 1997; Yang et al., 2008). The 677T variant has been associated with various psychological conditions including depression and/or loneliness, and with attention deficit hyperactivity disorder in specific patient populations (Hickie et al., 2001; Krull et al., 2008; Holmes et al., 2011; Kamdar et al., 2011; Lan et al., 2012). Because MTHFR and folic acid metabolism are important for providing metabolites for methylation, and because disulfiram and cocaine can both affect DNA and/or histone methylation levels, the pharmacogenetic effect in disulfiram treatment for CD may be related to the interaction of these epigenetic effects. "
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