Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency.
ABSTRACT We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.
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ABSTRACT: Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250 mg/day, N = 32) and placebo groups (N = 35) for 10 weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N = 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81-69% (p = 0.007). Conclusion: This study indicates that a patient's MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630.Frontiers in Psychiatry 01/2012; 3:109. DOI:10.3389/fpsyt.2012.00109
Article: Human Genetics Division Photo
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ABSTRACT: Some epigenetic mechanisms, including DNA methylation and histone deacetylation, act as transcriptional repression signals. In this study, we examined whether DNA methylation dependent transcriptional control regulates glial cell growth. Primary cultured mouse cortical glial cells were treated with the DNA methylation inhibitor 5-aza-deoxycytidine (5adC) or the histone deacetylase inhibitor sodium valproate (VPA), which inhibits DNA-methylation-dependent transcriptional repression. 5adC significantly reduced methylated C level determined by reversed-phase high-performance liquid chromatography (HPLC), while VPA did not. Treatments with these inhibitors significantly reduced cell number determined by MTT assay after 48 h. Both 5adC and VPA showed little cellular toxicity observed by live and dead cell staining. In contrast, both 5adC and VPA induced an abnormality in the cell cycle. Cells treated with the inhibitors represented a significantly higher ratio in the G2+M-phase and 5adC-treated cells showed a significantly lower ratio in the S-phase. Regarding the in vivo effect, prenatal treatment with VPA, which is an autistic model in rodents, significantly reduced the brain/body weight ratio in early postnatal days. Our data indicate that DNA-methylation- and histone-deacetylation-dependent transcriptional control is crucial for the regulation of glial cell growth. Our data suggest that abnormalities of epigenetic transcriptional regulatory mechanisms in glial cells cause an abnormal brain size, which may in turn cause mental diseases.Journal of Bioscience and Bioengineering 06/2008; 105(5):470-5. DOI:10.1263/jbb.105.470 · 1.79 Impact Factor