מום גנטי במתילציה באוטיזם- מחקר עדכני
בעקבות מסרים שהגיעו אלי, אני מצרפת
מאמר שאינני יודעת אם קראתם. נתונים חשובים לקרוא באנגלית יחסית פשוטה, על המום במתילציה באוטיזם, לעומת ילדים בריאים. Marvin Boris, M.D.; Allan Goldblatt, P.A.; Joseph Galanko, Ph.D.; S. Jill James, Ph.D. ABSTRACT Autism is a complex neurodevelopment disorder with numerous possible genetic and environmental influences. We retrospectively examined the laboratory data of 168 children sequentially referred to our facility with a confirmed diagnosis of autism or pervasive developmental disabilities (PDD). Since folate and methylation (single carbon metabolism) are vital in neurological development, we routinely screened children for the common mutations of the methylenetetrahydrofolate reductase gene (MTHFR), which regulates this pathway. All children had polymerase chain reaction (PCR) DNA evaluation to determine the frequency of the 677 and 1298 common polymorphisms in the MTHFRgene. We observed a significantly increased frequency of the homozygous mutation 677CT allele (TT): 23% in the autistic children compared to 11% in the control population ( <0.0001). Additionally, the heterozygous 677CT allele (CT) was present in 56% of the autistic children compared to 41% in the control population ( <0.0001). Somewhat paradoxically, the normal 1298AA allele was significantly higher in the autistic group, 55%, compared to the controls, 44% ( <0.05). Despite the increased frequency of normal 1298AA alleles, the compound 677CT/1298AC heterozygous mutations were more prevalent in the autistic population, 25%, than in controls, 15% ( =0.01). Overall, the data show an increased risk of autism spectrum disorder (ASD) associated with common mutations affecting the folate/methylation cycle. These associations by themselves may provide a partial explanation for a subgroup of children genomically at risk for ASD disorders. Increased folinic acid during pregnancy and early development may offset the genomic risk factors, and this deserves further study. Further, since folate-dependent methylation provides, in part, the methyl group for inactivation of monoamine neurotransmitters via the catecholamine-O-methyltransferase (COMT) system, this observation may help to further differentiate subtypes within the broad phenotype of ASD. A search for additional genomic and environmental risk factors should be undertaken. In particular, the methylation/transsulfation and COMT pathways should be investigated. P P P P Background It is generally accepted that the prevalence of autism and pervasive developmental disorders (PDD) has risen significantly in the last two decades. These disorders interfere with normal development of language and socialization. Atypical patterns of stereotypic and restricted activities are common features of these syndromes. Multiple theories regarding causality have been generated, and typically these focus on genetic vulnerability and environmental risk factors. As yet, no theory has gained wide acceptance. Association of MTHFR Gene Variants with Autism Clinically available testing for methylenetetrahydrofolate reductase (MTHFR) gene mutations (polymorphisms) has recently become available and had been incorporated into our evaluation process for developmentally delayed children. The MTHFR gene codes for an essential enzyme in folate metabolism. To further understand this condition, we retrospectively evaluated our findings regarding the genomic variations in the gene. MTHFR enzyme catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Methyltetrahydrofolate is essential in one-carbon-donor metabolism for the remethylation of homocysteine to methionine and the generation of metabolically active tetrahydrofolate in the methionine synthase reaction. Common polymorphisms in the MTHFR gene have been associated with reduced enzyme activity. A detailed review of folate metabolism andMTHFRis available from Schiver et al. MTHFR is located on chromosome 1 at 1p36.3. Common single nucleotide polymorphisms of the 677C T and the 1298A C alleles in the MTHFR gene decrease the activity of the enzyme. The 677C T allele has been associated with neural tube defects, cerebrovascular and cardiovascular disease, inflammatory bowel disease, colorectal cancer, and psychiatric disorders. The 677C T and the 1298AC gene variants are prevalent in many populations. The heterozygous 677CT genotype ranges from 13% in Africans to 51% in Italians and 44% in North American Caucasians. The homozygous 677TT rate in the last group is 12%. The prevalence of heterozygous genotype 1298AC among Caucasians in the United States was 47%, and that of the homozygous 1298AAmutant allele was 7.9%. The 677C T allele is characterized by a mutation of a cytosine to a thymine giving rise to an amino acid replacement of valine for alanine in the catalytic domain of the enzyme. Homozygosity for the mutant T allele is associated with a 60% reduction in enzyme activity. The 1298A C mutant allele has a cytosine substitution for adenine, resulting in a glutamate to alanine change within the Cterminal regulatory domain. Compound heterozygosity for both the 677CT and 1298AC is associated with a decrease of approximately 50%-60% inMTHFRactivity. In a study by Ramaekers et al., low 5-methyltetrahydrofolate levels in the spinal fluid of children who had normal neurodevelopment until age 4 to 6 months was associated with subsequent neurological regression. Addition of folinic acid as a dietary supplement corrected the symptoms. The observed favorable response to folinic acid further supports a central role for methylation in at least some developmental disorders. All the 168 Caucasian children, whose charts were retrospectively analyzed, were in the private practice of the principal investigator. A diagnosis of autism (73.8%) or PDD (26.2%) was previously made either by a neurologist, psychiatrist, neuropsychologist, or developmental pediatrician, and was confirmed by the investigator after referral. All the children meet Journal of American Physicians and Surgeons Volume 9 Number 4 Winter 2004
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