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Aberrations in Folate Metabolic Pathway and Altered Susceptibility

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Aberrations in Folate Metabolic Pathway and Altered Susceptibility Original article 171 Aberrations in folate metabolic pathway and altered susceptibility to autism Naushad Shaik Mohammada, Jamal Md Nurul Jaina, Krishna Prasad Chintakindia, Ram Prakash Singha, Usha Naikb and Radha Rama Devi Akellaa Objective To investigate whether genetic polymorphisms frequency was similar in both the groups (53.3 vs. are the underlying causes for aberrations in folate pathway 53.6%) and hence individually not associated with that was reported in autistic children. any risk. However, this allele was found to act additively in the presence of MTHFR 677T allele as evidenced by Basic methods A total of 138 children diagnosed as 8.11-fold (95% CI: 2.84–22.92) risk associated with autistic based on Diagnostic and Statistical Manual MTHFR 677CT + TT/1298AC + CC genotypes cumulatively. of Mental Disorders, fourth edition criteria and Autism Behavior Checklist scoring and 138 age and sex matched Conclusion MTHFR C677T is a risk factor, whereas children who are nonautistic were tested for five genetic MTRR A66G and SHMT C1420T polymorphisms polymorphisms, that is, cytosolic serine hydroxyl methyl reduce risk for autism. MTHFR A1298C acts additively in transferase (SHMT1 C1420T), methylene tetrahydrofolate increasing the risk for autism. Psychiatr Genet 19:171–176 reductase (MTHFR C677T and MTHFR A1298C), c 2009 Wolters Kluwer Health | Lippincott Williams & methionine synthase reductase (MTRR A66G), Wilkins. methionine synthase (MS A2756G) using PCR-restriction fragment length polymorphism methods. Fisher’s exact Psychiatric Genetics 2009, 19:171–176 test and logistic regression analysis were used for statistical analyses. Keywords: autism, methionine synthase reductase, methylene tetrahydrofolate reductase, serine hydroxymethyl transferase, single nucleotide polymorphisms, susceptibility Results MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic aCenter for DNA Fingerprinting and Diagnostics and bInstitute of Child Health, children (16.3 vs. 6.5%) with 2.79-fold increased risk Niloufer Hospital, Hyderabad, India for autism [95% confidence interval (CI): 1.58–4.93]. The Correspondence to Dr Radha Rama Devi Akella, MD, Consultant Medical frequencies of MTRR 66A allele (12.7 vs. 21.0%) and SHMT Geneticist, Diagnostic Division, Center for DNA Fingerprinting and Diagnostics 1420T allele (27.9 vs. 45.3%) were lower in autistic group (CDFD) 7-18, Nacharam, Hyderabad-500076, Andhra Pradesh, India compared with nonautistic group with odds ratios 0.55 Tel: + 91 40 27171462; e-mail: [email protected] (95% CI: 0.35–0.86) and 0.44 (95% CI: 0.31–0.62), Received 27 May 2008 Revised 12 December 2008 respectively, indicating reduced risk. MTHFR 1298C-allele Accepted 12 March 2009 Introduction dictated by a polygenic mode of inheritance as well as Autism (MIM:209850), one of the pervasive develop- being modulated by environmental exposures. mental disorders, manifests before 3 years of age and is characterized by impaired communication, social Moretti et al. (2005) have observed low cerebral methyl interaction, and creative or imaginative play. Clinically tetrahydrofolate in a 6-year-old girl with developmental the diagnosis of autism is based on Diagnostic and Statistical delay, psychomotor regression, seizures, mental retardation, Manual of Mental Disorders and International Classification of and autistic features, and marked improvement in motor Diseases, 10th Revision criteria. Folstein and Piven (1991) skills by folinic acid supplementation. James et al. (2004) have highlighted the role of genetic factors, the prenatal have observed low methionine, low S-adenosyl methio- and perinatal environment in the etiology of autism. nine (SAM)/S-adenosyl homocysteine (SAH) ratio, low Bailey et al. (1995) have shown that autism cysteine, and low glutathione levels, and no alteration was predominantly genetically determined, with high in homocysteine levels in autism. They also showed prevalence among monozygotic twins compared with beneficial effects of supplementation with folic acid/ dizygotic twins. A common genetic basis is assumed but folinic acid, betaine, and methylcobalamin in autistic as various forms or degrees of severity of autism have children. These studies indicate that defects in the folate been observed in a single family, susceptibility is probably pathway may play an important role in the pathophysiology 0955-8829 c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YPG.0b013e32832cebd2 172 Psychiatric Genetics 2009, Vol 19 No 4 of autism. These observations have resulted in consider- wide ethnic and population level variations in the able interest in the study of polymorphisms in genes distribution of these polymorphisms. Polymorphisms in involved in the folate pathway as risk factors for autism. other loci involved in folate metabolism such as reduced folate carrier (80G-A), transcobalamin II (776G-C), - We have hypothesized that low 5-methyl tetrahydro- catechol-O-methyltransferase (472G A), MTHFR - - folate could be because of alterations in the activities of (677C T and 1298A C), and glutathione-S-transferase two enzymes, that is, serine hydroxymethyl transferase (M1) have been studied by James et al. (2006) and (SHMT1, MIM:182144) and methylene tetrahydro- significant gene–gene interactions were found. Given the folate reductase (MTHFR, MIM:607093) because the interconnected nature of the folate pathway, it is possible former catalyzes the reversible conversion of serine that particular combinations of genetic variants may and tetrahydrofolate to glycine and 5,10-methylene underlie autism susceptibility. tetrahydrofolate and the latter catalyzes the flavin adenine dinucleotide-dependent conversion of 5,10- Here, we examine the associations between five folate methylene tetrahydrofolate to 5-methyltetrahydrofolate. pathway genetic polymorphisms, that is, SHMT1 Low methionine and low SAM/SAH ratio could be C1420T, MTHFR C677T, MTHFR A1298C, MTRR because of alterations in the activities of two enzymes, A66G, and methionine synthase (MS A2756G) and the that is, 5-methyltetrahydrofolate homocysteine methyl susceptibility to autism in a cohort of autistic children transferase (MTR, MIM:156570) and methionine and nonautistic children from South India. synthase reductase (MTRR, MIM:602568) because the former catalyzes the remethylation of homocysteine to Methods methionine in presence of 5-methyltetrahydrofolate as Participants cosubstrate and methylcobalamin as cofactor and the The study population consisted of autistic children latter is responsible for regeneration of MTR enzyme, (n = 138), nonautistic control children (n = 138). Re- which is inactivated because of oxidation of its cofactor cruitment took place during the period of 2001–2006. cob(I)alamin to cob(II)alamin, by reductive methylation A multidisciplinary team comprising of psychiatrists, in which SAM is used as methyl donor. clinical psychologists, speech therapists, and a psychiatric social worker evaluated the cases. The diagnosis of Among these four genes, two genes, that is, SHMT and autism was made in a two-tier system. Initially all the MTHFR encode possible rate-limiting enzymes within participants were evaluated for DSM-IV criteria. All the pathway. Increase in cSHMT expression increases the participants who met the criteria were subjected flux of one carbon metabolism through thymidylate to Autism Behavior Checklist (ABC) scoring based on synthesis and inhibits homocysteine remethylation by 57 questions. Parents were asked to answer all the competing with MTHFR for 5,10-methylene tetrahydro- questions. The scores for five different domains namely folate substrate (Herbig et al., 2002). Changes in MTHFR sensory stimuli, relating, body and object use, language, activity may tilt the balance of one-carbon metabolism and social self-help were obtained based on the parental in favor of DNA synthesis at the expense of methyl interview. Children who scored greater than 68 were supply (i.e. SAM) for methylation reactions; a suboptimal enrolled as cases and control children had ABC scoring methyl supply can lead to aberrant DNA methylation less than 21. In addition, children were assessed on (Xu et al., 2007). Among the several polymorphisms in these language function using Receptive Expressive, Emergent four crucial genes, five polymorphisms, that is, SHMT Language Scale and developmental assessment (using C1420T (L474F, rs1979277), MTHFR C677T (A222V, different tests including the Gessells Developmental rs1801133), MTHFR A1298C (E429A, rs1801131), MTR Test, the Raven’s Coloured Matrices, the Vineland Social A2756G (D919G, rs1805087), and MTRR A66G (I22M, Maturity test, and the Binet Kamat test for general rs1801394) are widely distributed throughout the globe, Mental Ability). The developmental quotient (DQ) in synonymous and except one (MTHFR A1298C), the autistic group ranged from 30 to 80 and most of all others are functionally relevant. The reported them have mild-to-moderate developmental delay. The frequencies of minor alleles for MTHFR C677T, mean age of cases was 4.4 ± 1.7 years (age group ranging MTHFR A1298C, MTR A2756G, and MTRR A66G from 2 to 10 years). In the study group, there were 120 polymorphisms in this population were 10, 40.7, (Radha males and 18 females. Rama Devi et al., 2004) 26.4, and 30.1% (Naushad et al., 2008), respectively. The frequency of SHMT C1420T Out of the 150 normal controls who were evaluated for polymorphism was not yet reported in this population.
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