Autism Abstracts 1

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Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence.
            (DeVilbiss et al., 2015) Download
Emerging evidence from epidemiological studies supports the notion that maternal folate status regulated by dietary and genetic factors early in pregnancy may influence the risk of autism spectrum disorders (ASD). In this review, we provide an overview of what is known about the role of folate in the aetiology of neurodevelopmental disorders; summarise relevant biological, genetic and epigenetic mechanisms; and synthesise the evidence from human observational studies and randomised controlled trials that have examined the relationship between maternal folate and ASD or related traits. Much of the existing literature on this topic is subject to limitations such as potential confounding by healthy behaviours and other dietary factors, and exposure assessed within limited exposure windows. As the existing evidence is inconclusive, further research remains to be conducted in order to verify this hypothesis. Complete assessment of maternal functional folate status through the pre- and peri-conceptional periods requires biological measurement of folate, vitamin B12 and homocysteine and genetic variants involved in one-carbon metabolism and epigenetic mechanisms. In addition to more complete assessment of maternal functional folate status, careful consideration of potential confounding is warranted.

Cerebral folate receptor autoantibodies in autism spectrum disorder.
            (Frye et al., 2013) Download
Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

Folate and methionine metabolism in autism: a systematic review.
            (Main et al., 2010) Download
BACKGROUND:  Autism is a complex neurodevelopmental disorder that is increasingly being recognized as a public health issue. Recent evidence has emerged that children with autism may have altered folate or methionine metabolism, which suggests the folate-methionine cycle may play a key role in the etiology of autism. OBJECTIVE:  The objective was to conduct a systematic review to examine the evidence for the involvement of alterations in folate-methionine metabolism in the etiology of autism. DESIGN:  A systematic literature review was conducted of studies reporting data for metabolites, interventions, or genes of the folate-methionine pathway in autism. Eighteen studies met the inclusion criteria, 17 of which provided data on metabolites, 5 on interventions, and 6 on genes and their related polymorphisms. RESULTS:  The findings of the review were conflicting. The variance in results can be attributed to heterogeneity between subjects with autism, sampling issues, and the wide range of analytic techniques used. Most genetic studies were inadequately powered to provide more than an indication of likely genetic relations. CONCLUSIONS:  The review concluded that further research is required with appropriately standardized and adequately powered study designs before any definitive conclusions can be made about the role for a dysfunctional folate-methionine pathway in the etiology of autism. There is also a need to determine whether functional benefits occur when correcting apparent deficits in folate-methionine metabolism in children with autism.

Aberrations in folate metabolic pathway and altered susceptibility to autism.
            (Mohammad et al., 2009) Download
OBJECTIVE:  To investigate whether genetic polymorphisms are the underlying causes for aberrations in folate pathway that was reported in autistic children. BASIC METHODS:  A total of 138 children diagnosed as autistic based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria and Autism Behavior Checklist scoring and 138 age and sex matched children who are nonautistic were tested for five genetic polymorphisms, that is, cytosolic serine hydroxyl methyl transferase (SHMT1 C1420T), methylene tetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C), methionine synthase reductase (MTRR A66G), methionine synthase (MS A2756G) using PCR-restriction fragment length polymorphism methods. Fisher's exact test and logistic regression analysis were used for statistical analyses. RESULTS:  MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (16.3 vs. 6.5%) with 2.79-fold increased risk for autism [95% confidence interval (CI): 1.58-4.93]. The frequencies of MTRR 66A allele (12.7 vs. 21.0%) and SHMT 1420T allele (27.9 vs. 45.3%) were lower in autistic group compared with nonautistic group with odds ratios 0.55 (95% CI: 0.35-0.86) and 0.44 (95% CI: 0.31-0.62), respectively, indicating reduced risk. MTHFR 1298C-allele frequency was similar in both the groups (53.3 vs. 53.6%) and hence individually not associated with any risk. However, this allele was found to act additively in the presence of MTHFR 677T allele as evidenced by 8.11-fold (95% CI: 2.84-22.92) risk associated with MTHFR 677CT+TT/1298AC+CC genotypes cumulatively. CONCLUSION:  MTHFR C677T is a risk factor, whereas MTRR A66G and SHMT C1420T polymorphisms reduce risk for autism. MTHFR A1298C acts additively in increasing the risk for autism.

Maternal plasma folate, vitamin B12 levels and multivitamin supplementation during pregnancy and risk of Autism Spectrum Disorder in the Boston Birth Cohort (ABSTRACT)
            (Raghavan et al., 2016) Download
Data are from the Boston Birth Cohort, an ongoing longitudinal prospective birth cohort study that recruited low-income urban, primarily minority mother-offspring pairs (n=1,391) at the Boston Medical Center and followed them from birth through childhood between 1998–2013. Based on electronic medical records, children were diagnosed as having ASD (n=107) or categorized as ‘typical’ (n=1284). n this urban low-income minority birth cohort, we observed an elevated risk of ASD associated with high maternal plasma folate levels (>59 nmol/L), which far exceeds the excess cutoff suggested by the WHO (>45.3 nmol/L); however reported maternal vitamin supplementation was protective. Excess maternal vitamin B12 (>600 pmol/L) in pregnancy was also shown to be associated with greater ASD risk in offspring. The risk of ASD was highest if mothers had both excess prenatal folate and vitamin B12 levels.

Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.
            (Rogers, 2008) Download
The inverse association between maternal folate status and incidence of infants born with neural tube defects (NTD's) was recognized over twenty years ago and led the US health agencies in the early 1990s to recommend that women of childbearing age consume 400 microg of folic acid each day. The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's. However, this same time period directly coincides with what many feel is the apparent beginning and continuous increase in the prevalence of Autism and related Autism Spectrum Disorders (ASD's) in the US. Are these similar time frames of changes in maternal folate status and possible Autism prevalence a random event or has improved maternal (and fetal) folate status during pregnancy played a role? It is not only plausible but highly likely. A particular polymorphic form to a key enzyme required to activate folate for methylation in neurodevelopment, 5-methylenetetrahydrofolate reductase (MTHFR), demonstrates reduced activity under low or normal folate levels but normal activity under conditions of higher folate nutritional status. A consequence of the presence of the polymorphic form of this enzyme during normal or reduced folate status are higher plasma homocysteine levels than noncarriers and the combination of these factors have been shown in several studies to result in an increase rate of miscarriage via thrombotic events. However, the incidence of hyperhomocysteinemia in the presence of the polymorphism is reduced under the common condition of enhanced folate status and thereby masks the latent adverse effects of the presence of this enzyme form during pregnancy. Of great importance is that this polymorphism, although common in the normal population, is found in significantly higher frequency in Autisic individuals. It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates. This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period. If these numbers have increased then so have the absolute number of infants that after birth fail to maintain the higher folate status experienced in utero thus leading to an increased number of cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well as other methionine cycle enzymes related to folate metabolism and methylation at birth as part of newborn screening programs could determine which newborns need be monitored and maintained on diets or supplements that ensure adequate folate status during this critical postnatal neurodevelopment period.

Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children.
            (Surén et al., 2013) Download
IMPORTANCE:  Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders. OBJECTIVE:  To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified [PDD-NOS]) in children. DESIGN, SETTING, AND PATIENTS:  The study sample of 85,176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. MAIN OUTCOME MEASURE:  Specialist-confirmed diagnosis of ASDs. RESULTS:  At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61,042) had autistic disorder, compared with 0.21% (50/24,134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use. CONCLUSIONS AND RELEVANCE:  Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.

Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders.
            (Virk et al., 2016) Download
OBJECTIVE:  To evaluate whether early folic acid supplementation during pregnancy prevents diagnosis of autism spectrum disorders in offspring. METHODS:  Information on autism spectrum disorder diagnosis was obtained from the National Hospital Register and the Central Psychiatric Register. We estimated risk ratios for autism spectrum disorders for children whose mothers took folate or multivitamin supplements from 4 weeks prior from the last menstrual period through to 8 weeks after the last menstrual period (-4 to 8 weeks) by three 4-week periods. RESULTS:  We did not find an association between early folate or multivitamin intake for autism spectrum disorder (folic acid-adjusted risk ratio: 1.06, 95% confidence interval: 0.82-1.36; multivitamin-adjusted risk ratio: 1.00, 95% confidence interval: 0.82-1.22), autistic disorder (folic acid-adjusted risk ratio: 1.18, 95% confidence interval: 0.76-1.84; multivitamin-adjusted risk ratio: 1.22, 95% confidence interval: 0.87-1.69), Asperger's syndrome (folic acid-adjusted risk ratio: 0.85, 95% confidence interval: 0.46-1.53; multivitamin-adjusted risk ratio: 0.95, 95% confidence interval: 0.62-1.46), or pervasive developmental disorder-not otherwise specified (folic acid-adjusted risk ratio: 1.07, 95% confidence interval: 0.75-1.54; multivitamin: adjusted risk ratio: 0.87, 95% confidence interval: 0.65-1.17) compared with women reporting no supplement use in the same period. CONCLUSION:  We did not find any evidence to corroborate previous reports of a reduced risk for autism spectrum disorders in offspring of women using folic acid supplements in early pregnancy.

High plasma neopterin levels in Chinese children with autism spectrum disorders.
            (Zhao et al., 2015) Download
BACKGROUND:  Neopterin, a pteridine mainly synthesized by activated macrophages, is a marker of inflammation, immune system activation and an active participant in Autism spectrum disorders (ASD). The aim of this study was to assess the clinical significance of plasma neopterin levels in ASD. METHODS:  Eighty patients diagnosed with ASD and 80 sex and age matched typically developing children were assessed for plasma levels of neopterin at admission. Plasma neopterin levels were measured using a human ELISA kit and severity of ASD were evaluated with the Childhood Autism Rating Scale (CARS) score. RESULTS:  We found that the mean plasma neopterin level was significantly (P<0.0001) higher in children with ASD as compared to controls. Plasma neopterin increased with increasing severity of ASD as defined by the CARS score. Based on the ROC curve, the optimal cutoff value of plasma neopterin level as an indicator for auxiliary diagnosis of ASD was projected to be 8.5nmol/L, which yielded a sensitivity of 84.2% and a specificity of 80.1%, with the area under the curve at 0.876 (95% CI, 0.825-0.928). Elevated neopterin (≥8.5nmol/L) was an independent diagnosis indicator of ASD with an adjusted OR of 12.11 (95% CI: 5.48-28.11; P<0.0001). CONCLUSIONS:  These results indicated that autistic children had higher plasma levels of neopterin, and elevated plasma neopterin levels may be associated with severity of ASD among Chinese children.

 


References

DeVilbiss, EA, et al. (2015), ‘Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence.’, Br J Nutr, 114 (5), 663-72. PubMed: 26243379
Frye, RE, et al. (2013), ‘Cerebral folate receptor autoantibodies in autism spectrum disorder.’, Mol Psychiatry, 18 (3), 369-81. PubMed: 22230883
Main, PA, et al. (2010), ‘Folate and methionine metabolism in autism: a systematic review.’, Am J Clin Nutr, 91 (6), 1598-620. PubMed: 20410097
Mohammad, NS, et al. (2009), ‘Aberrations in folate metabolic pathway and altered susceptibility to autism.’, Psychiatr Genet, 19 (4), 171-76. PubMed: 19440165
Raghavan, R, MD Fallin, and X Wang (2016), ‘Maternal plasma folate, vitamin B12 levels and multivitamin supplementation during pregnancy and risk of Autism Spectrum Disorder in the Boston Birth Cohort’, FASEB, 30 (1), S151.6. PubMed:
Rogers, EJ (2008), ‘Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.’, Med Hypotheses, 71 (3), 406-10. PubMed: 18514430
Surén, P, et al. (2013), ‘Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children.’, JAMA, 309 (6), 570-77. PubMed: 23403681
Virk, J, et al. (2016), ‘Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders.’, Autism, 20 (6), 710-18. PubMed: 26408631
Zhao, HX, SS Yin, and JG Fan (2015), ‘High plasma neopterin levels in Chinese children with autism spectrum disorders.’, Int J Dev Neurosci, 41 92-97. PubMed: 25660944