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Summary of Advances Cover 2013
Summary of Advance
In Autism Spectrum Disorder Research
Question 3: What Caused This to Happen and Can It Be Prevented?

Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey - Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG. Transl Psychiatry. 2013 Jul 9;3:e278. [PMID: 23838889]

These differences were most pronounced in the frontal lobes, a brain area that is key to social cognition. Both the behavioral and brain differences observed in the treated monkey offspring mirror some of the differences that have been observed in children with ASD, suggesting the possibility that exposure to maternal autoantibodies in humans may in some way be contributing toward the development of ASD in children. While the similarities between humans and monkeys in terms of brain structure and social complexity lend credibility to this hypothesis, these findings need to be replicated and further explored in future studies. Additional research may help identify the mechanisms by which maternal autoantibodies may affect brain development and behavior so that scientists can better understand how this may contribute to ASD and identify molecular targets for interventions.

Autism risk across generations: a population-based study of advancing grandpaternal and paternal age - Frans EM, Sandin S, Reichenberg A, Långström N, Lichtenstein P, McGrath JJ, Hultman CM. JAMA Psychiatry. 2013 May;70(5):516-21. [PMID: 23553111]

Several recent studies have shown an increased risk for ASD in the children of older fathers. Sperm cells from older men have more "de novo" or spontaneous mutations, which are mutations that have newly arisen in the sperm cells (i.e., they were not inherited from a parent), but they can be passed down to the next generation. These mutations can result from errors in copying DNA during the cell division process that generates sperm or from exposure to environmental factors that damage DNA. One possible explanation for the role of de novo mutations in increasing risk for ASD in children of older parents is that while a small number of such mutations in reproductive cells may have little or no effect, the accumulation of many such mutations over time can result in cellular and molecular functions that are altered strongly enough to give rise to ASD symptoms in the next generation. Since the mutations in a sperm cell are passed to the offspring, not only do the children of an older father have an increased risk of developing ASD, but those children also can pass the same mutations on to their future children. It is therefore possible that the age of a child's grandfather could impact his or her risk of developing ASD. This study used the extensive and meticulous record-keeping of the Swedish population registry to analyze information from 5,933 people with and 30,904 people without ASD. First, the study confirmed previous findings that the children of older fathers have an increased risk of ASD and found that, in this population sample, 6% of risk for ASD was attributable to paternal age over 40. The researchers also found that men who had fathered a daughter when they were 50 years or older were 1.79 times more likely to have a grandchild with autism, and men who had fathered a son when they were 50 years or older were 1.67 times more likely to have a grandchild with autism, compared with men who had fathered children when they were 20 to 24 years old. The researchers calculated that 3% of autism risk in their sample was attributable to grandpaternal age on both the paternal and maternal sides, with the highest risk found in grandfathers who had their own children after age 50. Overall, this study provided the first evidence that a grandfather's age is associated with risk of childhood autism, independent of paternal or maternal age, with the genetic effects persisting across generations. The study also corroborated previous findings that advanced paternal age is a risk factor for ASD. Future work to identify more specific genetic changes that cause an increase in ASD risk for the grandchildren of older grandfathers may provide further insight into how ASD develops.

Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children - Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T, Schjølberg S, Davey Smith G, Øyen AS, Susser E, Stoltenberg C. JAMA. 2013 Feb 13;309(6):570-7. [PMID: 23403681]

Recent research indicates that the use of prenatal folic acid supplements around the time of conception is associated with a lower risk of ASD. It has been known for some time that that prenatal folic acid supplements reduce the risk of neural tube defects in children; by comparison, little has been known about whether such supplements might protect against other neurodevelopmental disorders such as ASD. For ethical reasons, it has not been possible to use a randomized control trial to study the association between the use of prenatal maternal folic acid supplements and the subsequent risk of ASD in the offspring. However, observational studies of mothers who do and do not use supplements can be used to address this question. In this study, 85,176 children from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa), born between 2002 and 2008, were assessed. Mothers were recruited for MoBa at ultrasound examinations around week 18 of pregnancy. Cases of ASD (autistic disorder, Asperger syndrome, pervasive developmental disorder–not otherwise specified [PDD- NOS]) in offspring were subsequently identified via several mechanisms: parental report at various time-points, professional and parental referrals, and data on clinical diagnoses as recorded by the Norwegian Patient Registry. In children whose mothers took folic acid from 4 weeks before to 8 weeks after the start of pregnancy, 0.10% had autistic disorder—the most severe form of ASD—compared with 0.21% in those whose mothers did not take folic acid. No association was found between folic acid supplementation and Asperger syndrome or PDD-NOS. However, the small number of children with these diagnoses in the current sample meant that the power was limited. Although these correlational findings suggest an association between prenatal folic acid supplementation and a decreased risk of autistic disorder, it is important to note that they do not establish causality. Moving forward, it will be important to replicate these findings and to conduct research to understand the mechanism by which folic acid may be acting as a protective factor against development of ASD.

Question 3

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