Overview: Maternal autoantibody-related autism spectrum disorder (MAR ASD) is characterized by specific maternal antibodies that respond to certain proteins in the fetal brain. When examining the plasma of expectant mothers, researchers found that mothers with a reactivity to one of the nine MAR ASD patterns were eight times more likely to have a child diagnosed with autism.
Source: UC Davis
Autism is a neurological disorder that affects 1 in 44 children in the US. It has a wide range of characteristics with different intensities and causes. One type of autism is maternal autoantibody-related autism spectrum disorder (MAR ASD).
MAR ASD is characterized by the presence of specific maternal immune proteins known as autoantibodies that respond to certain proteins found in the fetal brain. The maternal autoantibodies (IgG) cross the placenta and gain entry into the developing brain. Once there, they can cause changes in the way the brain develops in the offspring, leading to behaviors linked to autism.
Two new studies from the UC Davis MIND Institute extend our understanding of this type of autism. They found support for predictive protein patterns in expectant mothers’ blood and associations of MAR ASD with higher intensities of autistic features.
MAR ASD Patterns Linked to Autism Before Birth
Judy Van de Water of the MIND Institute and a team of researchers showed that autoantibody binding to nine specific combinations of proteins (known as MAR ASD patterns) successfully predicts autism in previously diagnosed children.
They tested maternal blood samples collected during pregnancy to see if they could validate the identified patterns. They wanted to see if the patterns accurately predicted autism in the children.
Their research results were published in Molecular Psychiatry.
“Previously, we identified nine patterns associated with MAR ASD. In this study, we wanted to check the accuracy of these patterns in predicting MAR ASD. To do that, we tested plasma from pregnant mothers collected by the Early Markers for Autism (EMA) study,” said Van de Water, senior author of the study. Van de Water is a UC Davis professor of immunology and neurodevelopment.
The study screened the plasma of 540 mothers of autistic children, 184 mothers of children with intellectual disabilities but without autism, and 420 mothers from the general population of children with no known autism or intellectual disability at the time of the study.
It found reactivity to at least one of the nine MAR ASD patterns in 10% of the autistic group. This is compared to 4% of the intellectually disabled group for some patterns and 1% of the general population. Four patterns were only present in mothers whose children were later diagnosed with autism, making those specific autoantibody patterns highly predictive.
The study also found that a mother with reactivity to one of the nine MAR ASD patterns is about 8 times more likely to have an autistic child.
Several MAR ASD patterns were strongly associated with autism with intellectual disability. Others were associated with autism without intellectual disability. The protein pattern most strongly associated with autism was (CRMP1+CRMP2). It increased the chance of being diagnosed with autism by 16-fold and was not found in the non-autistic groups.
MAR ASD is equally present in all states
Previous research found the MAR subtype of autism in 20% of a sample of autistic children in Northern California. To date, this type of autism has not been studied in any state except California.
A team of researchers led by Kathleen Angkustsiri investigated MAR ASD in two new clinical sites: the Children’s Hospital of Philadelphia (CHOP) and the Arkansas Children’s Hospital and Research Institute (ACHRI).
Their study, published in The Journal of Developmental and Behavioral Pediatrics† recruited 68 mothers of autistic children, ages 2-12. The mothers provided blood samples and completed behavioral questionnaires about their children.
The study also included data from the children’s clinical diagnostic assessments. It used established diagnostic measures known as ADOS (the Autism Diagnostic Observation Schedule) and Social Communication Questionnaire (SCQ) to assess the children’s autistic characteristics.
MAR ASD was present in 21% of CHOPs and 26% of ACHRI samples. Overall, 23.5% of blood samples were considered MAR positive (+MAR), indicating that autoantibodies respond to known MAR ASD protein patterns.
“Our study showed similar MAR ASD frequencies in two other states, similar to what we observed in Northern California,” Angkustsiri said. Angkustsiri is an associate professor of developmental behavioral pediatrics at UC Davis Children’s Hospital and the UC Davis MIND Institute and the study’s lead author. “This suggests that the prevalence of MAR ASD is consistent across demographic and geographic settings.”
MAR ASD and autism characteristics
The study also examined the link between MAR ASD and the severity of autism. It showed that children born to mothers with +MAR antibodies had higher autism severity scores than those born to -MAR mothers. It found no significant differences in their IQ, adaptive function, or unusual behavior.
“MAR ASD positivity may be linked to more severe autism behavior,” Angkustsiri said. “Both the SCQ reported by parents and the ADOS assessed by clinicians supported these findings.”
Further research is needed to understand why mothers develop these antibodies and how long these antibodies can last. Testing for MAR ASD patterns can be used to assess the likelihood of a child having autism before features are present. The researchers aim to develop an accurate clinical test to provide clinicians with more tools for earlier diagnosis of ASD.
“We hope our work can help develop more tailored services based on the type of autism and the child’s strengths and specific challenges,” said Van de Water.
Co-authors of the Van de Waters study are Alexandra Ramirez-Celis, Joseph Schauer and Paul Ashwood of UC Davis, Lisa Croen, Cathleen Yoshida and Stacey Alexeeff of Kaiser Permanente and Robert Yolken of Johns Hopkins University.
Financing: Funding was provided by the NIEHS Center for Children’s Environmental Health and Environmental Protection Agency (EPA) grants (2P01ES011269-11, 83543201), the NIEHS-funded EMA study (R01ES016669), the NICHD-funded IDDRC (P50HD103526) and Consejo Nacional de Ciencia y Tecnologia (CONACYT-UC MEXUS) PhD Scholarships.
Co-authors of Angkustsiri’s study are Jill Fussell, Amanda Bennett, Joseph Schauer, Alexandra Ramirez-Celis, Robin Hansen and Judy Van de Water. The study was funded by the DBPNet Young Investigator Award UT5MC42432 and the NICHD-funded IDDRC (P50HD103526)
The authors recognize that medical terms such as “symptom” and “severity” are pathologizing and do their best to distance themselves from this historical terminology. In this article, the analysis is based on the “calibrated severity score” generated by using the diagnostic test the ADOS, which is why they use it in this case.
About this autism research news
Author: Nadine Yehya
Source: UC Davis
Contact: Nadine Yehya – UC Davis
Image: The image is in the public domain
Original research: Open access.
“Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability” by Judy Van de Water et al. Molecular Psychiatry
Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability
Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain and cause neurological changes and behaviors associated with autism in the exposed offspring.
We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk.
The aim of the present study was to validate the previously identified MAR ASD patterns (CRMP1 + GDA, CRMP1 + CRMP2, NSE + STIP1, CRMP2 + STIP1, LDHA + YBOX, LDHB + YBOX, GDA + YBOX, STIP1 + YBOX and CRMP1 + STIP1) and their accuracy in predicting ASD risk in a prospective cohort using maternal samples collected before parturition.
We used prenatal plasma from mothers of autistic children with or without concomitant intellectual disability (ASD = 540), intellectual disability without autism (ID = 184) and general population controls (GP = 420) collected by the Early Markers for Autism (EMA)). study.
We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR) = 7.81, 95% confidence interval (CI) 3.32 to 22.43; ASD vs ID: OR = 2.77, 95% CI (1.19-7.47)) showing that the MAR ASD patterns are strongly associated with the ASD group and can be used to assess ASD risk prior to onset of symptoms.
The pattern most strongly associated with ASD was CRMP1 + CRMP2 and increased the probability of an ASD diagnosis by a factor of 16 (3.32 to >999.99).
In addition, we found that several of these particular MAR-ASD patterns were strongly associated with ASD with intellectual disability (ASD + ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns can lead to earlier identification of ASD and facilitate access to appropriate early intervention services based on each child’s needs.