A successful pilot study conducted by Department of Health Services/ California Birth Defects Monitoring Program (CBDMP) and the National Institutes of Health (NIH), with collaborators at the Department of Developmental Services and The M.I.N.D. Institute, provides an important clue for researchers looking for causes of and cures for these conditions.

The abstract of this study is provided below. In brief, the study looked for biomarkers at birth in children with autism, mental retardation or cerebral palsy by analyzing newborn blood samples. The results are compelling: strikingly higher levels of four substances crucial in nervous system development in 95% of children with autism and mental retardation. Children with cerebral palsy had different biomarkers indicating prenatal exposure to common and treatable medical conditions may underlie many cases.

If the findings hold, there are dramatic implications. If we can identify babies at risk for these conditions at birth, we may be able to jump start intervention. Equally important, the possibility of biomarkers at birth gives scientists a new and highly promising research direction in the search for causes.

The next step in this research is to obtain funding so that CBDMP can confirm and expand upon these findings with a larger group. As this pilot project demonstrates, the Program is uniquely qualified to lead this effort. CBDMP has proven competency in data collection and state-of-the-art research. DHS archives newborn blood specimens and has an established relationship with the only laboratory in the country currently capable of performing this procedure. DDS Regional Centers are single points of entry into services-- 85-90% of affected children can be found and diagnostic information obtained. The CBDMP's demonstrated research capability, ability to find cases, and access to newborn blood specimens is unique in the nation.

The March of Dimes supports additional State funding for the California Birth Defects Monitoring Program to investigate causes of autism, cerebral palsy and mental retardation. Investing in this research-
* may uncover the causes of these serious disabilities and contribute to improved interventions;
* will contribute to answering critical public health questions; and
* positions the State to receive millions in Federal research money.

David Pisani and Ellen Powell EPowell@modimes.org
March of Dimes
1-888-898-2229

"Neuropeptides and neurotrophins in neonatal blood of children with autism, mental retardation, or cerebral palsy"
Key Findings and Implications
In the first study to find biomarkers for children with autism and mental retardation at birth, we found:
Strikingly higher levels of four substances crucial in nervous system development in children with autism;
The same high levels in children with mental retardation, suggesting a similar biologic process;
Elevated levels of the four substances in 95% of children with autism and/or mental retardation;
Children with cerebral palsy had biomarkers similar to healthy children.

This successful pilot study provides new hope for parents and an important clue for researchers looking for causes of and cures for these disabilities. The implications are phenomenal:
If we can identify babies at risk for these conditions at birth, we may be able to jump start intervention.
It is important to confirm these results. However, this is a very promising new lead that may help solve the puzzle more quickly.
Autism and mental retardation are among the most serious and common lifelong disabilities, and some reports suggest autism is on the rise.

Questions and Answers
What did the study find?
A: The study found that children with autism or mental retardation, when compared to children without these conditions, had higher levels in the blood at the time of birth of four specific proteins that are crucial to nervous system development.
How was the study conducted?
A: We conducted laboratory tests on blood samples from newborn children who were later diagnosed with autism, mental retardation or cerebral palsy and children who were free of these conditions. In each group there were approximately 60 children. All of the children were born between 1983 - 1985 to mothers living in one of four San Francisco Bay area counties. Those years and counties were chosen for study because of existing data from that period and for that location on children with cerebral palsy and "control" children. Building on existing data enabled researchers to conduct this research more quickly.
Where did the data come from?
A: The diagnostic data on children with autism or mental retardation was provided by the California Department of Developmental Services (DDS) and the Regional Centers. Blood samples were obtained through the Newborn Screening Program of the DHS Genetic Disease Branch. The study was approved by the California Committee for Protection of Human Subjects, which has responsibility for assuring the confidentiality of all data.
Aren't these data confidential?
A: Yes. Confidentiality of these data was maintained throughout the study. We have extensive procedures in place to protect the privacy of every child in our studies.
Why was autism the focus of the study?
A: Recent reports suggest that not only is autism common among children, but the condition may be increasing. Typically, autism, mental retardation and cerebral palsy cannot be reliably diagnosed until a few years after birth. If these conditions can be identified earlier, intervention that may help children with these conditions can begin sooner.
What is autism?
A: Autism is a severe disorder of communication and social interaction resulting in lifelong disability.
Who conducted the study?
A: The study was conducted by the California Birth Defects Monitoring Program (CBDMP) of the California Department of Health Services, and the National Institutes of Health (NIH), in collaboration with the California Department of Developmental Services. Funding was provided by CBDMP and NIH, with partial support from The M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute at the University of California, Davis.
Do the study findings mean we now have a way to positively identify children with autism or mental retardation at birth?
A: No. However, based on this exciting new finding, we can target our research with the hope of developing a screening tool in the future. First, our findings must be confirmed.
Why were these proteins selected for measurement?
A: We selected proteins that are known to have a role in regulating growth and development of the brain during gestation and proteins that are known to contribute to long term memory, learning and responses to sensory stimuli. These aspects of behavior are particularly important in autism. We found two neuropeptides and two neurotrophins, whose levels were dramatically higher in children with autism or mental retardation than in the "control" children or children with cerebral palsy.
Given that the diagnosis of autism is sometimes difficult, how can you be sure that the children in your study were correctly diagnosed? Are there similar concerns for cerebral palsy and mental retardation?
A: We are very confident. We know that the diagnosis of each of these conditions is quite complicated so we went to great lengths to confirm the diagnoses on all children in the study.
Do these findings confirm that autism and mental retardation are conditions that develop during gestation and are not due to environmental factors after birth?
A: Our findings showed abnormal levels of certain proteins present at birth in children with autism or mental retardation. These findings suggest a potential biological indicator at birth, but they do not address the more complex question of WHEN these conditions occur. We know that the brain develops from gestation through early childhood.
Is there any evidence that might suggest a link between autism and infant immunizations?
A: Although there has been much speculation about such a link, this study could not address that question.
Do these findings suggest that genes may play a role in causing autism or mental retardation?
A: There is considerable evidence already to indicate that there is a genetic component to autism and mental retardation. This research provides some clues for identifying which genes may be important in the development of these conditions.
Could these findings lead to prevention strategies that might be implemented after birth?
A: First, these findings must be replicated in further studies. If our findings are correct, we'll be able to identify children at risk for these conditions much earlier than currently, and practitioners can try various interventions to see what works.
Parents of children with autism have suspected that diet may play a role in their child's condition. Does this study provide any information on that issue?
A: No. Issues involving diet were not part of the study.
Do the results suggest a similarity between autism and mental retardation that we have not recognized before?
A: Yes. For the proteins we studied, children with autism and children with mental retardation without autism had the same result. As other proteins are studied, differences may become apparent.
Will these findings lead to a screening mechanism for all babies at birth?
A: It is much too early to know. First, we must be sure that these findings are true. Then scientists must develop the technology to screen large numbers of babies-if screening is appropriate. Finally, policymakers must determine whether widespread screening or some other mechanism would be beneficial.
Could the results also suggest that these proteins could be measured even before birth by drawing a sample of the unborn baby's blood?
A: Again, it's much too early to know. Our results are based on one point in time-the newborn period. We do not know how levels of these proteins are different at different points in time. Future research must address this question.
How confident are you of your results?
A: As is true for all research, the scientific process depends on getting the same results several times. With this new and startling finding, we are anxious to continue this work. We have enough confidence in this study to launch a bigger study, once funds become available.
How do you explain why levels of these proteins in the blood of children with cerebral palsy were different from the levels found in children with autism or mental retardation?
A: This result is consistent with current knowledge that cerebral palsy represents a different kind of problem in the brain than autism or mental retardation. We suspect that cerebral palsy has different origins than autism or mental retardation. This study supports that hypothesis.
Does this study suggest that if we could lower these high levels of proteins in children with autism or mental retardation that their condition would improve?
A: No. The study does not answer that question. We don't know whether the high levels of these proteins could cause autism and mental retardation, or whether the high levels are a sign of something else going wrong.
What is the next step?
A: First, in accordance with standard scientific protocol, we want to confirm these results by looking at blood samples from more children. Then we want to develop a database of children with these conditions so that we can look at other ways in which they are alike and different in order to find additional clues about causes. We also want to expand our communications efforts so that we can keep the public informed about this research as we go forward. Additional funding will be necessary to accomplish these goals.

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This abstract was presented at the annual meeting of the American Academy of Neurology, San Diego, May 3, 2000. The manuscript detailing these findings will be published in late summer.

NEUROPEPTIDES AND NEUROTROPHINS IN NEONATAL BLOOD OF CHILDREN WITH AUTISM, MENTAL RETARDATION, OR CEREBRAL PALSY
Karin B. Nelson, M.D., J.K. Grether, Ph.D., James M. Dambrosia, Ph.D., Lisa A. Croen, Ph.D., Ben F. Dickens, Ph.D., Robin L. Hansen, M.D., Terry M. Phillips, Ph.D.

Category: Autism, Mental Retardation, and Cerebral Palsy

Objective: To investigate whether concentrations of certain neuropeptides and neurotrophins in neonatal blood of children with autism, mental retardation (MR), or cerebral palsy (CP) differed from those in control children.

Background: The etiology of these developmental disabilities is incompletely understood and there is no known biomarker for these disorders.

Methods: Case status was identified from records of California state service agencies. Immunoassays were performed masked to outcome by recycling immunoaffinity chromatography on archived neonatal blood drawn for routine metabolic screening, measuring vasoactive intestinal peptide (VIP), calcitonin-related gene peptide (CGRP), brain derived neurotrophic factor (BDNF), neurotrophin 4 (NT4), substance P (SP), and antibodies to myelin basic protein (MBP), glial fibrillary acidic protein (GFAP) and neuron-axon filament protein (NAFP). Concentrations of analytes that best distinguished autism and MR from controls were chosen by recursive partitioning (CART).

Results: Concentrations of SP and antibodies to MBP were not different in the 4 outcome groups. Antibodies to GFAP and NAFP were significantly lower in children with autism and children with MR compared to control children, but there was considerable overlap in the distributions. Mean concentrations of VIP, CGR, BDNF, or NT4 were not different in children with autism who did or did not also have MR, nor among children with CP who were or were not also mentally retarded.

Children with concentrations of 2 or more analytes exceeding these values:
VIP >31.5 pg/ml, CGRP >32.8, BDNF >24.9, or NT4 >48.8

N (n) %
Autism 64 (62) 96.9 %
MR only 66 (61) 92.4 %
CP 65 (6) 9.2 %
Controls 54 (0) 0 %

Conclusions: Most children with autism or MR had concentrations of 2 or more of the measured neuropeptides or neurotrophins in peripheral blood in the earliest days of life that exceeded the levels indicated, while few children with CP and no control child did. These substances did not distinguish children with autism from those with MR.

Editor: Lenny Schafer | Eastern Editor: | News Wire: Ron Sleith
schafer@sprynet.com | Catherine Johnson PhD | <>
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More on the Blood Protein Study

[This from Susan Owens lwo@iadfw.net on some erroneous conclusions some are making from the recently reported blood protein study. The study appears to suggest that autism is a pre-natal phenomenon.]

Please don't be alarmed that the study results announced today may point to a condition that was present at birth. A child's in utero immune history may predispose him to later have an inappropriate response to vaccine: there may have been immunological things happening in mother that could have had an impact on her child's readiness for the world of germs and vaccines.

The study funded by the MIND Institute was reported to say that two autoantibodies were sought in the blood spots, and they did NOT find elevations of those two autoantibodies in children who later developed autism. Quite the opposite: despite elevations of these autoantibodies being quite common in older children with autism, these babies at birth had levels that were lower than those found in controls. I wish we knew if the total IgG antibodies from the blood spots were lower than usual, but maybe these scientists can look at that as they proceed.

As Teresa pointed out to us earlier, immediately after birth, a baby has either been free of infection in utero, or else has picked up an infection that crossed the placenta, or else became infected in the birth process. Immunoglobulins are a late-stage response to infection, and they take too long to be produced for there to be a chance that immunoglobulins found in a blood spot at birth would reflect a post-utero exposure to germ.

For that reason, the antibodies that are found in a baby at birth will be made up of either maternal IgG that crossed the placenta, or it will represent an infection that occurred in utero, or it will represent an anti-idiotypic antibody response to mother's IgG.

Anti-idiotypic antibodies are antibodies that form against other antibodies. Through anti-idiotypic processes, some fetal antibodies will form against the variable region of IgG antibodies that come into the fetal circulation from mother, and the shape of the fetus's new antibody's variable regions can be identical to the shape of the original antigen. By forming a cascade of these anti-idiotypes, the immune system will eventually down-regulate an immune response after an infection has abated, and in a fetus, this process gives him a safe environment to try out his immunological wings. This process is very normal.

So, in utero, the baby can form antibodies against the anti-idiotypes that he has just formed, and some of them will look like the antibodies formed from an original response to infection, but will be far lower in quantity than in a real infection. In this way the immune system is primed before birth to the antigens to which the mother has been exposed. It is really amazingly clever.

So what is of particular interest in the study results today is that those with autism may have had a lower exposure to maternal IgG than controls. Why would that happen? It ends up that what is happening in mother's immune system will determine how well her antibodies cross the placenta, and if her beta-2-microglobulin is elevated, as you would expect in a mother who had some sort of autoimmune disease, then her antibodies would have difficulty crossing the placenta. This sounds like nature is being wise, actually, for why would you want to start development with your mother's immunoglobulins attacking your own cells?

I'm sending two relevant studies separately. If you've forgotten the theory I presented last summer about beta-2-microglobulin, please feel free to check the archives.

Years ago when I was pregnant with Grace and knew my own autoimmune history, I was very concerned that my ob/gyn did not have tools to understand how he could protect my child from any repercussions from my immune history. There was very little science to base a strategy upon and we made some mistakes, I think. I have Grace's present immune problems to remind me that until the proper research is done to identify these relationships and popularize the notion that they require careful medical management, we may expect these problems will continue to increase and to effect even more families.

The words of the FDA today showing a new heart regarding vaccine policy should give us hope that attitudes really are changing. Perhaps we who wait for necessary funds for research will soon be able to roll up our sleeves and get to work.