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A study published today in Neuron  examines brain tissue of people diagnosed with autism to better understand the symptoms of autism, and when mutations in the DNA occurred. In other words, did the genetic mutation originate from the parents DNA, or did it happen sometime after the egg and the sperm formed an embryo?   Knowing when they occurred helps in understanding how autism can be passed on, how standard blood tests for autism should be used, and how often genetic mutations occur in brain tissue.

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Alissa D’Gama, from Boston Children’s Hospital and Harvard University, was first author on the study

To illustrate the importance of different mutations, here is a primer.   Most human genetic diseases are the result of inherited DNA mutations, in other words, those that are present in one of the parents. There is one big exception to this: cancer. But other genetic diseases, like sickle cell disease and cystic fibrosis, result from inherited DNA. Maybe the parent doesn’t have the same exact mutation, but a geneticist can trace the mutation to one of the parents. Because the mutation came from the parent, the mutation is present when the sperm and egg join and the embryo is formed. These mutations end up in all the tissues of the affected individual: blood, saliva, organs. So you can look at any of these tissues and still see the mutation. A doctor doesn’t need the organ of interest to study them.  They are inherited.

In contrast to an “inherited” mutation, is a “heritable” mutation. For example, there is more evidence to show that de novo mutations are important in autism diagnosis. You’ve heard word de novo or “of new”, meaning, they end up in the offspring but can’t be seen in either parent.  These mutations may be in the sperm and the egg or the cells that come before the sperm and egg, called the germline, but they aren’t in the blood or spit or cells of the parents. In other words, to a geneticist without sperm or eggs to study, they are de novo. These sorts of heritable mutations are in all cells, including blood, saliva, skin cells, and organs.   More and more, scientists are showing that in autism, these de novo mutations result in psychiatric issues like autism spectrum disorders.   Scientists know more about these mutations in the last 5 years than they ever did, and how they cause problems in the genetic code.  These are germline mutations.

But what scientists don’t know a lot about is the role of somatic mutations in neurodevelopmental disorders. These are mutations that happen AFTER the embryo started forming, and they affect a certain organ of interest. Because they are not in every cell in the body,  they are called somatic mutations. Only a subset of cells, or a specific organ, shows the mutation. This is the sort of mutation you see in cancer., and a biopsy is needed to see them.  A doctor would need the specific organ to find it.  This is the sort of mutation that occurs as cells constantly divide through your lifetime. If you think about how many times your cells turn over, it’s inevitable that a mutation is going to happen somewhere at sometime. They can be common and not harmful. However, sometimes, for example in cancer, they are harmful.

germlinesomatic[1]

Adapted from the National Cancer Institute and the American Society of Clinical Oncology

If you are lost right now, you are not alone.  This is pretty advanced genetics to most people.  See the image to the right to graphically explain the difference between somatic and germline
mutations.

Scientists have the resources to study germline mutations and de novo mutations in blood or saliva. But until recently, it has not been possible to study somatic mutations. How would you know if autism is the result of a somatic mutation? You’d have to study the brains of people with ASD. And that’s what a group at Boston Children’s Hospital did recently and just published their findings. While somatic mutations in autism are rare, they do exist.  Alissa D’Gama, the first author, explains why the project is important:

“Identifying a few cases with somatic mutations shows us that such mutations can occur in ASD and that somatic mutations may be another genetic mechanism that contributes to ASD risk. Understanding that some mutations can occur late in development and only be present in the brain has important implications for clinical genetic testing, as studying the blood will miss the somatic mutations present only in brain.”

So how does this impact people with autism? 1. Scientists now know that there are genetic mutations in the brain that are specific to tITBhe brain, and not found in other tissues; and 2.   These somatic mutations may be responsible for the neuropathology of autism spectrum disorders.   The word “may” is used because there is still so much researchers do not know, but could know, if there were more brains of people with autism to study.   This type of analysis was only possible through the accrued collection of dozens of brains of people with autism. Please consider registering for the Autism BrainNet at www.takesbrains.org. It is not binding like a consent, and when you register, you will continue to receive important updates like this.

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ASF Undergraduate Summer Research Grantee Dylan Ritter in the lab of  Dr.Dindot at Texas A&M

I first came in contact with Dr. Dindot at Texas A&M University in the late fall of 2013 when I was a college freshman. I had seen an article published that highlighted his success in creating a mouse model used to mimic the effects of a specific kind of autism spectrum disorder, Duplication 15q Syndrome (Dup 15q). For most people reading that, the article would stand merely as an informative story about some researcher in Texas. For me, that article had a totally different context.

 

My youngest brother, Travis, was diagnosed with Dup15q at the age of two when I myself was only four years old. For as long as I could remember, I had a younger brother that needed help brushing his teeth, could never speak to me, and somehow enjoyed the credits of a movie more than the movie itself. I never questioned it, but I was certainly aware that our family was different from a lot of others. Meeting other families that had children with Dup15q helped me realize this condition extended beyond my five-person family, and that there was research being performed to find therapeutic options and genetic factors behind this condition.

When talking with Dr. Dindot about his research, he surprised me by ensuring me that I would be on the workbench with my own projects doing real research. And that’s exactly how the summer of 2014 was spent. I learned so much about the condition, the laboratory environment, and all of the hard work being done to find answers. I decided that I would like to return to the lab to continue research in the summer of 2015, after my sophomore year. With most of the logistics figured out from the previous summer, I was able to speak with Dr. Dindot more about what was going on in the lab rather than figuring out where his lab was on campus. In discussions about my research, he proposed that I apply for a fellowship through the Autism Science Foundation, since they were eager to support the work of undergraduate researchers interested in autism. On March 9th, I was informed that I had been selected as one of five undergraduates to receive funding for my research. It was such an exciting feeling knowing that I had been chosen by a committee as someone they believe will succeed in research. With that extra motivation, I prepared myself for the summer ahead.

I had a variety of projects going on during my time, but that main one was the classification of one of the mouse models Dr. Dindot had designed. It was set up so that excess gene expression would mimic the effects of the extra chromosomal information present in Dup15q. However, there is a unique system in which a drug could be administered in order to suppress this extra expression. The theory behind it all was that if a mouse had normal gene expression, it should have a normal phenotype without the manifestations of Dup15q. By the end of the project, it was shown that after only three days of this treatment, the excess gene expression was reduced more than 60%, showing a major change between overexpression mice and wild-type mice.

Though this was just the beginning of the project, the hope is that these mice with slightly adjusted drug treatments may eventually reach gene expression comparable with wild-type mice. From there, it is possible to perform further analysis on these mice to see if there are any phenotypic changes that occur when the gene levels change in the mouse. With the amount of progress research has made in the past 20 or 30 years, there’s no way of even being able to guess where autism research will be in the next 20 or 30 years. All I can say is that I have been extremely humbled and honored to have the opportunity to represent the Autism Science Foundation, Texas A&M, and Ole Miss by doing what I love.

A summary of the recent evidence, by Thomas Frazier, PhD and Stelios Georgiades, PhD.

SG

Stelios Georgiades, PhD

Some family members of people with ASD often share many autism traits, but don’t have or show the number or severity of symptoms needed to be diagnosed. A recent study using the Interactive Autism Network looked at some features of autism in over 5500 individuals, some with multiple siblings with autism, some only one sibling. They wanted to determine if number of siblings with autism or sex of the sibling with autism influenced how these symptoms presented, if at all.

What did the researchers do?

Frazier_Thomas_724336 headshot

Thomas Frazier, PhD

When a family enrolls in the Interactive Autism Network not only do they enter in information about the person diagnosed with autism, they also fill out a form called the Social Responsiveness Scale on all family members. This is a quantitative measure of autism traits. Instead of saying autism: yes-or-no, the scale gives a number that corresponds to the presentation of features. It is used in people with autism, but has also been used to study features of autism of those without a diagnosis. Some people have higher levels than others but most people score around the middle.   The higher the number, the more features of autism that person exhibits. In this study, the analysis consisted of 5515 brothers and sisters, 2858 with ASD and 2657 without ASD. They looked at how autism symptoms occur in male-only ASD-affected families vs. female-only affected families or in families with single vs. multiple cases of ASD. They also looked at the siblings of ASD children who did not have the condition but who had language delay or speech patterns usually seen in children with ASD. The sex of the siblings was also taken into account in the analysis.

What did the researchers find?

The research found that

  • the non-ASD brothers and sisters (siblings) of children with ASD were more likely to show higher levels of symptoms if they were many members of their family with ASD,
  • the non-ASD boys in these families were more likely to have a higher number of symptoms, as were boys with language delay or speech patterns usually seen in children with ASD,
  • the children with ASD in families with several members with ASD had lower levels of symptoms than did the ASD children if they were the only child in the family with the condition, and
  • the likelihood of having more than one child with ASD in a family was higher if that family had female members with ASD, and
  • it is likely that girls need a much greater number of the genes related to ASD to produce the symptoms needed to warrant a diagnosis of ASD.

 What does this mean?

Both the sex and the number of children with ASD in a family strongly influence the risk of their non-ASD siblings having a high number of autism symptoms.  This again, links genetics to the causes of autism. These preliminary data suggest that siblings from certain families may have a higher likelihood of having children with ASD, but it is too early to base any family planning decisions on this data. It also emphasizes that girls have a higher genetic load, and that girls may be in some way, protected against some symptoms of autism.

 

References:

Frazier TWYoungstrom EAHardan AYGeorgiades SConstantino JNEng C. (2015)  Quantitative autism patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families.  Molecular Autism, 6:58.  Full text here:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623917/

A new study published this month in the Journal of Developmental and Behavioral Pediatrics confirms current belief that many children with Autism also have Apraxia of Speech.

Cheryl Tierney, MD, MPH of Penn State University, Susan Meyes, PhD and others investigated the efficacy of the Checklist for Autism Spectrum Disorder (CASD), a screening tool developed to determine if children should undergo complete diagnostic testing for autism (1). The researchers found that the screening tool does effectively indicate which children are at risk for autism, but they also came to another interesting conclusion (2).

Intervention approaches for autism and apraxia address different features of communication, therefore, it is important for clinicians to be aware that kids with autism may have undiagnosed apraxia of speech as well.

Intervention approaches for autism and apraxia address different features of communication, therefore, it is important for clinicians to be aware that kids with autism may have undiagnosed apraxia of speech as well.

Autism spectrum disorders are diagnosed by neuropsychologists and developmental-behavioral pediatricians. Language impairments present in autism are partially characterized by difficulties with taking the perspective of another person, with  non-literal language and with appropriately maintaining a topic (3).

Apraxia of Speech, however, is typically diagnosed by a speech-language pathologist, and is characterized by difficulty coordinating volitional motor movements required for clear and intelligible speech.

While autism and apraxia clearly have different features, a child with autism who has profound language delays such that he or she is minimally verbal or non-verbal may have undiagnosed childhood apraxia of speech, masked by his or her language deficits.

The study concluded that “autism and apraxia are highly comorbid. Thus, it is important to monitor all children diagnosed with apraxia for signs of autism and all children diagnosed with autism for signs of apraxia. This will help identify children as early as possible and allow them access to services appropriate to their needs.”

In evaluating children with autism, speech-language pathologists should rule out apraxia of speech. In requesting services or evaluations for their children, parents should also consider the intelligibility of any language the child may produce.

This post was authored by Stephanie Millman-Dorsch, ASF’s Community Relations Manager. Stephanie is a Master’s of Science Candidate in Communicative Sciences and Disorders at NYU, expecting to graduate this December.

NB: Dr. Mayes, who co-authored the study, is the primary developer of the CASD

References:
(1) CASD: Mayes, S. (2015). Checklist for Autism Spectrum Discorder (CASD). Retrieved October 23, 2015.

(2) Tierney, C., Mayes, S., Lohs, S. R., Black, A., Gisin, E., & Veglia, M. (2015). How Valid Is the Checklist for Autism Spectrum Disorder When a Child Has Apraxia of Speech?. Journal of Developmental & Behavioral Pediatrics36(8), 569-574.

(3) DSM-5: American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

Manuel Casanova, PhD, University of South Carolina

Manuel Casanova, PhD, University of South Carolina

Steven Chance, PhD, University of Oxford

Steven Chance, PhD, University of Oxford

Studies using brain tissues have revealed brain cells in the area called the cerebral cortex are organized in a specific way called “minicolumns”. In people with autism, this organization is different than those without autism. This has led scientists to ask what these columns do and how is it related to autism symptoms?

We asked two of the worlds leading researchers, Steven Chance of Oxford University and Manny Casanova at the University of South Carolina, who have studied the brains of people with autism, to weigh in on this topic. Specifically, we interviewed them to explain how the minicolumnar findings have impacted the field of autism research and led to discoveries that are important for families.

minicolumns

So, what is a cortical minicolumn and what do they do?

Steven Chance:  There are cells in the cerebral cortex that are arranged in columns. These ‘mini’-columns of cells are typically about one third the width of a human hair. In the typically developed brain, wider minicolumns seem to be associated with processing more individual features of incoming information.

Manny Casanova:  Minicolumns are a basic template that is used by neurons to figure out where neurons should go and where they should connect. They also help process the connections of different brain cells. Some people think of minicolumns as the microprocessor of a computer. Indeed, Vernon Mountcastle thoughtof minicolumns as the basic unit of information processing in the brain. More recent experiments have proven that these minicolumns help people to think and to act.

How are they different in people with autism?

Steven Chance: In ASD these minicolumns are between 5% and 10% wider than in those without autism. . This difference may not sound like much, but multiplied over hundreds of thousands of minicolumns throughout the brain it may contribute to a significant difference in brain organization. In addition to cognition and thinking like Manny Casanova pointed out, our lab has recently found these minicolumns in brain areas involved in basic sound and word processing, as well as in areas involved in complex social behavior.

Manny Casanova: Yes, minicolumns affect different aspects of behaviour. We have also found variability in the size of mini columns according to brain area. These changes are consistent with other neuropathological findings and indicate that the minicolumnopathy of autism is part of a process called cortical dysplasia. The presence of cortical dysplasia provides an explanation for intractable seizures and sensory abnormalities commonly observed in ASD. The pathology may be selective as to whom it affects as, on occasion, involved individuals have either a specific genetic or immunological profile.

What does this mean for people with autism?

Steven Chance: The differences in width and spacing of the minicolumns means that they may become too independent and overly focused on individual features in the environment.  This may explain the altered cognitive style or focus in many people with autism, and possibly explain the strengths of some people with autism in certain situations.

Manny Casanova: The findings help explain many of the symptoms observed in ASD. We are using the findings to provide new ways for screening for diagnosis, to provide for severity dependent outcome measures that do not rely on behavioral screening, and to introduce a possible therapeutic intervention.

Larger or smaller, what is it?

Steven Chance: The findings depend on the age of the individual. In other words, when the data from studies are compared while accounting for subject age, they suggest that minicolumns are wider in youth in autism but then become narrower in later life. This is interesting because it is consistent across the studies and reinforces tha autism as a developmental condition which changes across the lifespan. It also makes sense in the light of other MRI studies which have shown larger brains in ASD in early life, followed by a loss of this enlargement later on.

Manny Casanova: It may be that the age-related changes in the minicolumnopathy of autism may constitute an adaptive response meant to correct early changes in the cortex; or or it could be the beginning of a neurodegenerative process whose manifestation may appear later on in life.  We don’t know, we need more research using brains of people with autism at all ages and abilities.

These questions can only be answered with more brain tissue from individuals across the lifespan. You can help with the discoveries. Register to donate your amazing brain when you don’t need it anymore by going to www.takesbrains.org.

 

ASF accelerator grant awardee, Jennifer Foss-Feig, PhD

2015 ASF accelerator grant awardee, Jennifer Foss-Feig, PhD

“If you’ve met one person with autism, then you’ve met one person with autism.” This adage has become often-repeated in the autism community. It speaks to the uniqueness of each individual with autism and to the fact that no individual can be captured or fully described by his or her diagnosis. At the same time, it reflects what has become one of the greatest challenges facing autism science: variability in symptoms across people diagnosed with autism, otherwise known as heterogeneity. No one feature is reliably seen in every individual with autism, and any research sample can reflect only a subset of the diverse individuals who fall along the autism spectrum. In the latest diagnostic manual of the APA, a new, broader diagnostic category – Autism Spectrum Disorder (ASD) – replaced the categories we had all become familiar with: Autistic Disorder, Asperger’s, and PDD-NOS. For my colleagues at the Yale Child Study Center and I, the new DSM-5 umbrella “ASD” category opened the door for developing novel ways of conceptualizing and clustering heterogeneity among ASD features.

 

In a commentary published in the Journal of Autism and Developmental Disorders1 this month, we suggest a new way to consider autism symptoms. Borrowing concepts from the schizophrenia literature, we propose a new framework within which ASD-related features can be categorized. We introduce the idea of positive, negative, and cognitive feature clusters as a novel way to conceptualize ASD symptoms. Positive features include behaviors not present in typical development, but present in ASD, such as circumscribed interests or stereotyped motor movements. The negative feature dimension captures behaviors that are present in typical development, but delayed, deficient, or absent in some individuals with ASD, such as eye contact, social engagement, and spoken language. Finally, the cognitive dimension reflects patterns of thinking, behavior, and relating that are cognitively-driven and common among individuals with ASD, such as rigidity of thinking and difficulty with switching between tasks. These categories cut across social-communication and repetitive behavior domains that are currently the primary means of clustering symptoms in the DSM-5, which translates to how ASD is thought of and its features are grouped in both clinic and research settings. It may be easier to conceptualize this by looking at the table below.

 

DSM-5 Social Communication

Deficits

DSM-5 Restricted/Repetitive Behaviors
Positive Features Intrusive social initiatives; Exaggerated prosody or intonation of speech; Pronoun reversal Echolalia and stereotyped speech; Repetitive use of objects;

Repetitive hand mannerisms

Negative Features Difficulty with conversation; Lack of pointing; Reduced eye contact and range of facial expressions Non-functional play with toys; Narrowed range of interests;

Lack of imagination

Cognitive Features Difficulties with theory of mind and taking another’s perspective; Difficulty with non-literal language Insistence on sameness;

Rigid adherence to routines;

Black-and-white thinking

 

In this way, we offer new ways to conceptualize and organize hallmark symptoms of ASD. In addition, this way of thinking offers an opportunity to describe specific characteristics with new precision. For example, instead of indicating a child has “atypical facial expressions,” the new dimensions would allow separating of children who have exaggerated affect from others who show limited range of facial expressions.

 

In schizophrenia, the notion of positive, negative, and cognitive feature clusters has been quite useful to both clinical and research communities. In the clinic, assessing and labeling symptoms along these dimensions has been useful for deciding which medications to prescribe, predicting which patients will continue to struggle versus which will have quick remittance of symptoms, and identifying individuals in a “prodromal” phase before the onset of more acute symptoms. In the lab, this framework has been useful for clustering symptom dimensions in ways that correspond with experimental task performance and underlying brain differences. In other words, positive, negative, and cognitive symptom dimensions help researchers understand which underlying brain differences or cognitive and social processes are most affected in patients showing more positive versus more negative symptoms. This, in turn, provides clues to genetic underpinnings of different symptoms as well as new leads from which to develop treatments.

 

In the future, with further research, we hope to use what has been learned in schizophrenia and apply it to autism. It is our hope that the dimensions we propose offer new ways to capture and organize the heterogeneity that makes each individual with ASD unique in a way that makes us better able to talk about what we see, provide good clinical care, and solve the remaining puzzles of autism.

 

1 Foss-Feig, J. H., McPartland, J. C., Anticevic, A., & Wolf, J. (2015). Re-conceptualizing ASD Within a Dimensional Framework: Positive, Negative, and Cognitive Feature Clusters. Journal of Autism and Developmental Disorders, 1-10. http://link.springer.com/article/10.1007/s10803-015-2539-x

 

 

At a time when 1 in 68 children is diagnosed with autism, early identification, diagnosis and treatment is crucial to give children the best opportunity to reach their full potential. The ambiguity of the statement offered by the US Preventative Services Task Force (USPSTF) on autism screening is troubling and unfortunately, may be easily misinterpreted. While the task force does not explicitly recommend against screening for autism, they state there is insufficient evidence to support autism-specific screening in clinical settings. Instead, they have called for more research in this area.

As a result, the task force has failed to fully endorse screening despite an abundance of research that demonstrates it is effective in a variety of settings1-3, leads to earlier identification of autism4, and that this earlier identification provides opportunities for early intervention which improves the lives of children with autism5. Research has demonstrated that formal screening is more effective than relying on clinician judgement alone1,6. This is especially important in reducing racial and ethnic disparities in access to care7,8 Moreover, screening is quick, affordable and has no substantial risk. We intend to review the USPSTF report and its methodology to understand why it differs from other evidence-based recommendations from the American Academy of Pediatrics and from experts in the field of autism spectrum disorders. Every child deserves an early, accurate diagnosis and we are hopeful that after the review period the USPSTF reconsider their conclusions.  You can read more about the recommendations and response here.

There are a number of world renowned autism researchers who agree with this position.  They include:

The High Risk Baby Siblings Research Consortium (https://www.autismspeaks.org/science/science-news/bsrc-response-uspstf-call-more-research-universal-autism-screening)

Jill Harris, Children’s Specialized Hospital of NJ

Bryan King, Seattle Childrens Hospital

Ami Klin, Emory University

David Mandell, University of Pennsylvania

James McPartland, Yale University

Diana Robins, Drexel University

Celine Saulnier, Emory University

Amy Wetherby, Florida State University

  1. Robins DL. Screening for autism spectrum disorders in primary care settings. Autism : the international journal of research and practice. 2008;12(5):537-556.
  2. Miller JS, Gabrielsen T, Villalobos M, et al. The each child study: systematic screening for autism spectrum disorders in a pediatric setting. Pediatrics. 2011;127(5):866-871.
  3. Robins DL, Casagrande K, Barton M, Chen CM, Dumont-Mathieu T, Fein D. Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics. 2014;133(1):37-45.
  4. Herlihy LE, Brooks B, Dumont-Mathieu T, et al. Standardized screening facilitates timely diagnosis of autism spectrum disorders in a diverse sample of low-risk toddlers. Journal of developmental and behavioral pediatrics : JDBP. 2014;35(2):85-92.
  5. Pierce K, Carter C, Weinfeld M, et al. Detecting, studying, and treating autism early: the one-year well-baby check-up approach. The Journal of pediatrics. 2011;159(3):458-465 e451-456.
  6. Wetherby AM, Brosnan-Maddox S, Peace V, Newton L. Validation of the Infant-Toddler Checklist as a broadband screener for autism spectrum disorders from 9 to 24 months of age. Autism : the international journal of research and practice. 2008;12(5):487-511.
  7. Khowaja MK, Hazzard AP, Robins DL. Sociodemographic Barriers to Early Detection of Autism: Screening and Evaluation Using the M-CHAT, M-CHAT-R, and Follow-Up. Journal of autism and developmental disorders. 2015;45(6):1797-1808.
  8. Daniels AM, Halladay AK, Shih A, Elder LM, Dawson G. Approaches to enhancing the early detection of autism spectrum disorders: a systematic review of the literature. Journal of the American Academy of Child and Adolescent Psychiatry. 2014;53(2):141-152.
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