Tag: Pediatrics

Predicting Autism Risk

Credit: U.S. Government
At birth, blood samples are taken from newborns and used to screen for genetic diseases. A new research study will help determine whether these drops can also help predict autism risk.

New research study will analyze dried blood spots recorded from California newborns for 1,000 different molecules and chemicals; their tell-tale presence might predict autism risk years before symptoms appear, prompting early treatment and perhaps prevention

Within days of birth, a few drops of blood are collected from every newborn in California—and across the United States — which are then stored on filter paper and screened for dozens of genetic and congenital disorders, such as phenylketonuria (PKU), an inherited metabolic disorder that can result in intellectual disability, seizures, heart and behavioral problems.

Researchers at University of California San Diego School of Medicine have launched a Phase II research study to look for signs of another similarly devastating disorder, one that typically does not appear in seemingly healthy children until years later: autism spectrum disorder or ASD.

The UC San Diego Newborn Screening-Autism Risk Study is designed to determine whether the dried and stored blood drops of children later diagnosed with ASD contain within them the tell-tale presence and combinations of biological molecules and environmental chemicals that might predict the risk of a future ASD diagnosis.

“We know from the history of certain genetic diseases, such as PKU, that if children can be identified before the first symptoms have appeared, then the disease can be prevented, even though the children have the DNA mutations,” said Principal Investigator Robert Naviaux, MD, PhD, professor of medicine, pediatrics and pathology at UC San Diego School of Medicine. “I believe that over half of autism cases may be preventable if only we had a way to identify the children at risk before the first symptoms appear.”

Naviaux said the new study is important for two reasons: the dramatic rise in diagnosed cases of ASD and increasing evidence that early intervention in children at risk of ASD can significantly improve outcomes.

The prevalence of ASD has risen from 20 in 100,000 births in the 1970s to 1,700 in 100,000 in 2014, according to the U.S. Centers for Disease Control and Prevention — an 84-times increase. Approximately one in 59 children is diagnosed with ASD. Statistics from the U.S. Department of Education and other government agencies indicate autism diagnoses are increasing at the rate of 10 to 17 percent per year.

Changes in diagnostic criteria and reporting practices account for 60 percent of the rise, at most, according to previously published research. “This means that even by the most conservative estimates, the prevalence of ASD has increased at least 34 times,” said Naviaux. The overarching question for Naviaux and others is why? Is it genetics? The environment?

“Our genes have not changed significantly in the past 50 years,” said Naviaux. Single gene mutations play a causal role in approximately 10 percent of ASD cases. The vast majority of ASD cases are idiopathic or of unknown cause, most likely the result of a combination of genes, environmental factors or something yet to be identified.

“More than 1,000 genes can contribute to the risk and resistance a child has to ASD, but more than 95 percent of these genes are common variations also present in asymptomatic parents and children who don’t have ASD,” Naviaux said. “A clue to how the genetics of ASD is misinterpreted is the fact that many of the genes that contribute to ASD are the same genes that contribute to other disorders like schizophrenia and bipolar depression. In most cases, DNA only sets what is possible, not what is destined.”

The new Phase II study will focus on exposure and possible roles of chemicals and compounds (detected in blood) and how they might interact with genes.

Researchers will use a blood test developed in Naviaux’s lab to analyze the presence of more than 600 metabolites —typically small molecules produced by metabolism, the life-sustaining chemical reactions in all organisms. Metabolites from amino acids and antioxidants to vitamins and lipids serve diverse, crucial functions, including as fuel, signal carriers, structure providers, defenders and regulators among them.

Earlier research by Naviaux and others has found that persons with ASD appear to have a shared “metabolic signature.” That is, their biological chemistry is comparable, though their genetics are unique.

Testing will also look at more than 400 environmental chemicals in each dried blood drop. Exposure to these chemicals, such as commonly used pesticides, flame retardants, air pollutants, lead, mercury and polychlorinated biphenyls or PCBs, has been linked to several neurodevelopmental disorders, including ASD.

Naviaux and colleagues believe that the majority of ASD symptoms are the result of a treatable metabolic syndrome triggered by persistence activation of the cell danger response (CDR), a natural and universal cellular reaction to injury or stress.

Chronic CDR, they suggest, results in disrupted and incomplete healing at the metabolic and cellular levels. In ASD, the consequence may be dysfunctional neural circuits and internal systems, producing autism’s well-documented symptoms and behaviors.  

“Metabolism is the real-time result of our genes interacting with the environment,” said Naviaux. “Environmental chemical or biotoxin exposures —the ‘exposome’ — at critical developmental windows can produce delayed effects that become apparent only after months or years. By measuring metabolism and the exposome, it may be possible to identify children at risk for developing autism before the first behavioral symptoms appear.”

The study seeks 400 participants between the ages of three and 10 years old, meeting these requirements:

Born in California
Have a confirmed diagnosis of ASD from a licensed clinician or be a healthy child not taking any prescription medications (200 participants from each group)
Born after a normal term pregnancy of 37 to 42 weeks
Have not had a medical issue that required readmission to the hospital in the first month of life

The study requires parents of participating children to answer questionnaires covering pregnancy, labor and delivery, the child’s health history and that of the family.

Consented analyses will be conducted of dried blood drops recorded as part of California’s Newborn Screening program, which began in 1966 and now screens for 80 different genetic and congenital disorders. Blood spots have been saved and stored by the California Department of Public Health since 1982. No new blood tests or behavioral testing will be required for the Phase II study.  

Naviaux said he hopes to screen and enroll the full complement of participants by June 2020. Analyses of the identified and retrieved blood spots is expected to be complete by June 2021.

“We then hope to expand the testing program to states like New Jersey, New York, Pennsylvania and Washington by enlisting collaborators in each of those states who will be able to apply the new methods we have developed.  

“Each new state has slightly different policies and regulations regarding the collection and storage of dried blood spots from universal newborn screening programs, so this medium-scale expansion study will teach us what will be needed to launch a national study.”

A Calming Space

Children’s of Alabama Expands Sensory Pathway For Patients With Sensory Sensitivities

When Sladen Fisher got a bad cut on his earlobe at school, his mother, Jennifer Fisher, worried the sights and sounds of Children’s of Alabama’s Emergency Department would be too stressful for her son. That’s because Sladen has attention deficit hyperactivity disorder (ADHD) and sensory processing disorder.

At the time of the Sladen’s visit, Children’s of Alabama had just launched its Sensory Pathway, designed for patients with conditions such as ADHD, autism and Down syndrome. In 2016, the pathway began as a pilot project in the Emergency Department; however, it has since expanded to One Day Surgery and several inpatient units at Children’s of Alabama, including the Pediatric Intensive Care Unit, Pulmonary Care Unit and Special Care Unit. Future plans include expansion to ancillary and outpatient services.

The pathway made a lasting impact on Sladen. Back at school a few weeks later, he presented a report about someone he considers a hero. He chose Children’s of Alabama Child Life Specialist Shelby Smith, who stayed by his side during his visit, explained his treatment in terms he understood and provided him with an iPad and fidget toys for distraction and comfort.

“In his mind, she was a hero, someone who went above and beyond to help him,” Jennifer said. She made what could have been an incredibly difficult situation so amazing. She really was our hero.”The pathway has been equally impactful on Children’s of Alabama, said Michele Kong, M.D. associate professor in pediatric critical care at the University of Alabama at Birmingham (UAB) Department of Pediatrics.

“The pathway has been so empowering for our providers,” said Kong, who serves on the Sensory Pathway Task Force, also comprised of nurses, informatics specialists and child life specialists. Unit by unit, the task force provides education and training and is developing an online training module. The task force is also working with information technology specialists to flag patients with sensory sensitivities from the point of admission.

“We tailor education and training to suit each unit’s needs because each unit’s workflow and culture is different,” Kong said. “The success of the pathway is a direct reflection of our providers’ passion to learn. There’s buy-in from our providers because they know it’s good for their patients.”

As a parent, Kong, too, knows how jarring a hospital visit can be for a child with sensory sensitivities. Her oldest son, Abram, was diagnosed with autism at age 4. The diagnosis inspired Kong and her husband, Julian Maha, M.D., to found KultureCity®, a nonprofit that works to “create acceptance and inclusion for all individuals with unique abilities,” according to its mission statement. In 2019, KultureCity was ranked fourth on Fast Company magazine’s list of the most innovative companies in the world. KultureCity not only partners with local organizations in Birmingham, but also with national organizations such as the NBA and NFL.

“We never imagined it would reach this scale,” Kong said. “It impressed on us that there’s a lot of power when a collective group of people have the same belief and passion for change.”

When should a young girl visit a gynecologist?

According to the American College of Obstetricians and Gynecologist, girls should have their first gynecologic visit between the ages of 13 and 15 years old.

Photo by Moose Photos on Pexels.com

Parents of young teenage girls are probably thinking about how to help them navigate social media, classwork, and their social lives. However, as young teenagers begin to go through puberty, it is also important to help them understand how to manage their changing bodies. Scheduling an appointment with a pediatric and adolescent gynecologist is one way to do this.

According to the American College of Obstetricians and Gynecologist, girls should have their first gynecologic visit between the ages of 13 and 15 years old. Pediatric and adolescent gynecology is a subspecialty of gynecology that provides comprehensive care for girls from birth to early adulthood. Pediatric and adolescent gynecologists take special care of the emotional needs of their patients and families while providing the unique care that’s necessary to foster the child’s transition from pediatrics to adult gynecology.

We spoke with pediatric gynecologist Amber Truehart, MD, about other reasons a girl should visit a gynecologist before she becomes an adult.

Education and Examinations

Patient education is one highlight of building a relationship with a pediatric and adolescent gynecologist. During the first visit, the doctor will help reinforce an understanding of healthy body weight and good habits for healthy bones. This is also an opportunity for young patients to learn about basic female hygiene, normal versus abnormal vaginal discharge, and puberty. Additionally, depending on the patient’s individual needs, their physical and emotional development, and medical history, the doctor may perform a basic physical exam, possibly including a breast exam.

Menstrual Cycle

Most girls get their first period when they are between 10 and 15 years old. So, it’s likely that a young girl is beginning to think about her period around this time. A visit with a pediatric and adolescent gynecologist will help her learn about the menstrual cycle and what is considered normal or abnormal. She can also learn how to manage her cycle, pain relief, and how to deal with premenstrual syndrome (PMS).

Vaccinations

Young girls are able to get the HPV vaccine at their gynecologist’s office. The HPV vaccine helps protect children from developing the human papillomavirus, which can lead to six types of cancers later in life. The Centers for Disease Control and Prevention recommends two doses of the HPV vaccine, the first at age 11 and then six months later. If the child waits until age 15, they’ll need three doses of the vaccine.

Sex Talks

Let’s face it — it may be difficult for a young girl to talk to a parent about sex. Yet, it’s important that she have an avenue for these conversations. Getting her in front of an expert she trusts will help her get accurate information and learn about sexually transmitted infections, HIV, and pregnancy prevention. She can also talk with her gynecologist about safe and healthy intimate relationships, LGBTQ topics and having sex for the first time.

Special Assessments

For girls and young women who need complex gynecologic care, forming a doctor-patient relationship connects them with an expert who is poised to provide a full range of specialized services. Pediatric and adolescent gynecologists are trained to care for the intricate needs of children and teens who have physical or mental disabilities, congenital gynecologic abnormalities (present since birth), and underlying chronic health problems.

Exercise and Anxiety Reduction in Children with Autism

An Autism Intervention Research Network on Physical Health grant supports the research

Photo by Patrick Case on Pexels.com

The Center for Autism & Neurodevelopmental Disorders will begin a research study using physical exercise to reduce anxiety in children with Autism Spectrum Disorder (ASD) among underserved populations.

This initiative is made possible through a grant from the Autism Intervention Research Network on Physical Health (AIR-P). Jean Gehricke, Ph.D., associate professor of pediatrics at UC Irvine and a licensed clinical psychologist with The Center for Autism & Neurodevelopmental Disorders, is the principal investigator of the study. The four-year study is receiving $103,125 for its initial year, with the potential overall total of $790,625. Gehricke expects to enroll participants by early fall.

“We are excited to be chosen as the only site nationwide to receive this AIR-P grant to study the impact of exercise on anxiety, which is very common and can lead to poor outcomes in children with autism,” Gehricke said. “The grant will allow us to collect valuable data that could significantly improve long-term physical and mental health, particularly in underserved communities.”

A growing international body of research is confirming the wide-ranging benefits of exercise in reducing stress and improving the long-term health of children and adults alike. This study will determine the potential benefits of exercise in underserved children with ASD.

“We often tell our families to encourage their children with autism to get out and exercise,” said Kelly McKinnon, M.A., BCBA, co-investigator on the project. “It’s exciting to be able to study its impact and share the results with our families.”

The physical exercise research program is being designed to incorporate comprehensive new guidelines for physical exercise in children developed by the Centers for Disease Control and Prevention. Researchers will measure impact based on several key factors, including compliance, anxiety and salivary cortisol levels measured before and after completion of the exercise and control group interventions. Cortisol is a frequently used biomarker for stress, Gehricke explained.

Collecting this data will aid in the development of an evidence-based physical exercise intervention toolkit for the treatment of anxiety as well as other behaviors and improvement of physical health in children with ASD from underserved populations.

“Research is one of the core pillars of our mission,” said Catherine Brock, M.A., executive director of The Center for Autism & Neurodevelopmental Disorders. “With this grant and Jean Gehricke’s pioneering research efforts, we will be better able to help parents and families overcome obstacles they face and assist children in reaching their optimal potential.”

For more information, please visit http://www.thecenter4autism.org.

About The Center for Autism & Neurodevelopmental DisordersFounded in 2001 (originally as For OC Kids), The Center is home to a team of experts in the field of autism and neurodevelopmental disorders. Since its opening, The Center has been a leader in clinical services, research, education, and outreach, serving clients from birth through 22 years old.

In late 2012, a catalytic investment by the Thompson Family Foundation and the Children and Families Commission of Orange County provided $14.8 million to expand The Center for Autism & Neurodevelopmental Disorders.

The Center was established to provide help and hope to children, adolescents, young adults and their families challenged by autism spectrum and other neurodevelopmental disorders through excellent clinical care, innovative research, quality education, and community engagement. For more information, please visit http://www.thecenter4autism.org.

Taking Antidepressants During Pregnancy Increases Risk of Autism by 87%

Ground breaking study published in JAMA Pediatrics looks at outcomes of 145,456 pregnancies after antidepressant use

Credit: Hepingting, CC BY SA 2.0, https://flic.kr/p/95h8gu

Using antidepressants during pregnancy greatly increases the risk of autism, Professor Anick Bérard of the University of Montreal and its affiliated CHU Sainte-Justine children’s hospital revealed today. Prof. Bérard, an internationally renowned expert in the fields of pharmaceutical safety during pregnancy, came to her conclusions after reviewing data covering 145,456 pregnancies. “The variety of causes of autism remain unclear, but studies have shown that both genetics and environment can play a role,” she explained. “Our study has established that taking antidepressants during the second or third trimester of pregnancy almost doubles the risk that the child will be diagnosed with autism by age 7, especially if the mother takes selective serotonin reuptake inhibitors, often known by its acronym SSRIs.” Her findings were published today in JAMA Pediatrics.

Using antidepressants during pregnancy greatly increases the risk of autism, Professor Anick Bérard of the University of Montreal and its affiliated CHU Sainte-Justine children’s hospital revealed today. Prof. Bérard, an internationally renowned expert in the fields of pharmaceutical safety during pregnancy, came to her conclusions after reviewing data covering 145,456 pregnancies. “The variety of causes of autism remain unclear, but studies have shown that both genetics and environment can play a role,” she explained. “Our study has established that taking antidepressants during the second or third trimester of pregnancy almost doubles the risk that the child will be diagnosed with autism by age 7, especially if the mother takes selective serotonin reuptake inhibitors, often known by its acronym SSRIs.” Her findings were published today in JAMA Pediatrics.

Bérard and her colleagues worked with data from the Quebec Pregnancy Cohort and studied 145,456 children between the time of their conception up to age ten. In addition to information about the mother’s use of antidepressants and the child’s eventual diagnosis of autism, the data included a wealth of details that enabled the team to tease out the specific impact of the antidepressant drugs. For example, some people are genetically predisposed to autism (i.e., a family history of it.) Maternal age, and depression are known to be associated with the development of autism, as are certain socio-economic factors such as being exposed to poverty, and the team was able to take all of these into consideration. “We defined exposure to antidepressants as the mother having had one or more prescription for antidepressants filled during the second or third trimester of the pregnancy. This period was chosen as the infant’s critical brain development occurs during this time,” Prof. Bérard said. “Amongst all the children in the study, we then identified which children had been diagnosed with a form of autism by looking at hospital records indicating diagnosed childhood autism, atypical autism, Asperger’s syndrome, or a pervasive developmental disorder. Finally, we looked for a statistical association between the two groups, and found a very significant one: an 87% increased risk.” The results remained unchanged when only considering children who had been diagnosed by specialists such as psychiatrists and neurologists.

The findings are hugely important as six to ten percent of pregnant women are currently being treated for depression with antidepressants. In the current study, 1,054 children were diagnosed with autism (0.72% of the children in the study), on average at 4.5 years of age. Moreover, the prevalence of autism amongst children has increased from 4 in 10,000 children in 1966 to 100 in 10,000 today. While that increase can be attributed to both better detection and widening criteria for diagnosis, researchers believe that environmental factors are also playing a part. “It is biologically plausible that anti-depressants are causing autism if used at the time of brain development in the womb, as serotonin is involved in numerous pre- and postnatal developmental processes, including cell division, the migration of neuros, cell differentiation and synaptogenesis – the creation of links between brain cells,” Prof. Bérard explained. “Some classes of anti-depressants work by inhibiting serotonin (SSRIs and some other antidepressant classes), which will have a negative impact on the ability of the brain to fully develop and adapt in-utero”

The World Health Organization indicates that depression will be the second leading cause of death by 2020, which leads the researchers to believe that antidepressants will likely to remain widely prescribed, including during pregnancy. “Our work contributes to a better understanding of the long-term neurodevelopmental effects of anti-depressants on children when they are used during gestation. Uncovering the outcomes of these drugs is a public health priority, given their widespread use,” Prof. Bérard said.

About this study:Takoua Boukhris, Odile Sheehy, Laurent Mottron, MD, PhD, and Anick Bérard, PhD, published “Antidepressant use during pregnancy and the risk of autism spectrum disorder in children” in JAMA Pediatrics on December 14, 2015.

Anick Bérard, PhD, is a professor at the University of Montreal’s Faculty of Pharmacy and a researcher at the CHU Sainte-Justine Research Centre.

This study was supported by the Canadian Institutes of Health Reseach (CIHR) “Quebec Training Network in Perinatal Research”, and the Fonds de la recherche du Québec – Santé (FRQ-S).,

Dr. Bérard is the recipient of a FRQ-S research Chair on Medications and Pregnancy. Dr Bérard is a consultant for plaintiffs in litigations involving antidepressants and birth defects.

The University of Montreal is officially known as Université de Montréal.

Measuring Mutations in Sperm May Reveal Risk for Autism in Future Children

Spontaneous mutations in paternal sperm are linked to autism spectrum disorder; researchers have developed way to quantify those mutations and assess chances the mutations will cause disease.

Credit: UC San Diego Health Sciences
In this illustration of sperm mosaicism, mutated sperm are depicted in red.

The causes of autism spectrum disorder or ASD are not fully understood; researchers believe both genetics and environment play a role. In some cases, the disorder is linked to de novo mutations that appear only in the child and are not inherited from either parent’s DNA.

In a study published December 23, 2019 in Nature Medicine, an international team of scientists, led by researchers at University of California San Diego School of Medicine, describe a method to measure disease-causing mutations found only in the sperm of the father, providing a more accurate assessment of ASD risk in future children.

“Autism afflicts 1 in 59 children and we know that a significant portion is caused by these de novo DNA mutations, yet we are still blind to when and where these mutations will occur,” said co-senior author Jonathan Sebat, PhD, professor and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine. “With our new study, we can trace some of these mutations back to the father, and we can directly assess the risk of these same mutations occurring again in future children.”

Recent studies suggest gene-damaging de novo mutations are involved in at least 10 to 30 percent of ASD cases, with the number of mutations rising with the father’s age at time of conception. De novo mutations occur spontaneously in parents’ sperm or eggs or during fertilization. The mutation is then present in each cell as the fertilized egg divides. Studies now point to male sperm as a particularly important source of these mutations, with the chance of the mutation recurring within the same family generally estimated at 1 to 3 percent.

“However, such estimates are not based on actual knowledge of the risk in an individual family, but instead are based on frequencies in the general population,” said co-senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine. “When a disease-causing mutation occurs for the first time in a family, the probability that it could happen again in future offspring is not known. Thus families must make a decision with a great deal of uncertainty.”

For their study, Gleeson, Sebat and colleagues analyzed the sperm of eight fathers who were already parents of children with ASD. The goal was to look for the presence of multiple, genetically different material in cells in the same person, a phenomenon called mosaicism. Using deep whole genome sequencing, they found variants in offspring that were matched only in the fathers’ sperm.

“While medical textbooks teach us that every cell in the body has an identical copy of DNA, this is fundamentally not correct. Mutations occur every time a cell divides, so no two cells in the body are genetically identical,” said first author Martin Breuss, PhD, an assistant project scientist in Gleeson’s lab.

“Mosaicism can cause cancer or can be silent in the body. If a mutation occurs early in development, then it will be shared by many cells within the body. But if a mutation happens just in sperm, then it can show up in a future child but not cause any disease in the father.”

The researchers determined that disease-causing mutations were present in up to 15 percent of the fathers’ sperm cells, information that could not be determined through other means, such as blood samples.

“My laboratory has a long-standing interest in understanding the origins of pediatric brain disease, and how mutations contributes to disease in a child,” said Gleeson. “We previously showed that mosaicism in a child can lead to diseases like epilepsy. Here, we show that mosaicism in one of parents is at least as important when thinking about genetic counseling.”

If developed into a clinical test, the researchers said fathers could have their sperm studied to determine their precise risk of recurrence in future children. The methods might also be applied to men that haven’t had children yet, but who want to know the risk of having a child with a disease.



Co-authors include: Danny Antaki, Morgan Kleiber, Oanh Hong, Madhusudan Gujral, William M. Brandler, Ileena Mitra, and Melissa Gymrek, UC San Diego; Renee D. George, Kiely N. James, Laurel L. Ball, Xiaoxu Yang, Sara A. Wirth, Jing Gu, Camila A. B. Garcia, Damir Musaev, An Nguyen, Jennifer McEvoy-Venneri, and Evan Sticca, Howard Hughes Medical Institute at UC San Diego and Rady Children’s Institute for Genomics of Psychiatric Diseases; Renatta Knox, Howard Hughes Medical Institute at UC San Diego, Rady Children’s Institute for Genomics of Psychiatric Diseases and Weill Cornell Medical College; Martha Cristina Cancino Botello and Javiera Uribe Fenner, Hospital Universitari Mutua de Terrassa, Spain; Maria Cárcel Pérez, Maria Arranz, and Amaia Hervás, Fundacio Docencia i Recerca Mutua Terrassa, Spain; Andrea B. Moffitt and Zihua Wang, Cold Spring Harbor; and Orrin Devinsky, New York University School of Medicine.

Funding for this research came, in part, from EMBO Long-Term Fellowship (ALTF 174-2015), the Marie Curie Actions of the European Commission (LTFCOFUND2013, GA-2013-609409), Erwin Schrödinger Fellowship by the Austrian Science Fund (J 4197-B30), the National Institutes of Health (U01MH108898, R01NS083823, MH076431, MH113715), the Simons Foundation Autism Research Initiative, the Howard Hughes Medical Institute, the Silverman Family Foundation and Finding A Cure for Epilepsy and Seizures.

Disclosure: Martin Breuss, Danny Antaki, Morgan Kleiber, Kiely N. James, William M. Brandler, Jonathan Sebat and Joseph Gleeson are inventors on a provisional patent (PCT Ref. No. SD2017-181-2PCT) filed by UC San Diego and titled “Assessing risk of de novo mutations in males.”