Can Genetic Testing Help Shed Light on the Autism Epidemic?
Autism cases are still on the rise, and scientists don't know why. In April, the Centers for Disease Control (CDC) reported that rates of autism had increased once again, now at an estimated 1 in 59 children up from 1 in 68 just two years ago. Rates have been climbing steadily since 2007 when the CDC initially estimated that 1 in 150 children were on the autism spectrum.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning.
The standard explanation for this increase has been the expansion of the definition of autism to include milder forms like Asperger's, as well as a heightened awareness of the condition that has improved screening efforts. For example, the most recent jump is attributed to children in minority communities being diagnosed who might have previously gone under the radar. In addition, more federally funded resources are available to children with autism than other types of developmental disorders, which may prompt families or physicians to push harder for a diagnosis.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning. William Graf, a pediatric neurologist at Connecticut Children's Medical Center, says that when a nurse tells him that a new patient has a history of autism, the term is no longer a useful description. "Even though I know this topic extremely well, I cannot picture the child anymore," he says. "Use the words mild, moderate, or severe. Just give me a couple more clues, because when you say autism today, I have no idea what people are talking about anymore."
Genetic testing has emerged as one potential way to remedy the overly broad label by narrowing down a heterogeneous diagnosis to a specific genetic disorder. According to Suma Shankar, a medical geneticist at the University of California, Davis, up to 60 percent of autism cases could be attributed to underlying genetic causes. Common examples include Fragile X Syndrome or Rett Syndrome—neurodevelopmental disorders that are caused by mutations in individual genes and are behaviorally classified as autism.
With more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information.
Having a genetic diagnosis in addition to an autism diagnosis can help families in several ways, says Shankar. Knowing the genetic origin can alert families to other potential health problems that are linked to the mutation, such as heart defects or problems with the immune system. It may also help clinicians provide more targeted behavioral therapies and could one day lead to the development of drug treatments for underlying neurochemical abnormalities. "It will pave the way to begin to tease out treatments," Shankar says.
When a doctor diagnoses a child as having a specific genetic condition, the label of autism is still kept because it is more well-known and gives the child access to more state-funded resources. Children can thus be diagnosed with multiple conditions: autism spectrum disorder and their specific gene mutation. However, with more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information. What's more, the presence or absence of a mutation doesn't necessarily indicate whether the child is on the mild or severe end of the autism spectrum.
Because of this, Graf doubts that genetic classifications are really that useful. He tells the story of a boy with epilepsy and severe intellectual disabilities who was diagnosed with autism as a young child. Years later, Graf ordered genetic testing for the boy and discovered that he had a mutation in the gene SYNGAP1. However, this knowledge didn't change the boy's autism status. "That diagnosis [SYNGAP1] turns out to be very specific for him, but it will never be a household name. Biologically it's good to know, and now it's all over his chart. But on a societal level he still needs this catch-all label [of autism]," Graf says.
"It gives some information, but to what degree does that change treatment or prognosis?"
Jennifer Singh, a sociologist at Georgia Tech who wrote the book Multiple Autisms: Spectrums of Advocacy and Genomic Science, agrees. "I don't know that the knowledge gained from just having a gene that's linked to autism," is that beneficial, she says. "It gives some information, but to what degree does that change treatment or prognosis? Because at the end of the day you have to address the issues that are at hand, whatever they might be."
As more children are diagnosed with autism, knowledge of the underlying genetic mutation causing the condition could help families better understand the diagnosis and anticipate their child's developmental trajectory. However, for the vast majority, an additional label provides little clarity or consolation.
Instead of spending money on genetic screens, Singh thinks the resources would be better used on additional services for people who don't have access to behavioral, speech, or occupational therapy. "Things that are really going to matter for this child in their future," she says.
Story by Big Think
It is a mystery why humans manifest vast differences in lifespan, health, and susceptibility to infectious diseases. However, a team of international scientists has revealed that the capacity to resist or recover from infections and inflammation (a trait they call “immune resilience”) is one of the major contributors to these differences.
Immune resilience involves controlling inflammation and preserving or rapidly restoring immune activity at any age, explained Weijing He, a study co-author. He and his colleagues discovered that people with the highest level of immune resilience were more likely to live longer, resist infection and recurrence of skin cancer, and survive COVID and sepsis.
Measuring immune resilience
The researchers measured immune resilience in two ways. The first is based on the relative quantities of two types of immune cells, CD4+ T cells and CD8+ T cells. CD4+ T cells coordinate the immune system’s response to pathogens and are often used to measure immune health (with higher levels typically suggesting a stronger immune system). However, in 2021, the researchers found that a low level of CD8+ T cells (which are responsible for killing damaged or infected cells) is also an important indicator of immune health. In fact, patients with high levels of CD4+ T cells and low levels of CD8+ T cells during SARS-CoV-2 and HIV infection were the least likely to develop severe COVID and AIDS.
Individuals with optimal levels of immune resilience were more likely to live longer.
In the same 2021 study, the researchers identified a second measure of immune resilience that involves two gene expression signatures correlated with an infected person’s risk of death. One of the signatures was linked to a higher risk of death; it includes genes related to inflammation — an essential process for jumpstarting the immune system but one that can cause considerable damage if left unbridled. The other signature was linked to a greater chance of survival; it includes genes related to keeping inflammation in check. These genes help the immune system mount a balanced immune response during infection and taper down the response after the threat is gone. The researchers found that participants who expressed the optimal combination of genes lived longer.
Immune resilience and longevity
The researchers assessed levels of immune resilience in nearly 50,000 participants of different ages and with various types of challenges to their immune systems, including acute infections, chronic diseases, and cancers. Their evaluationdemonstrated that individuals with optimal levels of immune resilience were more likely to live longer, resist HIV and influenza infections, resist recurrence of skin cancer after kidney transplant, survive COVID infection, and survive sepsis.
However, a person’s immune resilience fluctuates all the time. Study participants who had optimal immune resilience before common symptomatic viral infections like a cold or the flu experienced a shift in their gene expression to poor immune resilience within 48 hours of symptom onset. As these people recovered from their infection, many gradually returned to the more favorable gene expression levels they had before. However, nearly 30% who once had optimal immune resilience did not fully regain that survival-associated profile by the end of the cold and flu season, even though they had recovered from their illness.
Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance.
This could suggest that the recovery phase varies among people and diseases. For example, young female sex workers who had many clients and did not use condoms — and thus were repeatedly exposed to sexually transmitted pathogens — had very low immune resilience. However, most of the sex workers who began reducing their exposure to sexually transmitted pathogens by using condoms and decreasing their number of sex partners experienced an improvement in immune resilience over the next 10 years.
Immune resilience and aging
The researchers found that the proportion of people with optimal immune resilience tended to be highest among the young and lowest among the elderly. The researchers suggest that, as people age, they are exposed to increasingly more health conditions (acute infections, chronic diseases, cancers, etc.) which challenge their immune systems to undergo a “respond-and-recover” cycle. During the response phase, CD8+ T cells and inflammatory gene expression increase, and during the recovery phase, they go back down.
However, over a lifetime of repeated challenges, the immune system is slower to recover, altering a person’s immune resilience. Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance despite the many respond-and-recover cycles that their immune systems have faced.
Public health ramifications could be significant. Immune cell and gene expression profile assessments are relatively simple to conduct, and being able to determine a person’s immune resilience can help identify whether someone is at greater risk for developing diseases, how they will respond to treatment, and whether, as well as to what extent, they will recover.
In November 2021, Mickayla Wininger’s then one-month-old son, Malcolm, endured a terrifying bout with RSV, the respiratory syncytial (sin-SISH-uhl) virus—a common ailment that affects all age groups. Most people recover from mild, cold-like symptoms in a week or two, but RSV can be life-threatening in others, particularly infants.
Wininger, who lives in southern Illinois, was dressing Malcolm for bed when she noticed what seemed to be a minor irregularity with this breathing. She and her fiancé, Gavin McCullough, planned to take him to the hospital the next day. The matter became urgent when, in the morning, the boy’s breathing appeared to have stopped.
After they dialed 911, Malcolm started breathing again, but he ended up being hospitalized three times for RSV and defects in his heart. Eventually, he recovered fully from RSV, but “it was our worst nightmare coming to life,” Wininger recalled.
It’s a scenario that the federal government is taking steps to prevent. In July, the Food and Drug Administration approved a single-dose, long-acting injection to protect babies and toddlers. The injection, called Beyfortus, or nirsevimab, became available this October. It reduces the incidence of RSV in pre-term babies and other infants for their first RSV season. Children at highest risk for severe RSV are those who were born prematurely and have either chronic lung disease of prematurity or congenital heart disease. In those cases, RSV can progress to lower respiratory tract diseases such as pneumonia and bronchiolitis, or swelling of the lung’s small airway passages.
Each year, RSV is responsible for 2.1 million outpatient visits among children younger than five-years-old, 58,000 to 80,000 hospitalizations in this age group, and between 100 and 300 deaths, according to the Centers for Disease Control and Prevention. Transmitted through close contact with an infected person, the virus circulates on a seasonal basis in most regions of the country, typically emerging in the fall and peaking in the winter.
In August, however, the CDC issued a health advisory on a late-summer surge in severe cases of RSV among young children in Florida and Georgia. The agency predicts "increased RSV activity spreading north and west over the following two to three months.”
Infants are generally more susceptible to RSV than older people because their airways are very small, and their mechanisms to clear these passages are underdeveloped. RSV also causes mucus production and inflammation, which is more of a problem when the airway is smaller, said Jennifer Duchon, an associate professor of newborn medicine and pediatrics in the Icahn School of Medicine at Mount Sinai in New York.
In 2021 and 2022, RSV cases spiked, sending many to emergency departments. “RSV can cause serious disease in infants and some children and results in a large number of emergency department and physician office visits each year,” John Farley, director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a news release announcing the approval of the RSV drug. The decision “addresses the great need for products to help reduce the impact of RSV disease on children, families and the health care system.”
Sean O’Leary, chair of the committee on infectious diseases for the American Academy of Pediatrics, says that “we’ve never had a product like this for routine use in children, so this is very exciting news.” It is recommended for all kids under eight months old for their first RSV season. “I would encourage nirsevimab for all eligible children when it becomes available,” O’Leary said.
For those children at elevated risk of severe RSV and between the ages of 8 and 19 months, the CDC recommends one dose in their second RSV season.
The drug will be “really helpful to keep babies healthy and out of the hospital,” said O’Leary, a professor of pediatrics at the University of Colorado Anschutz Medical Campus/Children’s Hospital Colorado in Denver.
An antiviral drug called Synagis (palivizumab) has been an option to prevent serious RSV illness in high-risk infants since it was approved by the FDA in 1998. The injection must be given monthly during RSV season. However, its use is limited to “certain children considered at high risk for complications, does not help cure or treat children already suffering from serious RSV disease, and cannot prevent RSV infection,” according to the National Foundation for Infectious Diseases.
Until the approval this summer of the new monoclonal antibody, nirsevimab, there wasn’t a reliable method to prevent infection in most healthy infants.
Both nirsevimab and palivizumab are monoclonal antibodies that act against RSV. Monoclonal antibodies are lab-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. A single intramuscular injection of nirsevimab preceding or during RSV season may provide protection.
The strategy with the new monoclonal antibody is “to extend protection to healthy infants who nonetheless are at risk because of their age, as well as infants with additional medical risk factors,” said Philippa Gordon, a pediatrician and infectious disease specialist in Brooklyn, New York, and medical adviser to Park Slope Parents, an online community support group.
No specific preventive measure is needed for older and healthier kids because they will develop active immunity, which is more durable. Meanwhile, older adults, who are also vulnerable to RSV, can receive one of two new vaccines. So can pregnant women, who pass on immunity to the fetus, Gordon said.
Until the approval this summer of the new monoclonal antibody, nirsevimab, there wasn’t a reliable method to prevent infection in most healthy infants, “nor is there any treatment other than giving oxygen or supportive care,” said Stanley Spinner, chief medical officer and vice president of Texas Children’s Pediatrics and Texas Children’s Urgent Care.
As with any virus, washing hands frequently and keeping infants and children away from sick people are the best defenses, Duchon said. This approach isn’t foolproof because viruses can run rampant in daycare centers, schools and parents’ workplaces, she added.
Mickayla Wininger, Malcolm’s mother, insists that family and friends wear masks, wash their hands and use hand sanitizer when they’re around her daughter and two sons. She doesn’t allow them to kiss or touch the children. Some people take it personally, but she would rather be safe than sorry.
Wininger recalls the severe anxiety caused by Malcolm's ordeal with RSV. After returning with her infant from his hospital stays, she was terrified to go to sleep. “My fiancé and I would trade shifts, so that someone was watching over our son 24 hours a day,” she said. “I was doing a night shift, so I would take caffeine pills to try and keep myself awake and would end up crashing early hours in the morning and wake up frantically thinking something happened to my son.”
Two years later, her anxiety has become more manageable, and Malcolm is doing well. “He is thriving now,” Wininger said. He recently had his second birthday and "is just the spunkiest boy you will ever meet. He looked death straight in the eyes and fought to be here today.”