The push to display newborns for uncommon autism-linked genetic situations | Spectrum
Earlier this month, researchers reported unpublished preliminary results from a pilot drug study for ADNP syndrome, a rare genetic disorder often accompanied by autism.
During the nearly one-year study, 10 children, ages 6 to 12, took a low dose of ketamine. The drug is approved for the treatment of depression and is used in higher doses as a sedative. However, studies suggest that it may also increase expression of the ADNP gene, a copy of which in these children has partially or completely lost its function and disrupts their early neurological development.
The results of the study, led by Alexander Kolevzon, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai in New York City, were encouraging, the families of the participants were told: the children showed improvements in social behavior, attention and sensory sensitivities and other areas and they had no serious side effects.
Ketamine may not prove helpful for these children in the longer term or in larger cohorts in future studies. But for some, the results represent a crucial step in screening all newborns for ADNP syndrome, says Sandra Sermone, founder of the ADNP Kids Research Foundation, which funded the study. Without some type of treatment to change the course of the disease, mandatory screening is moot. But “the moment we have a drug that shows effectiveness,” says Sermone, the parent of a teenager with ADNP syndrome, “we rush to newborn screening.”
Sermons isn’t the only rare disease proponent with newborn screening in mind. With the cost of genetic testing falling and treatments closer to the clinic, parents and researchers alike are speaking more urgently about the need to address genetic disorders associated with autism – including Angelman, Rett, Fragile-X, and DDX3X syndromes Identify newborn babies.
Currently, the process of adding a condition to the newborn screening list in the United States is lengthy and complicated. A foundation that funds research into Angelman Syndrome supports the Newborn Screening Reauthorization Act, introduced in January, which increases the budget for the U.S. newborn screening program from $ 11.9 million to $ 31 million among other things should investigate ways to speed up the process.
In the meantime, individual federal states are piloting their own expansion programs. An optional screening project in North Carolina is evaluating hundreds of conditions – some related to autism – to be added to its list in 2022. And New York has developed its own add-on called ScreenPlus that checks for more than a dozen conditions, including Sanfilippo syndrome, a progressive neurological disorder that is often accompanied by autism.
Despite the benefits – including the ability to start treating some potentially life-threatening traits in infancy – the prospect of advanced screening raises a number of questions. Since so much is still unknown about how genes contribute to neural development, identifying a genetic disorder in a newborn can create unnecessary uncertainty about the child’s progress. And some features, including those that simply reflect the breadth of human neurodiversity, may not warrant intervention.
“These are the topics we all grapple with and discuss,” says Huda Zoghbi, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas. Acknowledging the trade-offs between the need to identify children who may benefit from them and the worry of finding mutations that may never have an impact, she adds, “A lot depends.”
Illustration by Nan Cao
Treatment horizon:
For a condition to deserve screening, there must be reliable testing and strong evidence that existing treatment given shortly after birth can improve the child’s outcome – a guideline sometimes referred to as “screening only if you can Intervention “is called. ”
That bar could soon be met for several genetic disorders associated with autism, researchers say.
In March, Zoghbi and her colleagues showed that intense exercise can delay the onset of motor problems and memory loss in a mouse model of Rett syndrome, an autism-related genetic disorder that primarily affects girls. Training is only useful to the mice if it is performed before such challenges arise – a window of time that people without newborn screening would miss.
A small number of girls with the Rett mutation never develop the characteristics of the condition, but behavioral treatments are so safe that there is no reason not to follow up on any cases that test positive as newborns, Zogbhi says. “If you know you have an opportunity to do something about it that could change course for thousands of girls, do it.”
Another team showed that behavioral training can alleviate motor impairment in a mouse model of DDX3X syndrome. And growth hormone therapy can be “somewhat groundbreaking” for people with Prader-Willi syndrome associated with autism, especially when given as early as 3 to 6 months of age, says Stormy Chamberlain, associate professor of genetics and Genomics at the University of Connecticut.
Gene therapies are associated with higher risks and costs than other treatments, but they also appear to be increasingly viable for some autism-related conditions. Work on Angelman mice has shown that altering gene expression at an early stage of development can relieve anxiety, repetitive behavior, and epilepsy. A clinical trial of gene therapy for Angelman Syndrome was put on hold in late 2020, but the drug’s promise – as well as that of others under trial, along with one due to go to court later this year – allows for newborn screening for Angelman more urgent, says Chamberlain.
“The way to get things on the newborn screening panel is a steep climb,” she says. “In Angelman syndrome, there is an urge to do this because of the therapeutics.”
Right now, adding a new disease to the U.S. Recommended Screening List can take years, says Don Bailey, who served for six years on the federal advisory board that reviews the evidence for new supplements.
Part of the challenge is gathering enough data on rare diseases, he says: To identify even 20 babies for a study like Kolevzon’s, it may take millions of children to be screened. And collecting enough data can take several tries. Currently, each stakeholder typically has to raise their own disease-specific funding, which means researchers start from scratch every time to fund and set up studies.
In 2016, Bailey started a pilot infrastructure program called Early Check, which he hopes will serve as a prototype for data collection under several rare conditions. The program uses piggyback blood samples routinely drawn at birth in Bailey’s home state of North Carolina, where he is a distinguished fellow in early childhood development at the nonprofit research institute RTI International. Between 500 and 600 families sign up each month to have their newborn screened for a short and developing list of rare conditions, including fragile X syndrome, Bailey says.
Since the program started in late 2018, four infants with fragile X have been identified among 16,000 tests, covering about 5 or 6 percent of all babies born in the state annually. It takes a lot of effort to find these babies, says Bailey, but “we provide intensive early intervention services to these children.”
Ethical issues:
Early screening for rare diseases should benefit children and their families as well as researchers, say scientists.
Children with genetic disorders of autism may have other medical problems, such as heart defects. Newborn screening would ensure these issues are caught early, says Silvia De Rubeis, assistant professor of psychiatry at the Seaver Center for Autism Research and Treatment at the Icahn School of Medicine on Mount Sinai in New York City and lead investigator on the DDX3X mouse study.
“Knowledge is always power, isn’t it?” De Rubeis says. “It is power for patients – for young people and adults – for their families, their advocates, and also for us as researchers.”
Parents who are aware of their child’s genetic condition can also enroll them in clinical trials, if any, and connect with stakeholders or other support systems. This expands the population available to study the affected gene and could also help mitigate the catch-22 associated with admitting newborn screening panels: adding a condition to the list requires the Evidence that early treatment works, but early treatment cannot be tested without identifying participants at or shortly before birth.
And newborn screening could also reduce existing disparities in diagnoses that contribute to unequal access to treatment based on race, gender, income, or other demographic factors. “You try to think of a different program that every baby, every family has free access to,” says Bailey. “It’s a great model for public health and offers tremendous equity.”
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These benefits of screening need to be carefully weighed against other considerations, experts say, including the inevitable risk of revealing genetic information that some people may prefer not to know.
Many mutations lead to a number of possible outcomes that will only become apparent later. The state newborn screening committee is trying to avoid these types of “patient on hold,” says Bailey. Some mutations cannot affect a child’s health at all. Many parents find the additional knowledge useful, says Bailey, but it can also create stress and potentially change the way parents interact with their child. “The price you pay is watch and wait,” says Bailey.
To some, that price still seems high for rare conditions. For example, ADNP syndrome makes up less than 1 percent of people with autism, which in turn makes up only about 1 to 2 percent of the population. “Do you go to newborn screening for every single child? I mean, I don’t know, ”says Kolevzon, thinking out loud.
It might make sense for ketamine or some other drug to improve results, he adds. “Do you want to do this from birth? Yes, I think you would, provided it is safe. “
