Marina Sarris

A version of this story appeared on the Interactive Autism Network website in 2017. It was updated for SPARK in 2019.

Sandra Sermone refused to wait. She had seen her son Tony through heart surgery, a feeding tube, brain scans, countless blood tests, and medical appointments. This little boy who struggled to eat, talk, and play was getting worse. All Tony’s doctors could tell Sandra was that his many problems — including severe developmental delays, poor vision and autism — were probably caused by a genetic condition. They didn’t know which one: all the usual tests had come back normal. “Everyone said to wait and see. They didn’t push for any major therapies. I think they thought he was going to die,” Sandra Sermone said.

Sermone had three things: a telephone, a computer, and an inability to be discouraged. She would find an answer for what was happening to her child. She placed hundreds of calls to hospitals and research centers, looking for a medical study that would take him. (SPARK, the nation’s largest genetic study for autism, had not yet launched.) Finally, she got Tony accepted into an Undiagnosed Genetic Syndrome study at Duke University in North Carolina, a long flight from their home in Washington state. At Duke, Tony underwent whole exome sequencing, a lab test that looks for changes in the genes that encode proteins in the body.

Within months, the researchers told her they had found something extremely rare. Tony, then 6, had a change within his ADNP gene. He was among the first dozen people in the world to be diagnosed with ADNP, or Helsmoortel-Van Der Aa, syndrome.

But that is not the end of Tony’s and Sandra’s story. In fact, it was just the beginning. What Sandra, who is now a SPARK participant, would do next would set the stage for much, much more.

RAISING SUPERMAN

Sometimes mothers just know. Sermone sensed something was not quite right when she was seven months pregnant with Tony and his fraternal twin, Rocco. One twin didn’t move as much as the other. When the boys were born in early 2008, she also had a gnawing feeling about Tony. He looked different from Rocco and their older sister, Sophia, in a way that seemed to mean something.

At the time, the doctors told her not to worry. So did friends and family. A relative told her she was “just stressed out” and had with post-pregnancy hormones, Sermone said.

Within a few weeks of the twins’ birth, she learned that Tony had multiple heart defects and other conditions, although Rocco was fine. Doctors began testing Tony for an array of genetic syndromes most parents have never heard of: DiGeorge, Smith-Lemli-Opitz, Angelman, Noonan, Prader-Willi, and Sotos. Those tests came back negative, but still his list of problems grew. He had delays in walking and talking, cortical vision impairment (a vision problem based in the brain, not the eyes), gastroesophageal reflux disease, excess fluid in the brain, low muscle tone, and difficulty swallowing and eating.

Before he finished kindergarten, Tony would undergo an alphabet soup of medical tests (EKGs, EEGs, MRIs, CTs, echocardiograms, ultrasounds, barium swallow studies) and five surgeries (two to repair heart defects).¹ Tony took the pokes and prods in stride. His mother calls him her Superman, “more powerful than a locomotive,” as the announcer on the old TV show would intone at the start of every episode. She wrote, “Once I watched as they had to take blood out of a vein on his head. He didn’t even flinch and the young student/tech helping hold him down said, ‘Wow, this is one [tough] boy.’ I burst out laughing and said, ‘Yes, yes he is!’”²

So when the specialists at Duke handed her a piece of paper that said “ADNP mutation,” it gave her a reason, but not necessarily the reason, for his medical problems. “They told me that ADNP is associated with some of Tony’s conditions, but Tony is way more complicated, so he probably has something else, too,” she recalled. With only a handful of known cases, no one had cataloged all the symptoms of ADNP syndrome — or all the people who have it.

THE HUNT FOR ANSWERS BEGINS

When she got back from Duke, her first order of business was to find out more about ADNP, or activity-dependent neuroprotective protein. What would this change to a single gene on chromosome 20 mean for Tony’s future? “There was very little information on this syndrome, and I had a massively complicated kiddo who didn’t fit the bill,” she said.

She turned on her computer and began searching. Researchers at the University of Antwerp in Belgium had recently linked ADNP mutations to 10 cases of autism.³ Besides autism, many of those people had similar diagnoses, including intellectual disability, feeding problems in infancy, low muscle tone, and speech delay. They also had similar facial features: a prominent forehead, a high hairline, a broad bridge of the nose, and a thin upper lip. Sandra remembered her concern that Tony’s features seemed a bit different at birth. She emailed those researchers. She wanted to help them with their work, and she wanted to find other parents of children like Tony.

Frank Kooy, professor of cognitive genetics at University of Antwerp, recalled meeting Sermone online. “We were pleasantly surprised by being contacted by the mother of an ADNP kid from over the Atlantic,” he said by email. The Belgians knew of a few other families in the United States and agreed to pass along her contact information to those patients’ physicians.

Parents of newly diagnosed children — whatever the diagnosis — often find comfort in meeting others who are traveling their path. Soon Sermone was on the phone with those parents, swapping information. She began to suspect that the complicated web of symptoms Tony experienced had only one cause. “These ADNP kids were almost identical, physically and developmentally, and much more medically complex than what was known,” she said. That gave her an idea.

A MOMMY-DETECTIVE ON THE CASE

Sandra Bedrosian Sermone became, in her own words, a “crazy obsessed, highly caffeinated, middle of the night, internet stalking, Mommy-Detective.” She searched for anything she could find about this newly discovered syndrome — and anyone who could help her.

In 2014, she didn’t know where her sleuthing would lead. At first, she just wanted to find more families like hers. So she created a Facebook page dedicated to ADNP. The University of Antwerp helped by posting a link to it on its website. Within a month, she found 10 families. Five months after that, she created a questionnaire asking each family about their child’s growth, development, and medical history, intrigued by the children’s similarities. Does your child have a heart defect? Did she aspirate or gag a lot as a baby? When did he get his first teeth? (Tony’s baby teeth came in unusually early.) Does she speak? What therapies and medications does he get? And so on.

She began collecting the answers on Excel spreadsheets. She’s not a scientist, but she began conducting research like one. She reached dozens more families, in North and South America, Europe, Australia and the Middle East. She assembled her spreadsheets on a wall of her home, with photos of each person, like you would see on a detective show. “She’s doing what a clinical geneticist might do,” Raphael Bernier, PhD, an autism researcher at University of Washington, said at the time.

Families were eager to help. Some of their children had been in medical limbo for longer than Tony, shuttling between doctors who could not put a name to their condition or tell them what kind of future to expect. Sandra Sermone is cheerful, funny, and friendly; it’s not hard to understand why strangers would spend an hour or more sharing intimate details of their children’s lives with her. They didn’t have to wait for her results, either. They could visit a website she created, ADNPkids.com, to see what she was learning from them.

REACHING OUT TO RESEARCHERS

But her outreach did not end with families. She began calling and emailing researchers on three continents — including some of the top experts in autism genetics. “At first, it was desperation. There was so little known about ADNP. I just wanted to reach out and say, ‘What do you need from me? I want to be part of your research.’” After contacting a researcher, she would send him or her a disc with Tony’s medical records. “I am quite a talker, and once I get going, I get very excited about sharing the information I’ve learned about ADNP.”

In 2015, she dialed the genetics office at Oregon Health and Science University, across the Columbia River from her home. She reached associate professor Brian J. O’Roak, PhD. “She had no idea I was involved in the discovery of ADNP and its relation to autism,” he recalled. Soon she met with him and Eric J. Fombonne, the prominent French psychiatrist and autism expert.

As a geneticist, O’Roak said, it’s not unusual to be contacted by the parent of a child with a rare condition. “But it is uncommon to be contacted by a parent who is this involved and really pushing for the science to happen.”

EXPLORING THE AUTISM CONNECTION

During her own investigation, Sermone found that more than 80 percent of children with ADNP syndrome have autism. But the true percentage may be higher. People with ADNP syndrome have a somewhat narrower set of autism symptoms, which could confuse some doctors, she said.

At first, doctors thought Tony was too social and connected to his parents to have autism. But he had other symptoms of autism: severe speech delay, repetitive motions such as flapping his hands, and trouble playing with toys the way other children do. He ignored other children, including his brother and sister. Sermone wishes his autism had been diagnosed sooner, so he could have begun applied behavioral analysis, an autism therapy, at a younger age. Other families have told her similar tales, she said.

Tony’s autism diagnosis was confirmed at the University of Washington, where he participated in the TIGER (The Investigation of Genetic Exome Research) study. There she met Bernier, who, along with others, had discovered some rare gene changes in children with autism.^4,5 “ADNP plays a huge role in brain development, but it also regulates and controls the operation of other genes,” Bernier explained.

Sandra and husband Richard enrolled Tony, now 11, in two projects of the Simons Foundation Autism Research Initiative: the Simons Variation in Individuals Project, and SPARK. SPARK, which launched two years after Tony’s diagnosis, offers participants an easier path to genetic testing than the one that led to Tony’s ADNP diagnosis.

SPARK participants can provide a saliva sample at home and drop it in the mail. SPARK analyzes those samples for changes in ADNP, along with almost 100 other genes and chromosome segments linked to autism. SPARK will tell participants if they have one of these genetic changes; about 10 percent do so far.⁶

THE STORY OF ADNP AND THE BRAIN

The story of ADNP began more than 15 years ago, in a lab in Israel.^7,8 Illana Gozes, a professor of clinical biochemistry at Tel Aviv University, discovered ADNP and its vital role in brain development, learning, and memory while searching for genes and proteins that protect nerve cells. Her lab has studied the role of ADNP in brain-based disorders such as Alzheimer’s and schizophrenia. ADNP influences the work of many other genes, like a master switch of sorts.^9-11 Gozes’ research team thought ADNP might play a role in autism.^12-14 “When we discovered that without ADNP, the brain does not form, and when we saw that ADNP-deficient mice are socially impaired, we suggested a connection to autism,” Gozes recalled in an email.

Gozes was on Sermone’s short list of researchers to contact. With the information she gathered from other ADNP families, she worked with Gozes, Kooy, and others on scientific papers. In February 2017, for example, a medical journal published their research on a link between ADNP syndrome and early tooth eruption, a connection Sermone had noticed through her parent interviews. Most of the 54 children studied had a nearly full set of teeth by age 1, an early warning sign of the syndrome.¹⁵

BRIDGING THE GAP BETWEEN FAMILIES AND RESEARCHERS

Sermone became an example of what can happen when patients and families work together with researchers. “I’m a true believer that researchers could accomplish 100 percent more if they involved parents,” she said, “because we see everything about our children.”

Of course, researchers need people to study. So like an evangelist, Sermone spreads the word to parents she meets, in waiting rooms and elsewhere. Participate in research, join SPARK, find out if your child has a genetic change, she tells them.

Some parents are skeptical of genetic tests or studies, she said. “Sometimes families ask me, ‘Why should I do genetic testing? I already know my child has autism,’ and I like that I am able to tell them that it is incredibly important.” Their child may have a genetic change like ADNP syndrome, she tells them.“Why is that important to know? Because we have a drug in the pipeline.”

THE BRASS RING: A DRUG TREATMENT

Gozes and a pharmaceutical company in Israel have developed a drug called CP201 (davunetide) they want to test on people with ADNP syndrome. The U.S. Food and Drug Administration (FDA) has designated it an orphan drug — one that treats a rare condition. (About 200 people worldwide have an ADNP diagnosis). That designation can help smooth the way for a future clinical trial of the drug. Sermone was there in 2018 when company officials and American researchers met with the FDA about CP201.

Clinical trials cost money. Sermone is working to raise funds and awareness for such research through a nonprofit she created, the ADNP Kids Research Foundation. The foundation plans to launch a patient registry that researchers could use. Its medical and scientific advisory board includes Gozes, Bernier and two experts from the Seaver Autism Center at New York’s Icahn School of Medicine at Mount Sinai. Seaver is trying to unravel the biology of ADNP by studying several dozen people. Tony is among them, Sermone said.

Sermone’s advocacy has even greater urgency. Tony, who has a unique change to his ADNP gene, has experienced a loss of skills more than once. “His disease is now labeled as degenerative,” she said. Receiving that news, and watching him “go backwards” after years of therapies, is “extremely heartbreaking,” she said.

Despite his hardships, Tony is Tony: a happy 11-year-old who likes music, Mickey Mouse Clubhouse, watching football on TV, and playing on his iPad. So his mother keeps pushing for an ADNP breakthrough. She emails researchers, posts ADNP news on websites she runs, and takes calls from parents, often late into the night.

In late February 2019, she will fly to Washington, D.C., for Rare Disease Week on Capitol Hill. The week is organized around Rare Disease Day, which is observed worldwide on February 28. Advocates will lobby Congress for legislation and funds for rare disorders, which in the U.S. are considered to be those that affect fewer than 200,000 people. Sermone will tell lawmakers about orphan drugs, about rare disease research, about autism. And she will tell them about Tony.

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