The HADDS community gathers at the Houston convention in a rare case

Not many children and young adults met before they traveled from all over the world to gather in Houston. They were brought together by a common diagnosis that, until six years ago, was a mystery.

All of them were diagnosed with EBF3-induced developmental ataxia syndrome (HADDS). The neurodevelopmental disorder causes a range of symptoms, including developmental delays and autism-like tendencies. Dr. Hsiao Tuan Chao, a pediatric neurologist and researcher at the Jan and Dan Duncan Institute for Neurological Research, and colleagues identified the disorder in 2016 when she was a postdoctoral research fellow at Baylor College of Medicine.

Worldwide, fewer than 1,000 people have been diagnosed with HADDS since its discovery, Zhao said. For many of the children and young adults who attended the HADDS 2022 conference, held July 21-23 at Duncan NRI at Texas Children’s Hospital and Baylor, this was the first time they had met someone else with the same diagnosis.

“They are part of the community,” Zhao said. “Who can understand what you are going through better than another family going through something very similar?”

Denholm Wilmer, 25, traveled from Australia. He and his mother are the first known example of a mother and son sharing the condition.

Wilmer didn’t know he had HADDS until he was 20, but since that time he’s become an active member of the Facebook group that connects families living with the condition. He was excited to come to the conference to meet them in person.

“We are all interconnected,” Wilmer said. “We all understand each other.”

HADDS is caused by a mutation in the EBF3 gene, and symptoms can range in severity. Common symptoms include autistic-like tendencies. developmental delays, including speech and walking; balance and coordination issues; Difficulty expressing feelings and high pain tolerance. Zhao said many children with ADHD find it difficult to laugh or smile, and not cry when they are hit or get injections.

Zhao believes that many children and young adults with HADDS are underrated, because they look different. But many of them are bright and high-performance. Wilmer, for example, works as a delivery driver and loves to repair cars, build computers, and even fly planes in his spare time.

“They are who they are. It’s just a part of them,” Zhao said.

make discovery

Zhao’s interest in genetic research dates back to her childhood. Her mother was a special education teacher and later worked at Rossdale School in Austin, which serves students with disabilities.

She spent the summer volunteering at her mother’s school, and saw for herself the challenge of educating children with disabilities.

“It really brought back the fact that we should understand this better,” she said.

Her first introduction to what was eventually identified as HADDS came during her medical residency at Dr. Hugo Bellin’s lab at Baylor. The first case assigned to her was Chase Morita, a Hawaiian boy who was part of a clinical study by the National Institutes of Health’s Undiagnosed Diseases Network. Zhao said he was smart, but had a hard time talking and smiling when he was a kid.

Chase’s genetic sequencing showed several abnormalities, including a change in the EBF3 gene. This stood out because the gene is important for brain development, Zhao said, serving as a “master regulator” for other genes.

“It basically controls which switches need to be turned and which switches need to be turned in order for your cells to develop the way they are supposed to function,” she said. “If you get rid of it even just a little bit, it will kind of have a cascading effect.”

However, Chase’s condition remained poor for years, because the mutation was not recognized in anyone else. Zhao and her colleague, Dr. Michael Wangler, reached out to Baylor Genetics to ask if they had seen anyone else with a mutation in the same gene.

The lab directed them to two other children, one of whom was a 5-year-old girl from Houston. Zhao Wangler met a Houston girl.

After meeting her, Zhao realized that one of her patients named Colette Lemerre, who was less than one year old and also lives in Houston, likely had the same condition.

“When you hear from multiple families, you kind of know. Everything just clicked,” said Wangler, an assistant professor of molecular and human genetics in Baylor, Texas for Children. “I found a new medical condition.”

Colette’s parents, Ashley and Marc Lemerre, noticed early on that their daughter’s eyes were not focused and that she never laughed or cried. But they couldn’t figure out why. MRI, lumbar puncture and blood tests did not provide an answer.

Collette eventually did a genetic test, and the results showed a mutation in the EBF3 gene. Zhao broke the news that Collette had HADDS in 2016, months before she and her colleagues publicly revealed their discovery of the disorder. Ashley Lemmer said she would never forget the phone call.

“She’s on the phone crying, and I’m on the phone crying. Like — I can’t believe I got an answer, that her neurologist found out,” she said.

Colette was late in learning to walk and talk, and could barely speak until the age of 4. But she is now 7 years old and speaks at an average level for her age. She also reads in second grade even though she just finished kindergarten.

LeMaires started a Facebook group that connected HADDS patients. In 2019, they and two other families formed the nonprofit HADDS Foundation to promote awareness, research, and support for individuals with the condition. The Foundation hosted the 2019 and 2022 conferences.

“It just made the most sense in the world for us to do that,” said Marc Lemerre. “It was clear that this doesn’t happen to everyone, and we really wanted to be able to take advantage of our experience and use it to help grow the community.”

Find more answers

The reason for the mutation in the EBF3 gene is not clear. Strong mutations can only occur in an individual, Zhao said, while milder mutations can occur in families. These stronger mutations will cause more severe symptoms.

Some of these genetic changes are really powerful. “It’s like the raging Colorado River,” she said. “It’s hard to miss.” “And some of the other changes will be like opening a small faucet…that will lead to minor changes.”

At the moment there is no cure for HADDS. With early identification, Zhao said, the child can begin treatment to improve his balance, speech, and other things.

“We know they do very well with treatment, and the earlier we start treatment, the better,” Zhao said.

Zhao now leads her own lab at Duncan NRI, where she and her team continue to study the EBF3 gene. She believes it could provide a better understanding of how the brain works, which could help researchers understand how neurodevelopmental disorders occur.

She and her colleagues also hope to identify more older HADDS patients. They need more data to help them predict how the disease will present in older patients. By now, they know that young adults may develop psychological symptoms such as anxiety and ADHD.

While the HADDS community is small, Zhao believes it could be much larger. It is difficult to measure true prevalence, because international data can be difficult to obtain. But she estimates that 3,000 babies are born with this condition each year.

“We know this is actually very prevalent,” she said. “And what that means is that there are a lot of families that are still counting on us to provide answers.”

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