Healing and hope for families affected by fragile X in Eastern Europe

Reviewed by Kate Anderton, B.Sc. (Editor)Jan 23 2020

Mothers and fathers and their young children crowded into an old, government-run children's hospital in Belgrade, Serbia, colorful, cartoonish drawings covering its hallway walls. Parents struggled to soothe their anxious, wriggly boys and girls. But they were patient, polite. It was, after all, a day unlike any other. A day for hope.

Doctors and scientists -; experts in the rare and severely disabling fragile X syndrome -; had arrived from the United States, including six from the UC Davis MIND Institute. They came to offer the families useful information and maybe open doors to desperately needed help in a region of the world that, until fairly recently, hardly recognized fragile X syndrome, let alone knew how to diagnose or treat it.

The visit was part of a two-day educational conference organized by Dragana Protic, a Serbian medical doctor and scientist. Protic's training in neurodevelopmental disabilities at the MIND Institute under the guidance of Randi Hagerman, inspired her to improve the course of diagnosis, treatment and support for families affected by fragile X in Eastern Europe.

The MIND Institute changed my professional life. It was important for me and for all of my country and the region because I came back and translated all my knowledge from the U.S. to Serbia."

Dragana Protic, a Serbian medical doctor and scientist

Held in a historic hotel in Belgrade's city center, the meeting drew neurologists, pediatricians, genetic counselors, speech pathologists, psychologists and families from Eastern Europe and beyond. Protic said her goal was "to increase knowledge of fragile X and to introduce this important field to our medical professionals and increase testing of fragile X."

There is no help for our child

To parents like Radoslav and Svetlana Cvijetic, the meeting and clinic visit meant much more. It was a chance to meet Hagerman, whose name kept popping up in Google searches when looking for help for their son. At the time, Radoslav said, a face-to-face with Hagerman seemed as unlikely as meeting actress Julia Roberts. A pediatrician, professor and endowed chair in fragile X research at UC Davis, Hagerman is an icon in fragile X research and treatment worldwide. She and her UC Davis physician-scientist husband Paul Hagerman, discovered the related genetic disorder FXTAS, and the couple has conducted hundreds of studies on fragile X syndrome and its related conditions over 40 years. Paul Hagerman attended the Serbia conference to update participants about the current scientific thinking about FXTAS.

The Cvijetics are the parents of 6-year-old Demetrije, an affectionate, joyful boy diagnosed with fragile X syndrome. Demetrije cannot talk, use a spoon to feed himself or manage his own toileting needs. He has never attended school.

When Demetrije was 4 and not yet talking, the couple took their toddler to several doctors in Belgrade who told them there was nothing unusual about his development because he was a boy -; and boys, they said, are late bloomers. The couple refused to accept this explanation and finally found a lab at the University of Belgrade where they paid to get him tested for genetic abnormalities. That's when they learned he had fragile X syndrome, a condition that often causes many disabilities and for which there is no cure.

"From the doctor there was nothing," said Radolsav Cvijetic. "No care. No therapy. There is no help for our child. We must do for ourselves."

The news was catastrophic for the family, especially for Svetlana, whose 18-year-old son from a prior marriage, Vuc, has a yet-to-be diagnosed neurodevelopmental disorder and has severe disabilities and is nonverbal. Vuc now lives with grandparents in another city; Svetlana fears he will be one day be institutionalized.

A city and country in transition

To a casual tourist, Belgrade seems like any other old European city. It bustles with outdoor cafes that dot the cobblestone sidewalks, grand bronze sculptures of national heroes and a pervasive odor of cigarette smoke. But the city that was once the capital of the former Socialist Federal Republic of Yugoslavia has struggled for years to achieve economic growth and prosperity. The Balkan nation continues to be plagued by political unrest, particularly with the Kosovo and Bosnian conflicts, resulting economic sanctions and trade embargoes, the global financial crisis and recurrent recessions. Its application to join the European Union is still pending after 10 years.

Serbia's universal health care system faces related challenges. Historically it has struggled with corruption, mostly due to low physician salaries, as well as too few medical providers or hospital beds to care for the population. With the help of the World Bank and others, Serbia is working on reforms, including system restructuring and better medical training, to improve outcomes and help lift people out of poverty.

When it comes to care and services for people with neurodevelopmental disabilities like fragile X, there is a long way to go. Protic's published study found that medical professionals in Serbia know very little about fragile X, a problem she hopes to remedy through medical conferences and the country's newly launched Fragile X Society -; the only one for the entire Balkan region. With funding support from Sacramento's Serbian immigrant community, Protic already has set up the country's first fragile X testing site.

About fragile X

The "X" in fragile X syndrome refers to the X chromosome, where the mutated gene that causes the disorder is located. That gene, FMR1, is involved in making a protein important for the development of critical connections between nerve cells. When the cells can't make the protein, the nervous system can malfunction, leading to the signs and symptoms of fragile X syndrome. Fragile X affects one in 2,500 to 4,000 males and one in 7,000 to 8,000 females.

What the disorder looks like in children varies, but males are more severely affected. They are more likely to have intellectual disabilities and distinguishing physical characteristics like long, narrow faces, big ears, prominent jaw and forehead, unusually flexible fingers and flat feet. Affected individuals also frequently have speech and language delays, behavior challenges, ADHD and anxiety.

An estimated 50% of children with fragile X also have autism, and it's the most common single-gene cause of autism, accounting for about up to 6% of cases. And while children with fragile X and autism may share many characteristics, children with fragile X can be more interested in other people, make friends more easily and do better in social settings, Randi Hagerman said.

"I've known many boys with fragile X who have been voted Homecoming King," she told the conference audience -; one of many hopeful anecdotes she shared during her talk.

Introducing Eastern Europe to advances in fragile X treatments

As they've been doing increasingly over the past several years, MIND Institute experts brought a treasure trove of information to the people gathered in Belgrade to advance the region's understanding of fragile X and help clinicians and others begin to address the needs of the affected population.

MIND Institute Director Leonard Abbeduto, a psychologist, whose work includes using digital communication technologies to help parents support their children's language development, said the trip to Belgrade exemplifies the evolution of the MIND Institute, founded in 1998 to find and develop treatments for neurodevelopmental disabilities. The institute's International Training Program in Neurodevelopmental Disorders, which invites health care professionals and scientists from around the world to train at the MIND Institute, has had 24 participants from China, Philippines, Thailand, Turkey, Singapore, Spain, Ecuador, Colombia, Chile, Japan, Israel, South Korea and Serbia, including Protic. Many of them have taken their knowledge home to create their own programs.

"The MIND is a research, treatment and training center created out of the efforts of families who wanted to make life better for their children and other families," Abbeduto said. "We are really trying to build on what we've done to enhance our impact locally, nationally and internationally, which is why I was motivated to make the trip to Belgrade."

Joining colleagues from Johns Hopkins, Rush, Emory and other universities, MIND Institute speakers elaborated on the latest in clinical diagnosis and assessments for children with fragile X, family-focused language interventions, the latest in scientific discovery and DNA testing, new targeted treatments currently in use and others on the horizon, as well as the importance in involving patients and families in advocacy efforts.

I find that we have so much knowledge at the MIND Institute, I really want to share it," said Randi Hagerman. "Sometimes, in many other countries the doctors have never even heard of fragile X syndrome."

A chance to talk to experts

Maija and Cristian Sukreski traveled from Croatia to the meeting in Belgrade in search of advice to help their 3-year-old son, Petar, diagnosed a year ago with fragile X. The tiny, blond Petar is rambunctious, nonverbal and increasingly aggressive, hitting his parents when they attempt to calm him. It's a trait his mother worries could become dangerous as she tearfully ponders the future.

Their trip, Maija Sukreski said, was to find help.

"He is going to therapy now, and I hope he can receive other therapy that will be more effective to slow down the behavior problems and help him talk," she said.

In a small and drab clinic exam room, the couple awaited a chat with David Hessl, a MIND Institute psychologist and researcher known internationally for his work to refine psychological assessments for children with fragile X syndrome and other neurodevelopmental disorders. Petar stood, biting his hands then flapping them, a common autism characteristic referred to as stimming -; short for self-stimulating. They told Hessl about the boy's worrisome behaviors.

"The aggression is a form of communication," Hessl told the parents. "He's not angry with you. He's just overwhelmed."

Hessl suggested that instead of punishing Petar for hitting, they should reinforce good behavior with rewards of things he wants, like bananas, or special toys.

"When he hits, don't be emotional or reactive. Stay really neutral. Turn away," he said, adding: "Put a lot of time in this now and you will save yourself a lot of problems later. When his speech comes, he will probably be less aggressive."

In another exam room, Hagerman and Protic were talking to the Cvijetics while Demetrije chewed his knuckles, played with his father's iPhone and made frequent whimpering sounds.

"I don't know what the future will give us, but we are lucky with him in this moment." -; Svetlana Cvijetic

Protic had already arranged for genetic testing of the family using the most sophisticated techniques available. Flora Tassone, another MIND Institute researcher in Belgrade, is helping ensure that Serbia can provide state-of-the art genetic testing and that scientists understand how to use it

Hagerman took a quick history and turned her attention to the couple's shy 8-year-old daughter, Anja, who inherited the mutated X chromosome from her mother, Svetlana. Anja is a premutation carrier, meaning she does not have enough of the mutation to have fragile X, but has a 50-50 chance of having a child with the disorder and will herself probably have an IQ in the average range.

Hagerman then turned to Svetlana, whom her husband tenderly calls "an emotional woman." Tearfully, Svetlana told Hagerman that she has chronic muscle pains, difficulty with sleep, migraines and anxiety -; all conditions that researchers, including Hagerman, have demonstrated in controlled studies occur more frequently in premutation carriers than in those who don't carry the mutation.

Hagerman gave her practical suggestions, including quitting smoking, exercising regularly and treating the anxiety with available medications. She told her that the dietary supplement melatonin can help her sleep.

Radoslav Cvijetic then introduced Hagerman to his son, a boy with "no behavior problems, no arguing, no jealousy, nothing," he said. But also, without speech.

While Protic took notes, Hagerman went through a list of possible medications that could help him, including Metformin, the diabetes drug now undergoing tests in people with fragile X, and a multivitamin. She also urged the couple to encourage any kind of verbalization with Demetrije at home.

"I think you will find these recommendations helpful, and there will be other new treatments, so you have to think positive," she said. Svetlana stood up and kissed Hagerman on each cheek, elated at the potential for help.

And while the family understands that making such treatments available to families in need will take time in a country slow to change, they are confident that Protic will see that it happens. The conference and chance to meet the doctors from the MIND represented a "big, big step" and they are optimistic.

"I hope Demetrije can do some job in his life and he can learn to speak," said Svetlana, through her husband. "He knows a lot of things. Why not hope to marriage and have a wife and other things? I don't know what the future will give us, but we are lucky with him in this moment."