Chloe was diagnosed with leukodystrophy as a baby, but her symptoms didn’t conform with the known types of the disease. It wasn’t until she was 6 years old that Adeline Vanderver, MD, a neurologist at Children’s Hospital of Philadelphia, identified the cause of her condition — a rare genetic mutation. That knowledge has helped her doctors apply more effective treatments and has given Chloe’s parents something solid to hold onto as they face an uncertain future.

When Chloe was born, she appeared to be a healthy baby. The only concern was a failed hearing screening, but doctors told her parents, Sara and Justin, not to worry. Newborns can fail the test because of fluid in their ears.

Sara and Justin brought Chloe back a week later to repeat the test, which she failed again. By this time, her parents had another concern: Chloe’s eyes were constantly moving back and forth and up and down. Again, they were told not to worry, and that it was just a phase.

While Chloe’s eyes continued to dart around, she seemed to be progressing normally in other ways, like learning to roll over. But by the time Chloe was almost 4 months old, the couple noticed another problem: their daughter wasn’t developing good head control.

Pushing for answers

Sara and Justin pushed their doctors in St. Petersburg, FL, to take a closer look at Chloe’s problems. They repeated the hearing test, which showed a significant auditory processing delay. But an MRI didn’t reveal any answers, and genetic tests came back negative.

When Chloe was about a year old, her local doctors referred the family to a neurogeneticist in Miami. After reviewing her earlier MRI images, the specialist explained to the family that he could see a lack of myelin, the tissue that acts as an insulator around nerve fibers in the brain and spinal cord. This, combined with her symptoms, suggested she had a form of leukodystrophy.

That was the first time the family had heard of the condition, which is a group of rare, genetic disorders that affect the white matter of the brain and damage the myelin sheath.

By damaging the myelin sheath, leukodystrophies slow down or block messages between the brain and the rest of the body, resulting in problems with hearing, vision, speech and movement. Most leukodystrophies are degenerative, meaning symptoms will worsen over time. While there is currently no cure, identifying the cause and specific type of leukodystrophy can help physicians target therapies that will best manage each patient’s specific symptoms.

Years of uncertainty

With a name for Chloe’s condition, Sara and Justin began their own research, identifying and contacting other leukodystrophy families through Facebook and finding experts in its treatment.

Over the next few years, the couple brought Chloe to see several different specialists in search of a more precise diagnosis. Every path led to another dead end, including efforts to identify a genetic cause for the disorder. Whole exome sequencing (a type of genetic test that looks at all the pieces of an individual’s DNA that provide instructions for making proteins) turned up a minor abnormality inherited from both parents, but one that was not associated with symptoms like Chloe’s.

During this time, Chloe developed in some ways and lost ground in others. An assessment when she was 18 months old showed that physically, she was at a development age of 3 to 4 months, but cognitively, she was at 9 to 12 months.

As a toddler, Chloe couldn’t sit or stand up without help, but she could stand and take a forward step when supported. She couldn’t reach out and grab things, but she could hold onto an object placed in her hands. She loved being in the pool, where she could move her arms and legs freely. And she could laugh. She got her biggest laughs from watching Mickey Mouse Clubhouse.

“She was always happy,” Sara says. “We could take her anywhere.”

Unfortunately, the road ahead brought more obstacles than victories. When Chloe was 2 years old, she started having seizure-like episodes that weren’t seizures. Doctors prescribed medications to control her symptoms, but they didn’t work reliably, and sometimes seemed to make her even sicker. Years of different treatment approaches and multiple hospitalizations took their toll on Chloe. By early 2016, Sara and Justin were doing their best to care for Chloe, but they were frustrated after years of living with medical uncertainty.

Pinpointing the problem

Through the Facebook network of leukodystrophy parents, Sara came across Adeline Vanderver, MD, now the Program Director of the Leukodystrophy Center of Excellence at Children’s Hospital of Philadelphia (CHOP).

At their first appointment, Dr. Vanderver reviewed Chloe’s history and suggested they do whole genome sequencing instead of whole exome sequencing. Whole genome sequencing is only available to families at a few facilities across the United States — including CHOP — and offers invaluable clues into a person’s entire DNA, not just the genes that produce proteins. Dr. Vanderver suspected the earlier whole exome testing may have missed something, and new leukodystrophy research had identified additional links between genetic mutations and specific forms of the disease.

When the test results came back, Dr. Vanderver finally had an answer for the family. Chloe had a mutation in the TUBB4A gene that indicated her condition was an exceptionally rare form of leukodystrophy called hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Other patients with a mutation on this gene had been found to have this form of leukodystrophy, with symptoms similar to Chloe’s. The gene mutation had also been found to be de novo, which means it was not inherited from either parent.

“It made a big difference to know what it was,” says Sara. “Until that moment we had been told that the doctors didn’t know why she had the condition. We didn’t know whether we might pass it onto other kids. It’s a huge thing to know that we are not carriers.”

Finding a path forward

The family still has plenty of uncertainty to deal with. They know Chloe’s condition is progressive, and they can already see that happening.

Chloe used to be able to hold an object in her hand, but she no longer has the strength for that. She used to be able to bear weight on her legs, but no longer can. She still smiles, but no longer has the strength for laughter that she once had. They don’t know how that decline will unfold, or over how much time.

One small comfort is the fact that they’re not alone in their journey. Chloe’s care is now guided with support from experts across different specialties brought together by the Leukodystrophy Center. In addition to Dr. Vanderver, they have been cared for by Amy Waldman, MD, a pediatric neurologist who is Medical Director of the center, as well as experts in movement disorders and epilepsy.

The main goal of Chloe’s treatment is to manage her symptoms and focus on giving her the best quality of life possible. Finding the cause of Chloe’s leukodystrophy has helped. For example, the team was able to identify Chloe’s seizure-like episodes as dystonia, a common motor complication seen in kids with TUBB4A mutations. Her doctors can now use targeted medications to more effectively treat this specific problem.

Her parents appreciate the depth and range of the expertise they’ve found in the Leukodystrophy Center.

“It makes a tremendous difference to have all of these specialists in one place in Philadelphia,” says Sara. “They are so flexible and work so well together.”

Sara and Justin will continue to work with the medical team at CHOP to manage Chloe’s symptoms, to do what they can to slow the progression of her decline and to give her as much joy and comfort as possible.

“At the Leukodystrophy Center of Excellence, our mission is to provide families with better diagnosis, symptom management, and in the long term, cures for these disorders,” says Dr. Vanderver. As part of these efforts, the team at CHOP is working on research they hope will one day lead to a specific treatment for TUBB4A-associated leukodystrophy.