The road to an ultra-rare disease diagnosis can take a long, arduous and costly path, with scores of doctors and tests along the way. When patients finally find the culprit behind their misery, all too often, there is no effective treatment—and research moves slowly due to the limited number of patients who can enroll in clinical trials.
[Courtesy of Miesha Thomas]
Initially, a doctor dismissed their concerns, insisting Tilyn wasn’t in pain. By minimizing the complications, the doctor delayed diagnosis and treatment. “It took several more years before we were finally referred to a neurologist who ordered genetic testing,” said Tilyn’s mother, Miesha Thomas, a former horse dentist who lives in Moore, Oklahoma, and devotes time to advocacy for her now 6-year-old son’s extremely rare genetic condition.
“Tilyn’s journey has been a long road to answers,” she said. “For years, I knew something wasn’t right, but early in 2024, he was misdiagnosed with cerebral palsy. Just a few months later, after my own diagnosis with ankylosing spondylitis [an inflammatory type of arthritis] in May, we pushed for more answers. In July 2024, we finally received the correct diagnosis of TUBB4A leukodystrophy, or H-ABC.” H-ABC (Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum) is a rare, progressive genetic disorder caused by a single mutation in the TUBB4A gene. “Hearing those words was life-changing. But at the same time,” she added, “it gave us the clarity we needed to move forward.”
Like his mother, Tilyn was diagnosed with ankylosing spondylitis, which causes long-term pain and stiffness in the spine, often starting in the lower back and hips. He also suffers from juvenile arthritis and hip displacement. “There are so many domino effects that come with this,” Thomas said. Overall, she added, “We’ve faced many challenges. Tilyn now uses leg braces day and night, a walker, wheelchair, bath chair, and he’s undergone G tube [feeding tube] surgery following the discovery of a malrotation of his small intestine. It has been a whirlwind year of specialists, hospital visits, and constant adjustments to daily life.”
H-ABC is Tilyn’s greatest challenge. The ultra-rare disease, which affects roughly 200 children in the world, targets the nervous system’s white matter. In particular, this genetic variant leads to hypomyelination—insufficient myelin formation—and atrophy of the basal ganglia and cerebellum. Basal ganglia help control muscle movements but also play a role in learning, solving problems, and processing emotions, while the cerebellum processes input from other areas of the brain, spinal cord, and sensory receptors to provide precise timing for smooth and coordinated movements. Damage to these areas of the brain causes motor delays, stiffness, involuntary movements, speech and swallowing difficulties, and cognitive impairment. A diagnosis of H-ABC involves brain imaging with MRI and genetic testing to identify the specific mutation. There is no cure, but supportive care and therapies to palliate discomfort, and research into novel treatments offer hope for managing symptoms and improving quality of life.
Candidate drug designed to treat H-ABC
SynaptixBio, founded in 2021 and based in Oxford, U.K., is aiming to bring to market a therapeutic to treat H-ABC, the most severe form of TUBB4A leukodystrophy. It’s the only company licensed to commercialize a treatment.
The company has designed an antisense oligonucleotide (ASO) specifically to treat H-ABC. “This is classified as an ultra-rare disease, so there is a very limited patient population, making design of the clinical trial a major hurdle,” said Dan Williams, PhD, CEO and co-founder of SynaptixBio. “It’s very difficult to say how many patients there are, but through the H-ABC charities (in the U.K. and U.S.) formed to support patients and families, we have some idea of the likely numbers involved.” Every year, it’s estimated that 18,000 babies are born with a leukodystrophy, of which about 1,650 are TUBB4A-related, according to SynaptixBio’s website.
“We are totally focused right now on raising investment to support us through clinical trials of our candidate drug, which has orphan drug designation from the U.S.,” said Williams, who earned his doctorate in protein translation from Dundee University in Scotland. “It also qualifies for the FDA’s rare disease priority review voucher (PRV).”
Williams and his three co-founders—two of whom are also scientists—are excited that SynaptixBio has identified its lead development candidate that they expect to put through investigational new drug/clinical trial application enabling studies. “As a company, we are currently testing the molecule we have developed in the lab. Tests are in vivo to confirm biodistribution, pharmacokinetics, pharmacodynamics, and tolerability,” Williams said, explaining that “TUBB4A leukodystrophy is a monogenic disease involving a mutation in the TUBB4A gene, resulting in a gain of function toxicity. We are targeting that mutation with gene silencing technology at the mRNA level to alleviate its toxic effects.” The results within animal models, he noted, are “very good.”
Hope for a devastating condition
Among the researchers seeking to improve the quality of life and lifespan of individuals living with leukodystrophies is Adeline L. Vanderver, MD, program director of the Leukodystrophy Center of Excellence at the Children’s Hospital of Philadelphia (CHOP), which has entered into a research agreement with SynaptixBio.
“TUBB4A LD (leukodystrophy) is one of the most common hypomyelinating leukodystrophies,” Vanderver said. “It can present in early infancy, childhood, or adulthood with disease of varying severity. Most people develop problems primarily with motor skills, which can be severe enough to prevent walking and swallowing.”
ASOs have been designed to target a number of conditions like Duchenne muscular dystrophy and spinal muscular atrophy. ASOs are a form of “gene silencing” technology, wherein the mutated gene is stopped from making its associated toxic protein.
“The TUBB4A gene encodes a protein that makes microtubules, which are essential for moving proteins in the cell, particularly oligodendrocytes and neurons,” Vanderver explained. “Because there are many possible proteins that can help make microtubules, removing the TUBB4A protein is well tolerated, and in models of the disease this has been shown to improve function. We hope that antisense technology can help us do the same in affected people and improve their neurologic function.”
Pasqualone, a creative director at an advertising agency, initially became suspicious that something was wrong when his son started “missing mile markers,” such as not walking when most babies begin walking. At first, the boy’s pediatrician recommended physical therapy. About nine months later, it became clear that additional testing would be the next best course of action.
“An MRI showed there was some concern over white matter and the cerebellum being smaller than usual for a child that age,” Pasqualone said. “A smaller cerebellum is one of the characteristics of the disease. The MRI led them to strongly suspect it could be leukodystrophy, and genetic testing confirmed it was the TUBB4A variant.”
Now, Luca is being seen at Rush University Medical Center, which partners with the n-Lorem Foundation, a non-profit organization that creates ASOs for patients with nano-rare diseases caused by a single gene mutation. “Being a parent of a child with a nano-rare disease can be a lonely and dark road to travel with uncertainty at every turn,” Pasqualone said. “Nano-rare” refers to genetic conditions affecting only 1 to 30 patients worldwide, marked by unique, disease-causing mutations for which there are typically no existing treatments.
For parents with a child in this predicament, “the hope is [that] a drug could a) stop regression before it starts; and b) at some point help repair the TUBB4A gene or symptoms,” he said. “It’s a relief to know there are people aware and searching for a cure. That said, as a parent knowing your child’s disease is going to get worse, you are constantly holding your breath and praying for breakthroughs to happen sooner [rather] than later.
“Even in our case with n-Lorem, although they generously provide the drug at no cost, some well-known hospitals either would not—or could not—administer it to Luca without requiring us to cover significant out-of-pocket expenses, sometimes reaching into the six figures. Several other families are currently facing the same dilemma,” said Pasqualone.
He added that, “Even with the drug cost covered, families are still left to navigate the complex process of securing administration, which often falls into a gray area with insurance companies, since the treatment is considered experimental or part of a trial.”
Research identifies a new genetic disorder
Rose has a variant in the heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) gene, which causes developmental delay, intellectual disability, low muscle tone, and seizures in females. This variant was first identified by Jennifer M. Bain, MD, PhD, a Columbia University physician-scientist who specializing in pediatric neurology, and her then-colleague Wendy Chung, MD, PhD, who became chair of pediatrics at Harvard Medical School and Boston Children’s Hospital. They published their findings in the American Journal of Human Genetics in September 2016. The goal was “to identify, understand, treat, and ultimately cure those impacted by HNRNPH2 mutations,” according to the Yellow Brick Road Project (YBRP), a charitable foundation that funds research into these mutations.
In 2016, Bain identified six girls with variants in the HNRNPH2 gene. Each girl presented with developmental delay or intellectual disability, along with atypical muscle tone. Many of these children also suffered from seizures and conditions such as anxiety and autism spectrum disorder. In addition, Bain’s team found variants in HNRNPH2 that appeared to affect other organ systems aside from the brain. For example, the girls had abnormal growth, gastroesophageal reflux disorder, scoliosis and other skeletal conditions, heart problems, and atypical facial features.
Initially, “we thought that boys could not survive because we had not found them,” Bain told Inside Precision Medicine in explaining why her research originally only involved girls. Later, the researchers found boys with variants in the HNRNPH2 gene, but there are fewer boys than girls because the gene is located on the X-chromosome.
A subsequent paper, published in Neurology Genetics in February 2021, expanded the clinical characterization of the HNRNPH2-related neurodevelopmental disorder to include 33 individuals, ages 2 to 38, both females and males, with 11 different genetic variants. “I am working on the next one with 130 individuals,” Bain said.
Trish Flanagan’s daughter, Morgan, was 4 years old at the time of her HNRNPH2 diagnosis in February 2016. On a very cold day in January 2017, Flanagan and the parents of three other girls arrived for an in-person “meeting of the minds” with Bain and Chung at Columbia University Irving Medical Center. Two of the families were from New York; the other two traveled from Israel and Brazil.
“Since receiving our daughter’s diagnosis, it has been a series of many pieces coming together to create the path to a treatment,” said Flanagan, who lives in New Rochelle, N.Y., and works full time as an early childhood educator. “We’ve literally built a road. The doctors and a few families began a synergistic collaboration, and the YBRP was born.” She’s the co-founder, director, and president of this foundation, which has connected the family members of more than 200 patients with HNRNPH2 in 38 countries. It received non-profit status in late 2016 and began fundraising in February 2017. “This is a grass-roots effort,” Flanagan said. “Everybody started knocking on doors, sending emails to try to gain some traction.”
Targeting a specialized market
Meanwhile, McPherson said he expects the company’s lead product, rosiphersen, to target a specialized market for patients with HNRNPH2-related neurodevelopmental conditions. Although the drug is intended for a niche population, it fits in with the overall pediatric genetic treatment market, which he believes is valued at $51 billion.
“These genetic treatments can rescue function for a lot of these diseases that we’re seeing,” he said, explaining that “we’re fixing the underlying cause of the problems instead of treating the symptoms like many traditional small molecule programs have done in the past.”
At first, Elouise’s development appeared normal, but around age 3, she began to pull up her right arm when running. An MRI of her brain revealed hypomyelination and an undersized cerebellum and basal ganglia. “That was a telltale sign of some sort of a condition,” Sloan told Inside Precision Medicine. However, back then—in 2008—the TUBB4A genetic variant hadn’t been identified yet. “We had every test under the sun,” she said.
Eventually, Elouise was diagnosed with H-ABC, which ultimately robbed her of the ability to stand, walk, bathe, eat, or dress herself. She can no longer speak clearly. In addition, Elouise suffers from dystonia, which causes uncontrolled muscle movement in her arms and neck.
“Watching your own child deteriorate right before your eyes is a pain no parent should ever have to experience,” Sloan wrote on her LinkedIn profile. “But together, we can make a difference in the lives of families across the globe by giving children with H-ABC-related leukodystrophy a fighting chance.”
When public policy impedes progress
As if the challenges of living with a rare disease weren’t enough of a heartache for affected children and their parents, public policy can stand in the way of making strides in breakthrough treatments, Sloan said. “We, [and] numerous other advocates, are urging Congress to re-approve the FDA’s PRV, which has been delayed since December due to other priorities.”
This voucher provides tax incentives for investors in drug development and expedites review by the FDA. Cuts in research funding to the National Institutes of Health and changes in the FDA’s leadership and oversight also have a detrimental effect on drug development. “All of this and general lack of attention around rare diseases, despite the collective 30 million impacted in the U.S., makes the process very challenging, causing delays and placing lives in jeopardy,” Sloan said.
Even before the recent changes, in Bain’s experience, federal funding for rare diseases was very challenging to obtain. She noted that pharmaceutical companies are seldom interested in developing treatments for rare conditions because the limited pool of patients makes for an unprofitable and risky venture. “The foundations are picking up the dime that the government isn’t willing to do,” Bain said. “And we need fierce advocates on Capitol Hill to keep pushing rare disease forward. One in 10 people in the U.S. and worldwide has a rare disease. Rare diseases collectively are very common.” Overall, she added, there are more than 7,000 rare diseases.
There are also many barriers to surmount for parents trying to gain access to genetic testing for their children. “It is more and more widely available but some insurance doesn’t cover the expense of the test,” Flanagan noted. “Sometimes pediatricians don’t recommend more than simply treating the symptoms of developmental delay through early intervention. Sometimes families don’t know that a genetic diagnosis may very well illuminate other risks for their challenged child, in addition to helping them find a community and even treatments. We even made a video to underscore the importance called, Genetic Diagnosis Matters.”
Tilyn’s mother said she became more familiar with her son’s genetic mutation through Sloan’s foundation, which connected the family with the United Leukodystrophy Foundation. At that foundation’s conference, they first heard about SynaptixBio’s candidate drug. So, despite challenges that often feel overwhelming, Thomas is optimistic about the future.
“We are still new to this world, but we’re learning every day,” she said, while acknowledging that “our journey has been long and exhausting, marked by misdiagnosis, years of doubt, and searching for answers. But through it all, we’ve learned to be resilient and persistent—because Tilyn deserves nothing less. Today, with the right diagnosis in hand and the knowledge we’ve gained through the Foundation to Fight H-ABC and the United Leukodystrophy Foundation, we are finally looking forward with hope. The possibility of drug trials like the one being developed by SynaptixBio means families like ours can begin to see a future where there are real options, real treatments, and real hope.”
Susan Kreimer is a freelance medical writer in New York City.
