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Tag: Hudson Freeze

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One at a time: How a Sanford Burnham Prebys professor changes patient lives

AuthorMiles Martin
Date

February 22, 2022

Hudson Freeze, PhD

Having worked for decades to improve the lives of children with rare diseases, Hudson Freeze is still on the case.

Hudson Freeze, PhD is not your average researcher. His work focuses on congenital disorders of glycosylation, or CDG, a severe group of diseases that affect fewer than 2,000 children worldwide. Those conditions occur when sugar molecules on many of our proteins are absent or incomplete. That can lead to serious, often fatal, malfunctions in various organ systems throughout the body.

Although Freeze is not a clinician, he is deeply involved in identifying these rare CDG mutations, and providing families with answers to what is often a challenging diagnosis. Because CDG is a group of incurable diseases, families of children with CDG reach out to Freeze almost weekly, seeking help.

“If someone asks for help, I say, ‘Let me try,’” says Freeze. “Any glimmer of hope is a path worth pursuing, anything to make life easier for children with CDG.”

Freeze has been working on CDG for more than 25 years and has worked with more than 300 patients, and he has kept in touch with many of them over the years.

“Not a day goes by when I don’t think of them and their struggles—but mostly their smiles,” says Freeze. “It’s the reason we won’t give up on trying to understand them and maybe even finding treatments.”

Treating disease with sugar
Although CDG presents as permanent and irreversible mutations, Freeze’s research has been instrumental in discovering an approach to alleviate severe symptoms of CDG—such as seizures—in certain patients. The answer: sugar. Thanks to Freeze and others, there are about 30 patients worldwide who are now taking mannose, a simple sugar molecule, to help alleviate their CDG symptoms.

Today, the strategy of treating diseases with simple sugar molecules is being explored in other glycosylation disorders, as well as less-rare diseases such as multiple sclerosis, cancer and diabetes.

Hudson Freeze, PhD poses with Damian Omler, who has CDG.

Hudson Freeze, PhD poses with Damian Omler, who has CDG.

Rare Disease Day at Sanford Burnham Prebys
Freeze’s impact on the lives of families living with CDG extends well beyond the walls of his lab. Since 2010, he has organized an annual Rare Disease Day Symposium each February, where scientists, doctors and families gather from around the world to discuss the latest research and meet other families coping with rare diseases. Last year, the pandemic forced the Institute to press pause on the event, but this year, Rare Disease Day is back in San Diego and stronger than ever.

“It’s a chance for the global CDG community to come together, support one another and continue to put our heads together to find treatments,” says Freeze. “It’s always my favorite weekend of the year, and I’m thrilled that we’re able to do it again safely.”

The 2022 Rare Disease Day Symposium & CDG/NGLY1 Family Conference will take place February 25–27 at the Dana on Mission Bay Resort in San Diego. Scientific sessions will be held on the 25th and 26th, and the Family Conference will take place on the 27th.

Register Here

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Fighting rare diseases: Finding treatments and bringing hope to families

AuthorMonica May
Date

March 23, 2021

Hudson Freeze, PhD and José Luis Millán, PhD

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition that is incurable.

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition that is incurable.

Often, their own doctors have never heard of their disease, let alone know how to treat it.

But there is someplace they can turn to for help. The Human Genetics Program at Sanford Burnham Prebys provides insights into the genes and environmental factors that play a role in the development of childhood diseases. Their work often leads to better ways to diagnose, treat, and sometimes, even cure children.

On March 18, 2021, two patients whose lives were saved by discoveries made by Hudson Freeze, PhD, and José Luis Millán, PhD, joined the scientists for a conversation about what this work means to them and how their lives have been impacted. Watch the full discussion below.

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Our top 10 discoveries of 2020

AuthorMonica May
Date

December 14, 2020

notebook with Top 10 written at top of page

This year required dedication, patience and perseverance as we all adjusted to a new normal—and we’re proud that our scientists more than rose to the occasion.

Despite the challenges presented by staggered-shift work and remote communications, our researchers continued to produce scientific insights that lay the foundation for achieving cures.

Read on to learn more about our top 10 discoveries of the year—which includes progress in the fight against COVID-19, insights into treating deadly cancers, research that may help children born with a rare condition, and more.

  1. Nature study identifies 21 existing drugs that could treat COVID-19

    Sumit Chanda, PhD, and his team screened one of the world’s largest drug collections to find compounds that can stop the replication of SARS-CoV-2. This heroic effort was documented by the New York Times, the New York Times Magazine, TIME, NPR and additional outlets—and his team continues to work around the clock to advance these potential treatment options for COVID-19 patients.

  2. Fruit flies reveal new insights into space travel’s effect on the heart

    Wife-and-husband team Karen Ocorr, PhD, and Rolf Bodmer, PhD, shared insights that hold implications for NASA’s plan to build a moon colony by 2024 and send astronauts to Mars.

  3. Personalized drug screens could guide treatment for children with brain cancer

    Robert Wechsler-Reya, PhD, and Jessica Rusert, PhD, demonstrated the power of personalized drug screens for medulloblastoma, the most common malignant brain cancer in children.

  4. Preventing pancreatic cancer metastasis by keeping cells “sheltered in place”

    Cosimo Commisso, PhD, identified druggable targets that hold promise as treatments that stop pancreatic cancer’s deadly spread.

  5. Prebiotics help mice fight melanoma by activating anti-tumor immunity

    Ze’ev Ronai, PhD, showed that two prebiotics, mucin and inulin, slowed the growth of melanoma in mice by boosting the immune system’s ability to fight cancer.

  6. New test for rare disease identifies children who may benefit from a simple supplement

    Hudson Freeze, PhD, helped create a test that determines which children with CAD deficiency—a rare metabolic disease—are likely to benefit from receiving a nutritional supplement that has dramatically improved the lives of other children with the condition.

  7. Drug guides stem cells to desired location, improving their ability to heal

    Evan Snyder, MD, PhD, created the first drug that can lure stem cells to damaged tissue and improve treatment efficacy—a major advance for regenerative medicine.

  8. Scientists identify a new drug target for dry age-related macular degeneration (AMD)

    Francesca Marassi, PhD, showed that the blood protein vitronectin is a promising drug target for dry age-related macular degeneration (AMD), a leading cause of vision loss in Americans 60 years of age and older.

  9. Scientists uncover a novel approach to treating Duchenne muscular dystrophy

    Pier Lorenzo Puri, MD, PhD, collaborated with scientists at Fondazione Santa Lucia IRCCS and Università Cattolica del Sacro Cuore in Rome to show that pharmacological (drug) correction of the content of extracellular vesicles released within dystrophic muscles can restore their ability to regenerate muscle and prevent muscle scarring.

  10. New drug candidate reawakens sleeping HIV in the hopes of a functional cure

    Sumit Chanda, PhD, Nicholas Cosford, PhD, and Lars Pache, PhD, created a next-generation drug called Ciapavir (SBI-0953294) that is effective at reactivating dormant human immunodeficiency virus (HIV)—an approach called “shock and kill.”

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The one-of-a-kind kid

AuthorMonica May
Date

March 16, 2020

Damian Omler and family at his 5th grade graduation

11-year-old Damian Omler is the only known individual with his CDG mutation.

Donnie and Gracie Omler are used to the question, “What’s wrong with your son?” Now, they don’t have to say, “We don’t know.”

While the Omlers knew that something was off when their son Damian started to miss his early milestones—he struggled to sit up, make “goo-goo” sounds and put weight on his legs—a decade passed before they had an official diagnosis.

Doctors suspected Damian had a congenital disorder of glycosylation, or CDG, but couldn’t confirm the mutation type. The family began attending Sanford Burnham Prebys’ Rare Disease Day Symposiums, but unanswered questions made them unsure of how they fit into the CDG community.

Now, the Omler family has answers. Hudson Freeze, PhD, and his team determined that Damian has a never-before-seen type of CDG, now named CDG-GET4. This gene codes for a chaperone protein that guides other proteins to where they need to be in a cell. Freeze’s team found that in Damian’s case, one of these chaperone proteins was almost completely gone.

“After the diagnosis we sat and smiled for a long time,” says Donnie. “Obviously we are not done. But answers give us hope. There might be a treatment or supplement for Damian. We might be able to predict possible complications in the future.”

The Omler’s shared with KPBS how receiving answers changed their life.

Today, Donnie and Gracie focus on giving Damian a fulfilling life. He attends school, where he has friends and participates in sports. He plays with his 9-year-old brother, DJ. He loves rock music—and even attempted to strum a guitar recently. Donnie, a rock lover himself, clutches his heart with joy when describing this development.

Still, the Omlers recognize the challenges that Damian faces. He has seizures, needs help using the restroom and recently got a feeding tube. They attend the Institute’s symposiums to make sure they are up-to-date on information that might help Damian. They also fundraise as much as possible to help researchers do more.

“We are amazed at how much brainpower it takes to find a diagnosis, let alone treat the disease,” says Donnie. “There is no way we could have done this alone. Without these scientists, we would probably still be waiting for answers.”

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Families, physicians and scientists unite at Sanford Burnham Prebys’ 11th Annual Rare Disease Day Symposium

AuthorMonica May
Date

March 16, 2020

Rare Disease Day group photo

This year’s event centered on CDG, a rare genetic condition that affects around 1,500 people worldwide.

With more than 270 attendees and 30 world-renowned scientists and clinicians, Sanford Burnham Prebys’ 11th Annual Rare Disease Day Symposium was officially the largest in the event’s history. This year’s discussion centered on congenital disorders of glycosylation, or CDG, a rare genetic condition that affects around 1,500 people worldwide.

Malin Burnham, T. Denny Sanford and Debra Turner, honorary trustees of Sanford Burnham Prebys, opened the three-day meeting with moving remarks. A theme emerged: Medical advances are accelerated when key stakeholders work together—including scientists, physicians, people with CDG and their families, patient advocacy groups, granting agencies, industry and philanthropists.

“Our annual symposium aims to create an ecosystem in which key stakeholders can collaborate and communicate,” said Hudson Freeze, PhD, director of the Human Genetics Program at Sanford Burnham Prebys and symposium chair. “Together, we celebrate our successes, focus on challenges and discuss the future of CDG research.”

Presenters at the meeting described the power of the ecosystem. Since the first conference a decade ago where scientists reported on the basic biology of CDGs, today we have promising clinical trials for the most common CDG mutation. In addition, a historic nationwide effort to establish the natural history of CDGs launched this year—which addresses decades of unresolved questions and helps remove barriers to starting clinical trials.

First discovered in the 1990s, scientists now know that CDG is caused by mutations that disrupt the body’s normal process of attaching sugars to proteins. Children with CDG have varying degrees of speech and language difficulty, poor balance, motor control, vision problems, hearing impairments and seizures. 

Because CDG is rare, many patients bounce between doctors and clinics for years before they receive an accurate diagnosis. At the symposium, an innovative session called the “Doctor-is-in” session connects families with medical researchers and clinicians in small groups. For some medical researchers, the session is the first time they have met a person with CDG.

The conference was co-organized by Sanford Burnham Prebys and CDG CARE, a nonprofit organization founded by parents seeking information and support for CDG.

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Sanford Burnham Prebys scientist joins historic effort to help children with rare disease

AuthorMonica May
Date

October 3, 2019

Hudson Freeze, PhD

Hudson Freeze, PhD, professor of Human Genetics at Sanford Burnham Prebys, has joined a historic effort that establishes—for the first time—a nationwide network of 10 regional academic centers, Sanford Burnham Prebys researchers and patient advocacy groups to address decades of unresolved questions surrounding congenital disorders of glycosylation, or CDG, a rare disease that affects children. The consortium is funded by a $5 million, five-year grant from the National Institutes of Health (NIH). 

“We are extremely pleased that the NIH is investing in an initiative that will improve the lives of people affected by CDG,” says Freeze, who leads efforts to develop and validate disease biomarkers that will aid in diagnoses, and measuring treatment benefits during clinical trials. “Although globally the number of people living with CDG is relatively small, the impact on the lives of these individuals and their families can be profound. We look forward to working with the patients, families, physicians, scientists and other stakeholders focused on this important study.”

CDG is caused by genetic mutations that disrupt how the body’s sugar chains attach to proteins. First described in the 1990s, today scientists have discovered more than 140 types of mutations that lead to CDG. Symptoms are wide-ranging, but can include developmental delays, movement problems and impaired organ function. Some children may benefit from a sugar-based therapy; however, developing treatments for those who need alternative treatment options has been hindered by a lack of natural history data—tracking the course of the condition over time—comprehensive patient registry, and reliable methods to establish the CDG type.

Working together, the consortium will overcome these hurdles by: 

  • Defining the natural history of CDG through a patient study, validating patient-reported outcomes and sharing CDG knowledge 
  • Developing and validating new biochemical diagnostic techniques and therapeutic biomarkers to use in clinical trials 
  • Evaluating whether dietary treatments restore glycosylation to improve clinical symptoms and quality of life

Freeze will lead the efforts to develop and validate biomarkers for CDG, working alongside the Children’s Hospital of Philadelphia and the Mayo Clinic. The principal investigator of the CDG Consortium Project is Eva Morava, MD, PhD, professor of Medical Genetics at the Mayo Clinic. The patient advocacy groups involved are CDG CARE and NGLY1.org. 

Sanford Burnham Prebys and CDG Care will host the 2020 Rare Disease Day Symposium and CDG Family Conference from February 28 to March 1 in San Diego, which welcomes researchers, clinicians, children with CDG and their families, and additional CDG community members. Register to attend. 
 

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Year in review: SBP highlights from 2018

AuthorMonica May
Date

December 17, 2018

Sanford Burnham Prebys 2018 Year in Review

The science never stops at Sanford Burnham Prebys Medical Discovery Institute (SBP), and 2018 was no different. 

From an Alzheimer’s breakthrough to advancing promising medicines for pancreatic cancer and autoimmune disorders, our hardworking scientists were busy at the bench and beyond. As the year comes to a close, we are sharing a selection of our most widely read stories from the past 12 months. 

1.    Scientists uncover a potential near-term treatment for Alzheimer’s disease 
Jerold Chun, MD, PhD, and his team revealed that never-before-seen DNA recombination in the brain is linked to Alzheimer’s disease. The research suggests that existing FDA-approved drugs to treat HIV might hold potential as near-term Alzheimer’s treatments and provide an explanation for why previous clinical trials for Alzheimer’s disease have failed. The study was published in Nature.

2.    SBP women awarded American Heart Association Fellowships
The American Heart Association awarded grants to three SBP scientists. This funding advances projects that align with the organization’s mission of building healthier lives, free of cardiovascular disease and stroke. 

3.    Compound discovered at SBP enters Phase 1 clinical trial for pancreatic cancer
Solid tumors are often surrounded by thick fibrotic walls, making it hard for treatments to get access to the tumor cells. CEND-1, a drug candidate discovered in the lab of Erkki Ruoslahti, MD, PhD, has entered a Phase 1 clinical trial for metastatic pancreatic cancer. CEND-1 streamlines the delivery of cancer drugs deep into tumors. CEND-1 was licensed to the private company DrugCendR Inc. in 2015. 

4.    Scientists solve a medical mystery
Hudson Freeze, PhD, and his team joined collaborators around the globe to crack the case of Saul-Wilson syndrome, a rare form of dwarfism with an unknown cause. Now, the 14 known people with the syndrome and their families have answers: A gene alteration that affects the cell’s protein packager, the Golgi complex, causes the condition. 

5.    Immune therapy developed through SBP and Lilly collaboration enters Phase 1 clinical trial
A therapy that arose from a research collaboration between Eli Lilly and Company (Lilly) and SBP entered a Phase 1 clinical trial. The therapy is a biologic that inhibits inflammation—a common response linked to autoimmune diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease.

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

To help SBP scientists focus on pioneering research that transforms human health, donate now. 

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Parents gain answers about their child’s mysterious condition, thanks to SBP scientists

AuthorMonica May
Date

December 11, 2018

Hudson Freeze, PhD, Sanford Burnham Prebys

For the parents of a six-year-old Hispanic boy and a seven-year-old Qatari girl, answers remained elusive. Both children had alarming symptoms, including developmental delays, uncontrollable seizures and “floppy baby syndrome” (hypotonia). But despite doctors’ best efforts, the origin of the disease remained unknown. 

Now, these two children are linked by rare mutations in a gene called FUK—providing their families and doctors a better understanding of the cause of their medical conditions. Using biochemical techniques to analyze the boy’s cells, Sanford Burnham Prebys Medical Research Institute (SBP) scientists determined that a malfunctioning enzyme called fucokinase is to blame—caused by a mutation in the FUK gene. Because cells from the girl weren’t available, computer modeling was used—and indicated this same mutation likely caused the disease. The study published in the American Journal of Human Genetics.

Like a molecular spark plug, the fucokinase enzyme ignites one step in a cellular communication cascade—which culminates in the linkage of a sugar, fucose, to another carbohydrate. This final fucose-carbohydrate product is important for immune system regulation, tissue development, cell adhesion (“stickiness” to the environment) and more. 

Based on these findings, the scientists now know the condition is a congenital disorder of glycosylation (CDG), an umbrella term for disorders caused by abnormal linking of sugars to cellular building blocks, including proteins, fats (lipids) and carbohydrates. Although more than 130 types of CDGs exist, the boy and girl are the only known living individuals who have this mutation. 

“Our hope is that by reporting this information, we will help doctors grant more answers to patients and their loved ones,” says Hudson Freeze, PhD, senior author of the paper and director and professor of the Human Genetics Program at SBP. “Based on our findings, genetic databases around the world will now note this mutation causes disease—a potentially life-changing shortcut in the quest for answers.” 

The researchers analyzed skin and immune cells that were collected from the boy. They observed reductions in the amount of the fucokinase enzyme—as much as 80 percent in skin cells and more than half in immune cells, compared to a control protein. Consistent with these findings, downstream products typically created by fucokinase weren’t incorporated into the final fucose-carbohydrate product—indicating the enzyme was not working.

Because cells from the girl were not available, the scientists used computer modeling to predict the impact of her FUK gene mutation. This approach indicated the mutation occurs at an important site on the enzyme that would likely cause disease.

“We know that dampening down the activity of the FUK gene is linked to metastatic cancer—a deadly event that occurs when tumors gain the ability to travel throughout the body,” says Freeze. “In addition to providing long-awaited answers to these families, these findings could help us understand how certain cancers spread throughout the body, including liver, colorectal and skin cancers (melanoma).” 

Both children were identified through the National Institutes of Health’s Undiagnosed Diseases Network, which is designed to accelerate discovery and innovation in the way patients with previously undiagnosed diseases are diagnosed and treated. 

Additional study authors include: Jill Rosenfeld, Lisa Emrick, MD, Lindsay Burrage, MD, PhD, Brendan Lee, MD, PhD, William Craigen, MD, PhD, Baylor College of Medicine; Mahim Jain, MD, PhD, Johns Hopkins School of Medicine; David Bearden, MD, University of Rochester School of Medicine; and Brett Graham, MD, PhD, Baylor College of Medicine and Indiana University School of Medicine. The study’s DOI is https://doi.org/10.1016/j.ajhg.2018.10.021

Research reported in this story was supported by National Institutes of Health (NIH) grants R01DK099551, U01HG007709, and K08DK106453; Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (U54 HD083092), Diana & Gabriel Wisdom and the Rocket Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

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Meeting the “man who saved my son’s life”

AuthorMonica May
Date

November 15, 2018

Saraa and Baraa Ghoniem and Hudzon Freeze-CDG

“I’ve got really cool stuff in my body,” 6-year-old Baraa Ismail proclaimed to Hudson Freeze, PhD, professor in the Human Genetics program at Sanford Burnham Prebys Medical Discovery Institute (SBP).

And, indeed, he does. 

Baraa and his mother, Sara, didn’t know it at the time, but he was born with a rare change in his DNA that interfered with his body’s ability to attach a sugar to proteins—altering the course of his life. 

From birth, Baraa struggled with eating. He dealt with upset stomachs and lethargy, which is unusual for a young child. Sara searched high and low for an answer, but doctor visit after doctor visit, year after year, Baraa remained undiagnosed. 

After four years of uncertainty, Sara connected with Dr. Tawhida Yassin Abdel Ghaffar. She suspected a rare condition called congenital disorders of glycosylation (CDG) and ordered a test. Her instincts were correct—Baraa had one form of CDG. More than 130 types of the condition exist.  

In addition to working with her doctor, Sara was introduced to a new online community of parents and individuals with CDG. It was through a private Facebook group that she connected with another parent whose child has CDG. He told her, “You have to talk to Hudson Freeze at SBP.”

For more than three decades, Freeze and his team have studied CDG with the ultimate goal of developing a treatment. When Freeze heard from Sara, he recommended that she talk to her doctor about giving Baraa mannose, a nutritional supplement. 

Years ago Freeze helped discover that mannose can treat one specific form of CDG—incredibly reversing symptoms as quickly as days sometimes (note: Freeze is not a medical doctor). But it only works if a person has one kind of mutation; treatments are still limited for the 129 other types of CDG that exist. Freeze reasoned that even if he didn’t have Baraa’s genetic sequence in hand, if the boy had that mutation, the mannose would work. 

Incredibly, it did. Within a month, Baraa’s energy was back. And today, Baraa is a Flash-loving, book-devouring little boy who loves to run and sing. 

Baraa was doing so well that Sara even decided to take a vacation for the first time in years. She and Baraa traveled from their home in Egypt to visit her brother in Irvine, California—which happened to be a short drive from SBP. Sara reached out to Freeze, whom she calls “the man who saved my son’s life,” to see if a visit was possible. Freeze was delighted to meet with her and Baraa and give them a tour of his lab. 

“Really, my role was very small in this story,” says Freeze. “But what this illustrates is the importance information has for these families. A simple piece of information changed someone’s life. We’d love to grow so we can eventually become a true hub of information for these families—and help even more people like Sara and Baraa.”  

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Professor Hudson Freeze helps dreams come true for rare disease patient

AuthorHelen Hwang
Date

February 27, 2018

Morgan Webb Liddle rides Bailarino, coached by Olympian Steffen Peters

When Morgan Webb Liddle is riding a horse, it’s one of the only times she feels “free,” she says. “I was born to ride,” says Morgan, 25, who uses a wheelchair. Morgan and her mother Merell Liddle flew from Australia to attend SBP’s Rare Disease Day Symposium and Family Conference in February 2018.

During their trip to San Diego, Hudson Freeze, PhD, professor and director of SBP’s Human Genetics Program, arranged for Morgan to meet Olympic equestrian Steffen Peters. When they met, Morgan literally cried tears of joy. Freeze has been working with Morgan’s family to find a treatment for Morgan’s disease.

At Arroyo Del Mar Stables, Morgan received expert dressage coaching from Peters, who won a bronze medal in Rio de Janeiro. Morgan rode on a chestnut beauty named Bailarino, owned by Akiko Yamazaki, who gave Morgan special permission to ride her horse every day while she was attending the Rare Disease conference. Peters, impressed by Morgan’s riding, said, “What you do is much more amazing than what I do.”

Morgan suffers from CDG—which stands for congenital disorder of glycosylation—a disease that disrupts how the body’s sugar chains attach to proteins. Freeze is working on finding a cure for CDG. Liddle is one of the few adult CDG patients since many succumb to the potentially fatal effects of the metabolic disorder as children.

Her mother says, “Morgan has virtually no sense of balance. She does an amazing job just staying on the horse. She is currently working on new ways to ride because she has difficulty seeing the edges of the arena and the letter markers because of her poor peripheral vision.” Nevertheless, Morgan aims to compete in the Para-Olympics one day. Morgan has already won the Australian National Championship for Para-Dressage multiple times.

When Morgan was 14 years old, she was finally diagnosed for CDG after her physical and neurological condition began to worsen rapidly. Knowing the diagnosis was a huge relief for Morgan’s family since doctors were stumped by her illness. Freeze is one of the few experts in the world who helps diagnose and research treatments for CDG patients. “Hud has been amazing,” says Morgan’s mother.

“We share a special kinship,” says Freeze, who grew up with a disabled sister. “When I first met Morgan, she reminded me of my sister.”

For the symposium’s reception, Morgan performed a modern lyrical dance performance, while Freeze sang ABBA’s “I Have a Dream.” As the scientist and patient were preparing for their performance, Freeze said to Morgan, “We share a dream—to find a treatment for CDG.”