congenital disorder of glycosylation Archives - Sanford Burnham Prebys

Tag: congenital disorder of glycosylation

Institute News

SBP Rare Disease Day Symposium: We can’t do it alone

AuthorSusan Gammon
Date

March 5, 2018

Rare Disease Day group photo

The 9th annual Rare Disease Day Symposium once again opened its doors to the global community with a genuine interest in CDG—rare inherited disorders that affect a mere 1,200 patients worldwide. The conference, a joint scientific and family symposium, attracted more than 175 attendees from North America, Europe and Australia—the largest ever in the history of the event.

Malin Burnham and T. Denny Sanford, honorary trustees of SBP, kicked off the three-day meeting by emphasizing that advances in medicine require participation and exchange among all stakeholders—scientists, physicians, affected patients and their families, support groups, granting agencies, industry, and philanthropists.

“This annual event brings these stakeholders together from around the world to share in each other’s successes and challenges and discuss the future of CDG research,” said Hudson Freeze, PhD, director of Human Genetics at SBP and Symposium Chair. “We have gained tremendous momentum, and are especially thankful for the participants who share their time and expertise.”

Children with CDG—which stands for congenital disorders of glycosylation—have varying degrees of speech and language difficulty, poor balance, motor control, vision problems, hearing impairments and seizures.  Because the condition is so rare, many patients bounce between doctors and clinics for years before they receive an accurate diagnosis.

“Being the parent of a child with an undiagnosed or rare disease can be a lonely place,” said Darlene Schopman, mother of Nolin, a 6-year old boy diagnosed with CDG.

“We thought we were the only people in the world affected by Nolin’s type of CDG. We’ve since learned that there are nine more children with his specific condition. And now at this conference I’m meeting other families that have had similar experiences—there is an immediate connection—a common bond.”

The scientific session began February 23 with a keynote presentation by Leroy Hood, MD, PhD, president and co-founder of the Institute for Systems Biology. In all, 22 noted scientists and clinicians spoke on CDG research and future potential therapeutic avenues.

A highlight for families is the innovative “Doctor-is-in-session”, which directly connects families with medical researchers and clinicians in small groups. For medical researchers, the session is often their first opportunity to observe and interact with patients in person.

 

The conference was organized and run by SBP, members of CDG CARE (Community Alliance and Resource Exchange) and the nonprofit corporation NGLY.1.

The event was funded by donations, grants, and corporate and industry sponsorships, including support from Retrophin, a biopharmaceutical company focused on the discovery and development of drugs for the treatment of catastrophic diseases that are debilitating and often life-threatening, and for which there are currently limited patient options.

Institute News

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.”

Institute News

Diagnosing a rare disease in children

AuthorSusan Gammon
Date

February 6, 2018

Rare disease

Children born with the rare genetic disorder known as CDG often live for years before they receive a diagnosis.  CDG—which stands for congenital disorders of glycosylation—can cause serious, sometimes fatal, malfunction of different organs and systems in the body, including the nervous system, muscles and intestines. Children with CDG have varying degrees of speech and language difficulty, poor balance, motor control, vision problems, hearing impairments and seizures.

CDGs are difficult to diagnose partly because there are only about 1,800 known cases worldwide. But through global networking and the unwavering determination of researchers and clinicians, new patients are being discovered every year, providing important information to parents to help them better understand what they are dealing with.

Hudson Freeze, PhD, director and professor of the Human Genetics Program at SBP, is a one of the scientific leaders helping diagnose new cases of CDG. Freeze and his colleague, Bobby Ng, recently led an international team charged with diagnosing three unrelated individuals thought to have a new type of CDG—but not confirmed. The work, published in the American Journal of Human Genetics, confirmed that the three had a specific kind of CDG never seen before, adding to the more than 125 existing types of CDGs.

“All CDG disorders are caused by mutations that impair glycosylation—the complex process by which cells build long sugar chains that are attached to proteins called glycoproteins,” explains Freeze. “These sugar chains are crucial for cellular growth, communication and essential cell functions.

“There are many genes involved in proper glycosylation,” says Freeze. “When two parents happen to carry a mutation on the same gene, they end up with a one-in-four chance of passing both mutated copies on their child, and that causes the disorder.”

Increasingly, babies and children with unexplained health problems such as developmental delays and organ dysfunction undergo whole-exome sequencing, a technique that sequences the part of the genome that encodes proteins.

“Exome sequencing is used to find mutations in genes, but sometimes we don’t know if the mutations found actually translate to a genetic condition like CDG,” says Ng.

“Our lab steps in when a suspected mutation is found in one of the many enzymes involved in glycosylation,” says Ng. “We perform biochemical tests to confirm that the mutation impairs the glycosylation process, helping families narrow in on a CDG diagnosis.”

“The three patients in the current study are the only confirmed cases of the FUT8-CDG type in the world,” says Freeze. “These very rare diagnoses are only made possible when physicians, researchers and parents reach out across continents to families who’ve had nothing but questions.”

For the past 8 years, SBP has organized an annual symposium in San Diego where scientists, doctors, and families gather to discuss the latest in science and medicine, and meet other families coping with rare diseases.

For more information on the 2018 SBP Rare Disease Day Symposium and CDG Family Conference, click here.

Institute News

Uncovering the cause of a 12-year-old girl’s rare neurological disorder

AuthorSusan Gammon
Date

September 25, 2017

DNA research with a sample. Hand with a test tube on a DNA background shutterstock_653790793.jpg

The parents of a child with seizures, weak muscles, limited communication abilities and autism-like behavior problems recently got a long-awaited answer as to the cause of her disorder. Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identified the genetic variants causing this now 12-year-old girl’s neurological issues.

“One of the many tests performed by the specialists treating her suggested that her symptoms might stem from problems with the addition of sugars to proteins,” says Hudson Freeze, PhD “That’s why they came to us. There are lots of ways that the protein modification process—called glycosylation—can go wrong. We specialize in figuring out precisely which gene is responsible for an individual patient’s disease, using sequencing and measurements of cellular activities.”

Publishing in the American Journal of Medical Genetics, Freeze’s team showed that the patient carries variant sequences in both copies of a gene called SLC35A1, which encodes a protein that transports a specific sugar into the part of the cell where it’s used to modify proteins.

“She inherited two different mutations in the same gene from each of her parents,” says Bobby Ng, research assistant in the Freeze lab and lead author of the study. “Those mutations prevent the transporter protein from working, so that a crucial sugar—sialic acid—is missing from the ends of the sugar chains on many proteins located on the surface of cells.”

“Sialic acid is critically important for the function of a protein called NCAM that’s needed for the brain to develop properly,” Ng adds. “We think that’s why this patient’s problems are mostly neurological.”

This is only the third reported case of disease caused by mutations in the SLC35A1 gene. Ng, Freeze, and their collaborators had to devise entirely new assays to confirm that the mutations impaired transport of sialic acid and its attachment to proteins.

These three cases make up one class of a broader group of disorders known as CDGs, for congenital disorders of glycosylation. All CDGs are rare, but Freeze nonetheless believes strongly in the value of understanding them.

“CDGs may not be common, but many of them are extremely severe, affecting development and the function of multiple organs,” he says. “For the families whose children have a CDG, they’re the most important diseases in the world. And the only way we’ll ever find specific treatments that address their root causes is by investigating the pathology of each one.”