Rare Diseases Archives - Sanford Burnham Prebys
Institute News

Fighting rare diseases: Finding treatments and bringing hope to families

AuthorMonica May
Date

March 23, 2021

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.

Institute News

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

AuthorMonica May
Date

October 3, 2019

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. 
 

Institute News

“A Grand Canyon Aria” benefits SBP research

AuthorHelen Hwang
Date

June 4, 2018

A father’s love never dies, even when his child has succumbed to a fatal childhood disease. Alex Syed paid tribute to his daughter, Aria, by running a marathon through the majestic Grand Canyon in May 2018. Ten years ago, Aria passed away after suffering from congenital disorders of glycosylation, known as CDG—a disease that affects the way proteins and sugar molecules interact in the body.

In honor of his daughter, Syed raised more than $4,300 from 71 donors to fund important research in the laboratory of Hudson Freeze, PhD, professor and director of the Human Genetics Program at Sanford Burnham Prebys Medical Discovery Institute (SBP). Freeze is one of the world’s leading experts on CDG.

“Funding is always in short supply, so the donations that Alex raised in the name of Aria will bring us closer to finding a cure for other kids suffering from this devastating disease,” says Freeze. “Aria’s cells are in our lab to support experiments that will help build a database for possible therapies,” he adds.

To prepare for the run, which Syed dubbed “A Grand Canyon Aria,” he rose in the middle of the night to begin his 26-mile run from the South Rim via Bright Angel to North Rim, taking him over the mighty Colorado River.

Running through the Grand Canyon to raise money for Dr. Freeze’s research was Syed’s idea. He knows that rare genetic diseases do not receive a lot of funding from large pharma companies. “The almost-angelic work that Dr. Hud Freeze and his team are performing at SBP is truly unique,” says Syed.

To donate, go to sbpdiscovery.org/CDG.

Watch the video of Alex Syed’s run through the Grand Canyon in memory of Ari:

Watch the video from Dr. Hudson Freeze’s lab:

Institute News

“No surrender” to CDG

AuthorHelen I. Hwang
Date

September 9, 2016

From a farmhouse in rural Iowa, Crystal Vittetoe is fighting for her two babies afflicted with congenital disorders of glycosylation, known as CDG. She and her family have raised over $37,000 from a single fundraiser, and the donations keep coming in. “If we don’t fight for research, we are surrendering to CDG,” says Vittetoe.

“What Crystal has done for our research at the Institute is incredible. She’s raised enough money to pay for half a postdoc’s salary to do research for one year, and now we need to find the other half,” says Hudson Freeze, PhD, director of the Human Genetics Program at Sanford Burnham Prebys Medical Discovery Institute (SBP). “We have so many projects we start and want to complete. We need more hands on the projects. And if a family needs help, we don’t turn anybody away,” he says.

CDG is a collection of genetic diseases that causes mental and physical developmental issues, which leads to severe damage to multiple organs like the liver, heart and intestines.

The Vittetoes have two young children with CDG—two-year-old daughter Everlee (in the photo above) and one-year-old son Breckyn. Vittetoe drove from Iowa to SBP in La Jolla, Calif., for the annual Rare Disease Day Symposium at SBP. There, she met other families, scientists, doctors as well as Freeze to learn about the latest research and treatments that can help their kids cope with her illness. Worldwide, there are less than 1,500 known cases of CDG where children are born with the genetic disorders.

Vittetoe realized from the family’s visit to SBP that much more research was needed to figure out why CDG happens and how to lessen the her children’s suffering. She was inspired to raise money for the Rocket Fund, in honor of John Taylor (Rocket) Williams IV who would’ve turned 10 years old this year. Sadly, he passed away at the age of two.

In the past year, Everlee has been hospitalized six times. During one episode, she was having an hourly seizure for 24 hours with the last one enduring for 3.5 hours. “It’s so stressful, no matter if she’s having a stroke-like episode or just needs fluids,” says Vittetoe.

With the help of family and friends, Vittetoe held a dinner and silent auction at Lebowski’s Rock ‘N Bowl in her hometown of Washington, Iowa with a population of just over 7,000. The three-hour inaugural event raised a phenomenal amount of money that even surprised Vittetoe. “We were blown away,” she said.

The bar donated 15% of the tab and a friend, who’s also a singer, volunteered the entertainment. Over 300 people contributed to a free-will dinner donation for delicious pork loin from the family’s hog farm and scrumptious sides whipped up by the children’s grandmother.

Substantial seed donations, along with gifts from local businesses, raised an enormous amount of funds at the silent auction. The Vittetoes have been farming in Iowa for generations, and Crystal’s husband Jonathan approached the local seed dealers who all said “yes” to helping out the kids. And of course, neighborhood farmers came to support the Vittetoes who always need seed for their crops.

People contributed checks from $10 to $5,000, and every dollar counted. Other families with CDG children drove over six hours from as far away as Minnesota and Illinois to show their support.

The giving doesn’t just stop with the fundraiser hosted by the Vittetoe family. Recently Crystal’s grandfather passed away in Colorado and the family asked for memorial donations to the Rocket Fund.

Vittetoe says, “It’s your babies and if you don’t do something, you’re just waving the white flag. We’re not waving the white flag. We just want to do something for them.”

Note:

The next SBP Rare Disease Day Symposium will be held on February 24, 2017. The day-long event will focus on Alagille syndrome, a genetic disorder that causes liver damage due to abnormalities in the bile ducts, which carry waste from the liver to the gallbladder and small intestine. For more information, click here.

Photo credit: Drish Photography.

Institute News

Rare Disease Day symposium brings together experts on disorders of glycosylation

Authorjmoore
Date

March 2, 2016

The Rare Disease Day symposium on February 26-27 featured many fascinating talks from experts on numerous aspects of congenital disorders of glycosylation (CDGs), from fundamental work on glycosylation pathways to animal models to diagnosis in the clinic. Following are summaries of each presentation:

Lawrence Tabak, D.D.S, PhD, deputy director of the NIH—After presenting his research on glycosylating enzymes in the 1980s, which helped lay the foundation for understanding the processes that are impaired in CDGs, Tabak discussed several initiatives by the NIH, including the Precision Medicine Initiative and efforts to increase reproducibility.

William Gahl, MD, PhD, director of the National Human Genome Research Institute (NHGRI)—Gahl highlighted several successes of the Undiagnosed Diseases Program. Most relevant to the field of CDGs was the discovery of the gene underlying a new type of CDG, in which an enzyme responsible for generating a necessary precursor for protein glycosylation (uridine diphosphate) is inactivated. This work also found that supplementation with uridine was an effective therapy.

Shengfang Jin, PhD, scientist at Agios Pharmaceuticals Inc.Jin presented her work on a mouse model of PMM2-CDG, which is caused by mutations in the gene for phosphomannomutase 2. Her research has identified a promising biomarker for PMM2-CDG, which is one of the more common types of CDG.

Richard Steet, PhD, associate professor at the University of Georgia—Steet’s lab is developing a new method of identifying which proteins are glycosylated by particular enzymes, which is important for understanding how each CDG-associated mutation leads to disease.

Reid Gilmore, PhD, professor at University of Massachusetts Medical School—Gilmore gave a detailed view of how two CDG-associated mutations, in isoforms of the same component (STT3A and STT3B) of a major glycosylating enzyme, oligosaccharyltransferase, impair protein glycosylation.

Robert Haltiwanger, PhD, professor at the University of Georgia—In another presentation on fundamental glycobiology, Haltiwanger described the function of two enzymes in the same pathway (fucosylation) inactivated in certain CDGs. Mutations in these enzymes underlie Peters plus syndrome and a single case of an unnamed severe CDG, respectively.

Marjan Huizing, PhD, staff scientist at the NHGRI—Using a mouse model of GNE myopathy, a progressive muscle disease caused by mutations in an enzyme required for protein sialylation, Huizing’s lab identified a therapy, supplementation with the sugar ManNAc, which is now in phase 2 trials, and identified a key biomarker. The mouse model also suggested that sialylation problems may be associated with certain kidney diseases, which is now under investigation.

Raymond Wang, MD, clinical geneticist at CHOC Children’s Clinic—Wang told the story of how he and scientific collaborators diagnosed an unusual case that initially appeared to be a CDG because of abnormal glycosylation. The disease-causing mutation was finally identified to be in mitochondrial translation, highlighting the similarities between CDGs and mitochondrial diseases.

David Beeson, PhD, professor at the University of Oxford—Beeson described a subset of congenital myasthenias caused by mutations in glycosylating enzymes, which have distinct symptoms from other myasthenias. These mutations likely cause this disorder by selectively impairing processing of the receptor by which muscle cells receive signals from nerves—the nicotinic acetylcholine receptor.

Lance Wells, PhD, professor at the University of Georgia— Wells summarized his work on the molecular basis of dystroglycanopathies, a subgroup of muscular dystrophies that arise from defects in O-mannosylation enzymes. Most recently, his lab resolved the puzzle of how mutations in an enzyme involved in a different form of glycosylation could cause this disease—they showed that the enzyme’s function had been incorrectly assigned.

Taroh Kinoshita, PhD, professor at Osaka University—Kinoshita is an expert on the addition of sugar-based anchors to lipids (GPI anchors), which link many proteins to the cell surface. He presented some of the extensive work from his team on how mutations in GPI-synthesizing enzymes cause disease, including identification of a therapy, vitamin B6, for seizures in GPI deficiencies.

Eva Morava, MD, PhD, professor at Tulane University Medical Center and the University of Leuven—Morava described preliminary results of a clinical trial of galactose supplementation to treat PGM1-CDG, in which patients are deficient in phosphoglucomutase-1 (this also impairs glucose metabolism). In these patients, galactose improves liver function and endocrine abnormalities and normalizes clotting factors.

Lynne Wolfe, MS, C.N.R.P. clinical research coordinator at the NHGRI—Wolfe discussed the CDG natural history study underway at the NIH—its goals and progress so far. The findings of this study will serve as a resource both for future diagnoses and for researchers in the field to correlate pathways with symptoms.

Tadashi Suzuki, D.Sci., team leader at the RIKEN Global Research Cluster—NGLY1 is different from other CDG-associated genes—it encodes a deglycosylating enzyme, which helps degrade glycosylated proteins that aren’t properly folded. Suzuki’s team has shown that inhibiting another deglycosylating enzyme, ENGase, prevents the formation of aggregates of misfolded proteins, suggesting that it could be a therapeutic target.

Hamed Jafar-Nejad, MD, associate professor at Baylor College of Medicine—Using fruit flies as a model, Jafar-Nejad’s lab is investigating how NGLY1 deficiency affects development. These flies replicate many of the features of human disease, including growth delay and impaired movement, so they could yield important insights into pathogenesis.