Monthly Archives: March 2014

PUBLIC RELEASE DATE:

20-Mar-2014

Contact: Erin Digitale digitale@stanford.edu 650-724-9175 Stanford University Medical Center

STANFORD, Calif. Scientists and parents have worked together to identify a new genetic disease that causes neurologic, muscle, eye and liver problems in children. The discovery was unusually fast thanks to a combination of modern gene-sequencing techniques, social media and old-fashioned detective work.

One important clue was that affected children cry without making tears.

The new disease, called NGLY1 deficiency, is described in a paper that will be published online March 20 in Genetics in Medicine, the journal of the American College of Medical Genetics and Genomics. The paper describes eight children with mutations in the gene coding for N-glycanase 1, an enzyme that recycles defective products from a cellular assembly line. Children who lack this enzyme have varying degrees of movement disorders, including a characteristic combination of muscle contractions that causes abnormal tremulous movements. They also have developmental delays and liver problems. The gene defect is so rare that until recently, finding eight affected individuals would have taken several years; instead, the children were found in a matter of months.

"This represents a complete change in the way we're going about clinical medicine," said Gregory Enns, MB, ChB, associate professor of genetics in pediatrics at the Stanford University School of Medicine and co-lead author of the new paper. Gene-sequencing tools have sped the translation of findings between clinical and lab settings; in addition, scientists around the globe and lay people are contributing to the discovery process.

"This is happening so quickly because of the integration of the families with the researchers, and because so many people are coming at this from so many angles," said Enns, who is also a geneticist at Lucile Packard Children's Hospital Stanford and Stanford Children's Health. Other co-authors of the paper come from 12 research institutions across the United States, Canada, Germany and the United Kingdom.

"The relief of finally getting a diagnosis is just life-changing," said Kristen Wilsey, mother of Grace Wilsey, 4, who was the second American patient, and among the first few in the world, to be identified with NGLY1 deficiency. Grace's diagnosis was a pivotal moment not just for her San Francisco Bay Area family but also for defining the new disease, since the comparison of multiple patients allowed researchers to confirm that the disease existed.

The enzyme that is missing in NGLY1-deficiency patients is normally found in cells throughout the body. N-glycanase 1 helps break down incorrectly shaped proteins so their components can be reused. The new research confirmed that children with a defective NGLY1 gene do not make the N-glycanase enzyme. The researchers also observed that the children's liver biopsies contained an amorphous substance, which they suspected was an accumulation of protein that did not get recycled.

Here is the original post:
Scientists, parents join forces to identify new genetic disease in children

By Duke Medicine News and Communications

DURHAM, N.C. By combining the modern tools of gene-sequencing and social media, a team of researchers has confirmed the identification of a new genetic disorder that causes severe impairments in children.

The new disease, called NGLY1 deficiency, is reported online in the March 20, 2014, issue of Genetics in Medicine, the journal of the American College of Genetics and Genomics. The study describes the disease in eight patients, confirming the work of Duke Medicine scientists who originally identified the genetic mutation in a single young patient in 2012.

Children with the genetic mutation have a distinctive inability to produce tears when they cry, but also have movement disorders, developmental delays and liver problems. The genetic defect is so rare that without social media, the eight affected children would have remained unknown to each other and to scientists, but instead were connected within months.

After we got the original diagnosis, we worked really hard to find additional cases to confirm that we got it right, said senior author David Goldstein, Ph.D., director of the Center for Human Genome Variation at Duke. While we were working hard but making slow progress, the original family was writing about their experience and connecting with others on social media. They were able to find several more potential patients to be tested. This experience really brought home to all of us just how important family engagement is to this work and how important it is to think hard and long about every patients genome.

Duke researchers and scientists across two continents worked to sequence the entire genomes and exomes of the individual patients, revealing the newly identified genetic defect that was shared among them all.

The mutation causes a deficiency of the N-glycanase 1 enzyme, which is crucial in the process of recycling misshapen proteins so their components can be reused. In children with a defective NGLY1 gene, the proteins build up, resulting in impairments.

Because of the unusual clinical presentations - notably the absence of tears along with liver abnormalities - parents of other affected children in distant places recognized these features when they read social media posts by the original family, said co-lead author Vandana Shashi, M.D., a medical geneticist at Duke who evaluated the first patient. This enabled other children to be quickly identified and diagnosed.

After the first patient underwent sequencing at Duke, since NGLY1 had not yet been associated with human disease and since this was the only patient with mutations in the gene, Goldstein and Shashi consulted the Ad Hoc Genetics Committee at Duke. Charged with the task of advising Duke researchers on scientific and ethical issues related to genomic research, the committee reviewed the clinical and genomic data on the patient and approved the communication of the NGLY1 mutations to the family as likely causing the childs clinical symptoms.

"The Ad Hoc committee recognized that this study was venturing into uncharted territory, and we wanted to make the right decision, said Nancy C. Andrews, M.D., Ph.D., dean of the Duke University School of Medicine who chaired the ad hoc committee at the time of the decision. The guiding principle was that we had to do what was in the best interests of the patient and his family. I am delighted that this was how it turned out, and that this important discovery also benefits other patients around the world."

Go here to see the original:
Gene Sleuths and Social Media

Grace Wilsey was born with NGLY1 deficiency, which is caused by two mutations in the NGLY1 gene.

STORY HIGHLIGHTS

(CNN) -- What do you do when your baby lies limp in your arms, staring blankly into the distance while never crying?

What do you do when tests show signs of liver damage and your baby's seizures won't stop, but doctors can't tell you what's wrong or how to fix it?

Thanks to the Human Genome Project, which was completed in 2003, identifying new genetic mutations has gotten easier and cheaper. But geneticists often struggle to find patients who share these rare DNA quirks. Studying multiple patients with the same gene mutations and similar symptoms is crucial to identifying a new genetic disorder.

That's why a paper published Thursday in the journal Genetics in Medicine is so remarkable.

The paper identifies NGLY1 deficiency as an inherited genetic disorder, caused by mutations in the NGLY1 gene. The researchers have confirmed eight patients with these mutations who share several symptoms, including developmental delays, abnormal tear production and liver disease.

And they credit an "Internet blog" with bringing the patients and scientists together.

Grace's genome

Grace Wilsey's parents knew something was wrong right away. Their newborn daughter was lethargic. Her eyes seemed hollow and unfocused. She refused to eat. Doctors at the hospital ran multiple tests, but couldn't come up with a diagnosis.

More here:
Kids who don't cry: New genetic disorder discovered