Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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Michael Gambello

Genomics plus human intelligence

Emory geneticists Hong Li and Michael Gambello recently identified the first pediatric case of a rare inherited metabolic disorder: glucagon receptor deficiency. Their findings, published in Molecular Genetics and Metabolic Reports, show the power of gene sequencing to solve puzzles – when combined with human intelligence. Although the diagnosis did not resolve all the issues faced by the patient, it allowed doctors to advise the family about diet and possible pancreatic tumor risk.

The family of a now 9-year-old girl came to Li when the girl was 4 years old. Based on newborn screening, the girl had been diagnosed with a known disorder called arginase deficiency. Arginase breaks down the amino acid arginine; if it is deficient, arginine and toxic ammonia tend to accumulate. At birth, the girl had high arginine levels – hence the initial diagnosis.

The girl had a history of low body weight, anorexia and intermittent vomiting, which led doctors to place a feeding tube through the abdominal wall into her stomach. For several years, she was given a special low-protein liquid diet and supplements, aimed at heading off nutritional imbalance and tissue breakdown. However, she did not have intellectual disability or neurological symptoms, which are often seen with arginase deficiency.

In fact, her blood amino acids, including arginine, were fully normalized, and a genetic test for arginase deficiency was normal as well.  These results were perplexing. By reviewing all the clinical, biochemical and molecular data, Li concluded the girl did not have arginase deficiency, and began looking for an alternative diagnosis. Read more

Posted on November 15, 2018 by Quinn Eastman in Uncategorized Leave a comment

NGLY1 update

Emory Medicine readers may remember the Stinchcombs, a Georgia family caring for two daughters with a genetic neurological/developmental disorder called NGLY1 deficiency. We found their efforts to care for their daughters inspiring.

The rapid discovery of several children with NGLY1 deficiency, facilitated by social media, has led to a wave of research. Two recent papers represent advances toward finding treatments.

In PLOS Genetics, Japanese scientists showed that deleting the ENGase gene can partially rescue problems created by NGLY1 deficiency in a mouse model (RIKEN press release). That implies drugs that inhibit the ENGase enzyme might have similar positive effects.

Scientists knew that the NGLY1 enzyme removes chains of sugars from misfolded proteins that are stalled in cells’ production pipeline. ENGase is another enzyme that acts on those sugar chains, and its absence compensates for the lack of NGLY1. Read more

Posted on May 17, 2017 by Quinn Eastman in Neuro, Uncategorized Leave a comment

Four take-home thoughts on NGLY1

Please check out our feature in Emory Medicine magazine about two sisters with NGLY1 deficiency. This rare genetic disorder was identified only a few years ago, and now a surge of research is directed toward uncovering its mysteries.

  1. The Stinchcombs are amazing. Seth Mnookin’s July 2014 piece in the New Yorker, and especially, his comments at the end of an interview with The Open Notebook drove me to contact them. “The father cares for the two girls with this disease full time. The mother is working insane hours. And while all this is going on, they’re the most good-natured … I don’t know, they just seem like they’re happy.”
  1. Several research teams around the world are investigating NGLY1 deficiency and potential remedies. For the magazine article, I talked with Emory geneticist Michael Gambello, Hudson Freeze at Sanford Burnham and Lynne Wolfe at the NIH Undiagnosed Diseases Program. Even more: the Grace Science Foundation, established by the Wilsey family, is supporting research at Retrophin/Notre Dame and Gladstone/UCSF. The independent Perlstein lab is investigating NGLY1 deficiency in fruit flies (reminiscent of Emory research from a decade ago on Fragile X syndrome).
  1. There’s a long road ahead for rare genetic disorders such as NGLY1 deficiency. That’s why the title that EM editor Mary Loftus came up with, “In time to help Jessie,” is so poignant. When I read Abby Goodnough’s New York Times piece on RCDP, which is a rare inherited bone disease that also involves seizures, I thought: “That could be NGLY1 in ten years.” Still, progress is possible, as demonstrated by this recent NEJM report on exome sequencing and neurometabolic disorders from British Columbia.

Read more

Posted on June 7, 2016 by Quinn Eastman in Neuro Leave a comment

Emory team part of undiagnosed conditions challenge

An Emory team of geneticists and genetics counselors is participating in the Clarity Undiagnosed competition, hosted by Boston Children’s Hospital and Harvard Medical School.

The team is led by genetics counselor Dawn Laney MS, CGC, CCRC. Team members include: Madhuri Hegde, PhD, William Wilcox, MD,PhD, Michael Gambello, MD, PhD, Rani Singh, PhD, RD, Suma Shankar, MD, PhD, Alekhya Narravula, MS,CGC, Kristin Cornell, MS, CRC, Cristina da Silva, MS, Sarah Richards, MS, CGC and Kimberly Lewis, MS, CGC.

In Clarity Undiagnosed, five families of patients with undiagnosed conditions provide DNA sequence information and clinical summaries to up to 30 competing teams. The teams then do their best to interpret the data and provide answers, and a $25,000 prize will go to the team that solves the mysteries in the most complete way.

At the discretion of the families, short videos of the patients may be available to investigators through producers of a forthcoming documentary film, Undiagnosed, but the teams are barred from direct interaction with the families. A glimpse of some of the families is possible by viewing the trailer. Teams have until September 21 to submit their reports and the results of the competition will be announced in November.

Boston Children’s and Harvard held a similar competition in 2012, which attracted teams from all over the world.

The competition grows out of the NIH-sponsored Undiagnosed Diseases Network; Emory pharmacologists Stephen Traynelis and Hongjie Yuan have been working with the related Undiagnosed Diseases Program based at NIH (very complex 2014 paper, blog post on personalized molecular medicine).

Posted on July 16, 2015 by Quinn Eastman in Uncategorized Leave a comment

Next generation sequencing roundup

The increasing clinical use of next generation sequencing in genetic testing, especially whole exome and whole genome, continues to be a hot topic. The ability to contribute to diagnosis, clinical utility, incidental findings and whether insurance will cover next-gen sequencing are all changing.

A Nature Medicine article lays out a lot of the emerging business issues on next-gen sequencing. On the topic of incidental findings, Buzzfeed science editor Virginia Hughes last week reported stories of women who receive a cancer diagnosis as a result of having a prenatal genetic test.

“These cases, though extremely rare, are raising ethical questions about the unregulated and rapidly evolving genetic-testing industry,” Buzzfeed says.

At a recent Department of Pediatrics seminar, Emory geneticist Michael Gambello described examples of how whole exome sequencing, performed to diagnose intellectual disability or developmental problems in a child, can uncover cancer or neurodegenerative disease risk mutations in a parent. The question becomes, whether to notify the parent for something that may or may not be actionable. This is why Emory Genetics Laboratory’s whole exome sequencing service has an extensive opt-in/opt-out consent process.

Emory Genetics Laboratory executive director Madhuri Hegde, working with the Association of Molecular Pathology, has been a leader in pushing genetic testing laboratories to adopt best practices. Read more

Posted on March 11, 2015 by Quinn Eastman in Uncategorized Leave a comment

Rare disease diagnosis, accelerated by social media

Seth Mnookin’s long piece in the New Yorker, on how social media accelerated the diagnosis of several children with a rare genetic disorder, is getting a lot of praise this week. This is the same story that was on CNN.com in March, titled “Kids who don’t cry”, and that Emory Genetics Laboratory director Madhuri Hedge mentioned as a recent diagnostic success for the technique of whole exome sequencing.

Briefly: parents of or doctors treating several children with a previously unknown metabolic disorder, with multiple symptoms — absent tear production, developmental delay, movement deficits, digestive problems etc — found each other via Internet searches/blog posts. The problems were traced back to mutations in the NGLY1 gene.

Emory geneticists Michael Gambello, Melanie Jones (now at the Greenwood Genetic Center in South Carolina) and Hegde are co-authors on the Genetics in Medicine paper that lays everything out scientifically.

Gambello, Jones and Hegde were responsible for sequencing the DNA of a North Georgia family (they live in Jackson County), whose members are mentioned in Mnookin’s piece. The Gambello lab is developing an animal model of NGLY1 deficiency and is studying the mechanisms of how NGLY1 deficiency affects brain development.

Posted on July 18, 2014 by Quinn Eastman in Neuro Leave a comment