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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NGLY1

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

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

Next-generation sequencing, amplified by social media

Emory Genetics Laboratory, with its whole exome sequencing business accelerating, is launching a new Medical EmExome product to provide clinicians with additional confidence and coverage. To go with this, EGL director Madhuri Hegde sent us some examples of recent diagnostic successes.

One of these was part of a paper that was recently published in the journal Genetics in Medicine: a young girl with multiple symptoms (developmental delay, movement disorder, digestive and breathing problems) was diagnosed with a new type of metabolic disorder, having inherited two mutated copies of the NGLY1 gene.

Two parents whose children were diagnosed with NGLY1 mutations have an interesting commentary in the same journal, describing how next-generation sequencing and social media went hand-in-hand. [this story was also on CNN.com as “Kids who don’t cry”] Here is an excerpt from the parents’ essay:

Six of the eight patients presented in the accompanying article were linked together after parents, physicians, or scientists working on isolated cases searched online for “NGLY1.” They found a blog post describing the disorder written by the parents of the first confirmed patient. The blog chronicles the boy’s journey (initial evaluation, visits to multiple specialists, incorrect diagnoses, and ultimately the discovery of heterozygous mutations in NGLY1). It was this personal account that allowed the ordering physician, who had been tracking a second patient with NGLY1 variants, to feel confident that the two patients were suffering from the same disorder. Another patient was discovered, on a distant continent, when a parent’s Internet search for his/her child’s symptoms stumbled upon the aforementioned blog. This prompted the parents to suggest targeted NGLY1 sequencing to their child’s physician. Parent/patient-to-physician collaboration such as this is remarkable and is likely happening in other rare diseases with the advent of NGS.

As untrained people, we are not qualified to analyze whole-exome/whole-genome data. We cannot develop a therapeutic compound. We cannot design a diagnostic assay. That being said, parents can offer observations and ideas, and we can push for solutions. Nineteen months after the initial report by Need et al., five viable approaches to treatment are under active consideration, thanks to relentless digging by afflicted families…

Another case study Hegde sent us describes a baby that was born but died after just 10 days, unable to swallow and with poor muscle tone. During pregnancy, the mother had felt reduced fetal movement. For the baby, doctors ordered a variety of gene panels without finding abnormalities, but a muscle biopsy detected signs of congenital muscular dystrophy, type unknown. Whole exome sequencing was able to show that the baby’s disease came from inheriting two mutated forms of the RYR1 gene. Now the mother is pregnant again, and reports feeling lots of movement.

Posted on April 2, 2014 by Quinn Eastman in Uncategorized Leave a comment