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.

NGLY1 deficiency appears to result in the accumulation of proteins with the sugar chains attached, but exactly what causes problems in the human disease (is it particular accumulated proteins or perhaps depletion of the sugar chains’ components?) is still a mystery.

In the PLOS Genetics paper, heart defects are observed in the NGLY1-deficient mice but generally have not been seen in the human disease. Even so, the NGLY1-deficient mice have other symptoms that resemble those seen in humans, such as movement disorders and eye problems, and ENGase deletion helps them live longer.

To add to the ENGase finding, researchers from University of Utah including co-author Matt Might, the father of an affected child, have found that proton pump inhibitors (PPIs) inhibit ENGase. Their paper suggests that PPIs, which are over-the-counter drugs for stomach acid, could be tried in NGLY1-deficient patients.

However, the concentrations at which PPIs work on ENGase are higher than the concentrations needed to affect stomach acid production; this result may be viewed as a basis for more drug discovery research.

Also notable: a National Human Genome Research Institute study on affected children, and a preliminary finding in flies that the dietary supplement N-acetylglucosamine may help from University of Utah.