Grace Wilsey, one of the first patients identified in the world with the genetic disease NGLY1 deficiency, is receiving physical therapy as part of her treatment.
Gregory Enns, MD, pediatric geneticist at Lucile Packard Children’s Hospital Stanford and a professor of pediatrics at the Stanford University School of Medicine, recently worked with a large team of scientists from a dozen institutions around the world to identify a new genetic disease. The disease is described in a new scientific paper in Genetics in Medicine, the journal of the American College of Medical Genetics and Genomics. Below, Enns answers questions about the new disease.
What causes the new genetic disease?
The new disease, NGLY1 deficiency, is caused by defects in a gene called NGLY1. The function of the defective gene is known: Normally, NGLY1 codes for an enzyme with a housekeeping role inside cells throughout the body. The enzyme, N-glycanase 1, recycles defective proteins from a cellular assembly line. The new research confirmed that children with a defective NGLY1 gene do not make the N-glycanase enzyme. We also observed that the children’s liver biopsies contained an amorphous substance, which we suspect is an accumulation of protein that did not get recycled. But we don’t yet understand how these defects produce the symptoms seen in people with NGLY1 deficiency.
What symptoms characterize NGLY1 deficiency?
Patients have a distinct triad of problems: liver disease, a lack of tears when they cry and a characteristic combination of muscle contractions that causes abnormal tremulous movements. They also experience developmental delays and may show abnormalities on brain imaging. The exact combination of symptoms had never been documented in another disease.
How common is the disease?
NGLY1 deficiency appears to be extremely rare. So far, a worldwide total of about a dozen children, eight of whom are described in our new scientific report, have been identified with NGLY1 gene defects. However, at this stage we are likely detecting only the most severe form of NGLY1 deficiency. It’s quite likely that milder forms of the disease exist. Until we know more, we won’t be sure exactly how common the disease is.
How is NGLY1 deficiency diagnosed?
The early cases have been discovered by whole-genome or whole-exome sequencing, techniques that comprehensively survey an individual’s genetic material. Now that defects in the NGLY1 gene are known to be linked to a disease, some physicians may opt to examine this gene specifically. However, as whole-genome and whole-exome sequencing techniques become cheaper and more widely available, we think they will become more common diagnostic tools for physicians. In a clinical or research setting, looking at so many genes at once is useful not just for finding genetic mutations associated with known diseases but also for finding the next undiscovered genetic disease.
What’s the outlook for learning more about this disease?
The scientific outlook is good: NGLY1 deficiency is now the subject of research projects at Stanford and many other locations around the world. Researchers are conducting experiments in stem cells, fruit flies, mice, zebrafish and other models to understand how the gene defect and the symptoms are connected. They’re also looking for possible drug targets that could lead to effective treatments or even a cure.
In addition, the families of some of the first patients diagnosed are sharing the story of how they connected to each other and to researchers, in the hope that this will help families with many types of undiagnosed genetic diseases to advance research into the conditions that affect their kids. NGLY1 deficiency patients’ fathers Matt Wilsey and Matthew Might have co-authored an editorial about their experience for Genetics in Medicine, the scientific journal that published the report of the disease discovery, and also appear in a new podcast produced by the journal.
***
Learn more about this discovery and Grace Wilsey’s story in our press release.
