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Parents help find diagnosis for rare disease

 

EMBO Member Lars Steinmetz and Associate Member Shinya Yamanaka are part of an international team trying to find a solution for a rare disease that was first diagnosed thanks to the efforts of the parents of affected children.

 

A disease or disorder is defined as rare in Europe when it affects fewer than 1 in 2000. In the United States it has to affect fewer than 200, 000 Americans at any given time. Grace Wilsey was a huge puzzle to her parents and doctors after she was born. At the age of 4 months onwards her development was delayed, but initial diagnostic tests gave no clear answer about the cause of the problems. Whatever condition she had seemed to affect every organ in her body. What followed were visits from one doctor to another, incorrect diagnoses, tests and further tests. Frustrated by the lack of interest from the pharmaceutical industry as well as uncertainty from the medical community the parents of Grace set out to involve others in finding a solution.

 

Things started to fall into place about the cause of the disease after a small group of patients was identified. One of the crucial pieces of evidence arose from whole genome sequencing for Grace (other patients had their whole exome sequenced), which confirmed that those affected had defective copies of the NGLY1 gene. Another crucial clinical observation was a lack of tears in patients.

 

It turns out the NGLY1 gene encodes an enzyme that removes a sugar molecule from damaged proteins. “What is known is that NGLY1 helps to get rid of misfolded proteins in cells,” says Steinmetz, Associate Head of Genome Biology & Senior Scientist at the European Molecular Biology Laboratory in Heidelberg, Germany, Professor of Genetics at Stanford University and Co-director of the Stanford Genome Technology Center, who is working on the project. “When this enzyme is defective you could get an accumulation of protein aggregates in cells. However, NGLY1 could also be involved in other functions.”

 

For NGLY1 deficiency to arise, a person needs to inherit two faulty copies of the gene from his or her parents (autosomal recessive disorder). The condition affects a degradation pathway that takes place within the endoplasmic reticulum of cells in such a way that it leads to neurological dysfunction, abnormal tear production, and liver disease. NGLY1 deficiency patients show global developmental delay, movement disorder, and low muscle tone (hypotonia). Other common symptoms include elevated levels of liver transaminase enzymes, reduced head size (microcephaly), diminished reflexes and seizures

 

“NGLY1 happens to be a very central part of cellular metabolism and it is going to be linked to a lot more types of disorders as we work out what it is doing,” says Dr Gregory Enns, Director of the Biochemical Genetics Program at Stanford University. Much of the work that led to the diagnosis has been written up in a paper published in Genetics in Medicine.* Enns wrote the paper that included input from thirty-three authors from four countries around the world. The paper describes the DNA sequencing work and the findings from the study of eight patients.

 

“The parents really spearheaded putting the international team of scientists together,” says Steinmetz. To further the work on NGLY1 deficiency, the Wilsey’s established the Grace Wilsey Foundation (gracewilsey.org), which is led by people from science, medicine, business, and the public service. The foundation helps to coordinate fundraising. The Wilsey’s have also provided significant personal financial support for the research. Today a scientific team of glycobiologists, cell biologists, biochemical geneticists, chemists and experts in gene therapy are working on the project.

 

It has been a long path for the parents to reach a point where they have a diagnosis for the disease and some understanding of what goes wrong in the cells of patients. No one is under any illusion that the journey towards a cure will be straightforward. What is needed now is a concerted effort to understand the molecular events that arise from NGLY1 deficiency and to identify possible intervention points where new therapeutics or treatments would make sense. This is where the work of Steinmetz, Yamanaka and other members of the team that the Wilsey’s have put together hope to make contributions.

 

“We are now trying to find out why deficiencies in the NGLY1 gene cause many of the symptoms of these children and we are trying to find a cure,” says Yamanaka. “We still need to do a lot of basic research to do this and also to find out how frequent the disease is. At this point in time, we just do not know.”

 

*Enns G, Shashi V and Bainbridge M (2014) Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum–associated degradation pathway. Genetics in Medicine 16: 751–758.

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Tilmann KießlingTilmann Kießling
Head, Communications
T. + 49 160 9019 3839