Dietary Supplement Restores Enzyme Deficiency in Early Study

Pam Harrison

November 03, 2016

The absence of the N-glycanase 1 (NGLY1) enzyme, a rare autosomal recessive mutation that causes developmental delay, difficulties with movement, and the ability to produce tears, might respond to dietary supplementation, preliminary work suggests.

NGLY1 is a conserved component of the endoplasmic reticulum-associated degradation (ERAD) pathway, which is responsible for the degradation of misfolded proteins that accumulate in the lumen of the endoplasmic reticulum.

Normally, N-acetyl-D-glucosamine (GlcNAc) is removed from misfolded proteins and recycled back into the system. But without NGLY1, GlcNAc stays bound to the misfolded proteins, and that produces a deficit.

The Drosophila fruit fly analog of human NGLY1 deficiency is Pngl deficiency, said Clement Chow, PhD, assistant professor of human genetics at the University of Utah in Salt Lake City.

He described the fly model at the American Society of Human Genetics 2016 Annual Meeting in Vancouver, British Columbia, Canada.

"When raised on a normal fly diet, only about 25% of the flies make it to adulthood; most of them die during development," he said.

"When we supplemented their food with GlcNAc, that raised survival to about 70% to 80%. It was just that simple; they were eating it, and presumably GlcNAc restores what's missing in the fly," he told Medscape Medical News.

The flies also provided evidence that both the ERAD and cytoplasmic heat shock pathways are defective in cases of NGLY1 deficiency.

Many steps remain before the same approach can be tested in people with NGLY1 deficiency, Dr Chow explained. They would have to be treated from birth, which is a challenge in the management of human disease because infants are not usually diagnosed that early.

"Nevertheless, these data suggest a plausible pathophysiology for NGLY1 deficiency," he said. And "more important, our study points to a potential therapy with a simple, readily available, dietary supplement."

The fact that the disorder was only identified about 4 years ago is likely a reflection of the challenges involved in identifying mutations that turn out to be causative for rare diseases. Only about 50 patients in the world have been diagnosed with NGLY1 deficiency, Dr Chow reported.

"This deficiency is not something that newborns are ever going to be screened for," he said, although he noted that diagnostic whole-exome sequencing would reveal potential mutations.

"But we'd like to understand why GlcNAc is working, because that would tell us a lot more about the disease and why missing this enzyme is so devastating," he said.

Intriguing Research

This research is "intriguing," said Hudson Freeze, PhD, director of the human genetic program at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California

"Finding that GlcNAc has this profound effect on life and death in flies opens up opportunities for more fundamental research," he told Medscape Medical News.

NGLY1 deficiency is the only known human disease of deglycosylation, but there are more than 100 disorders of glycosylation, said Dr Freeze. Early clinical trials are using authentic dietary supplements to treat about half a dozen of these disorders.

"Sometimes, we don't understand the biology of these rare disorders well enough to go forward in terms of being able to do anything, so parents of these children are understandably desperate. And physicians don't know where to look, so it's very difficult," he explained.

"Consuming GlcNAc is probably not harmful, but if parents decide to give their children GlcNAc, it would be helpful for them to keep before and after records on its effects. In the long run, that may help physicians and other children with NGLY1 deficiency," Dr Freeze said.

Dr Chow and Dr Freeze have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2016 Annual Meeting: Abstract 183. Presented October 20, 2016.

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