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• Posted April 20, 2023

Research Reveals Cause of Deadly Disease Affecting Native American Kids

Scientists say their new study has overturned settled science, finding a new cause for a metabolic disease that causes neurological damage and sometimes death in Native American children.

The good news is that this may lead to better treatment for the condition.

While people with the inherited condition Glutaric Aciduria Type I (GA-1) had been believed to be affected by toxic substances produced in the brain, researchers looked instead to the liver because other metabolic disorders had been shown to break down proteins in the liver and then cause brain damage.

Treatments has included a strict, low-protein diet. That has shown limited success, and up to a third of children with the condition experience long-term neurological damage.

In the new report, senior study author Dr. Karl-Dimiter Bissig and colleagues launched experiments in mice specially bred to have GA-1. Bissig is an associate professor in Duke University's Departments of Pediatrics, Medicine, Biomedical Engineering and Pharmacology and Cancer Biology.

The research team found that catabolites, the residue left by the breakdown of an essential amino acid called lysine, accumulate in the liver and cross the blood-brain barrier.

When this happens, it leads to a toxic build-up of glutaric acid in the brain, causing nerve damage that impacts motor skills.

But the researchers cured the condition in mice with either a liver transplant or CRISPR gene-editing technology. They said that other liver-targeted gene therapies might also be effective and could be administered once in a lifetime.

"The original experiments led to the interpretation that the toxic catabolites were produced locally in the brain,"Bissig explained in a university news release. "What our work demonstrates is the importance of challenging paradigms, particularly as new technologies and research approaches are available."

The findings were published online April 19 in the journal Science Translational Medicine.

People with Native American, Amish and Irish heritage have high susceptibility to GA-1. The genetic variant common in Lumbee populations (a Native American group from North Carolina) seems to cause the most damaging disease.

GA-1 can be identified during newborn screenings, but U.S. states decide which diseases will be included in these screenings. GA-1 may be undiagnosed if it's not part of a state's chosen screening panel or if babies are delivered at home.

Early diagnosis and a low-protein diet have been lifesaving, but the benefits are concentrated in Amish- and Irish-heritage children, according to the study. They have historically had better access to health care services than Native Americans, researchers pointed out.

"With a better understanding of this disease, we can now work to develop treatments that are more effective and easier to access,"Bissig said. "It's much easier to treat the liver than the brain. We are now working to advance the more efficient and convenient therapies."

More information

The National Organization for Rare Disorders has more on GA-1.

SOURCE: Duke University, news release, April 19, 2023