Team discovers genetic basis of Alexander disease

Scientists have pinpointed the gene responsible for a rare and devastating childhood brain disorder called Alexander disease, solving a 50-year-old mystery regarding its cause.

Reporting in the Wednesday, Jan. 3, issue of the journal Nature Genetics, a team led by university researcher Albee Messing made the discovery after a genetic analysis of 13 cases of the disease. Because of the rarity of the disease, it took nearly two years to assemble enough cases from international sources to complete the study.

Alexander disease is in a family of disorders called leukodystrophies in which abnormalities arise in the myelin sheath, a protective insulation that covers nerves. It often strikes infants before their first year of age and causes catastrophic damage throughout the nervous system. Most children do not survive past age 6.

While genetics were always presumed to be the cause, confirming the hunch would have been impossible without an unexpected break several years ago in Messing’s lab. Messing and collaborator Michael Brenner of the University of Alabama at Birmingham developed a transgenic mouse that coincidentally exhibited the hallmark traits of Alexander disease, which narrowed the field for finding the responsible gene.

The Nature Genetics paper confirmed that mutations in a gene called GFAP — or glial fibrillary acidic protein — are associated with nearly all cases of Alexander disease. Messing says the mutation triggers production of an abnormal protein, which causes a buildup of fibers that damage the nervous system.

“Finding this gene would have been a shot in the dark without that initial discovery,” says Messing. “GFAP is a very well-known and widely studied protein among neuroscientists, because it’s the identifying feature of astrocytes.”

Astrocytes are one of the major cell types in all vertebrate nervous systems that maintain the function of neurons and their myelin sheaths. Scientists already know that GFAP proteins increase when spinal or brain injuries occur, but are not sure why. “This is going to open the door to understanding how astrocytes respond to disease or injury,” he says.

Identifying the genetic cause gives researchers a starting point, but possible treatments are likely well in the future, Messing says. “I think parents who have had children with Alexander disease will be relieved by finally knowing its cause,” he says. “It’s such a rare disorder that they have felt very isolated, thinking that no one was working to find answers.”

Other disorders that involve “protein aggregation” — or excess protein buildup that damages nerve function — include Alzheimer’s and Parkinson’s disease. Messing says scientists do not know whether these aggregations are a byproduct or a cause of the disease, or whether the process can be short-circuited with treatment.

The research is supported by the National Institutes of Health. Messing is a professor of pathobiological sciences at UW–Madison’s School of Veterinary Medicine, and a researcher with the Waisman Center, which focuses on childhood developmental disorders.

A number of collaborators in addition to Brenner were important to the project, including: Anne B. Johnson at Albert Einstein College of Medicine in New York; Odile Boespflug-Tanguay of the Clermont-Ferrand Medical School in France; Diana Rodriguez of St. Vincent de Paul Hospital in Paris; and James Goldman of Columbia University.
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— Brian Mattmiller, (608) 262-9772; bsmattmi@facstaff.wisc.edu