Waisman scientist tracks rare genetic disorder

An unexpected break put scientists at the Waisman Center on the trail of the genetic cause of Alexander’s Disease, a rare brain disorder in children.

Albee Messing, a Waisman Center investigator and professor of pathobiological sciences in the School of Veterinary Medicine, says finding the genetic link could lead to a better understanding of a class of diseases and injuries that affect the central nervous system. His team received a four-year, $1.2 million grant from the National Institutes of Health (NIH) this year to identify the gene.

The disease is one of a group of disorders called leukodystrophies, in which abnormalities develop in the growth of the myelin sheath. Myelin serves as a protective insulator for nerve fibers and is crucial to their normal function. Alexander’s Disease is one of several leukodystrophies that are assumed to be hereditary, but their genetic cause remains a mystery.

Alexander’s Disease often strikes at six months of age and causes severe mental and physical retardation. Most children do not survive past age 6. In a juvenile-onset form of the disease, death usually occurs within 10 years. The major diagnostic clue is the existence of a aggregated protein, called a “Rosenthal fiber,” in the brain.

The disease has been difficult to study because of its extreme rarity – the number of diagnoses worldwide each year are only in the dozens, Messing says. But in a previous study with mice, Messing and colleagues unexpectedly induced abnormalities in the brain that were identical to those produced in Alexander’s Disease.

Messing says they were initially studying a protein called GFAP (glial fibrillary acidic protein), which is a major building block for astrocytes. Astrocytes are important cells in the nervous system that maintain the normal functioning of neurons and their myelin sheaths. The researchers wanted to understand why, when spinal or brain injuries occur, GFAP production increases.

When researchers over-expressed the GFAP in mice, the mice developed Rosenthal fibers identical to those in Alexander’s Disease patients. The development was significant because it showed a genetic connection to the formation of these fibers.

For the new NIH study, Messing and his collaborator collected available cell samples from Alexander’s Disease patients. The international effort took more than a year. Although the disease is rare, Messing says this genetic study could be a model for understanding the role astrocytes play when the central nervous system is damaged or diseased.