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Supported in part by The Jack Palamaro Fund, Jelte Rijkaart Fund, and The Juanma Fund.


Alexander disease, a leukodystrophy, is a progressive and usually fatal neurological disorder in which the destruction of white matter in the brain is accompanied by the formation of abnormal deposits known as Rosenthal fibers. Rosenthal fibers are aggregations of protein that occur in the astrocytes, which are nonneuronal, supporting cells of the brain. These aggregates are found occasionally in other disorders, but not with the abundance or particular distribution in the brain that occurs in Alexander disease.

Department of Pediatrics Grand Rounds - Presented 02/02/2012
Why Rare Diseases Matter: The Changing Spectrum of Alexander Disease

Alexander Disease Mutation

The most common form of Alexander disease is the infantile form, which is typically defined as onset during the first two years of life. Usually there are several types of developmental delays (both mental and physical), followed by loss of milestones, an abnormal increase in head size, and often seizures. The juvenile form of Alexander disease is less common and is typically defined as onset between the ages of two and thirteen. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control. Survival is quite variable, with rare patients surviving several decades. Even rarer adult-onset forms of Alexander disease have been reported where the symptoms sometimes mimic those of Parkinson's disease or multiple sclerosis. The disease occurs in both sexes, and there are no ethnic, racial, geographic, or cultural/economic differences in its distribution.

Recent discoveries show that most patients (~90%) with Alexander disease have a mutation on chromosome 17 in the gene for glial fibrillary acidic protein (GFAP). GFAP is a filamentous protein of astrocytes and also accumulates as part of the Rosenthal fibers. The site of the mutation on the gene varies, and it occurs on only one of the two copies of each gene that is present in every cell. For most of these mutations it is clear that they cause Alexander disease, but exactly how they do so is not presently understood. In general, there is not a good correlation between the particular mutation and the form or severity of the disease. Most of the mutations occur spontaneously and are not inherited from the parents. For some of the adult-onset cases, patients do live long enough to have children of their own and the disease can then be inherited through multiple generations in an autosomal dominant fashion. However, not every patient with proven Alexander disease (i.e. proven by biopsy or autopsy diagnosis) has an identified mutation in GFAP, so that there may be other genetic or perhaps even non-genetic causes that have yet to be identified.

At present, there is no exact animal model of Alexander disease. Transgenic mice with added copies of a normal human GFAP gene developed Rosenthal fibers and died at an early age, but did not display all of the features of true Alexander disease. Most recently, mice have been engineered to produce the same mutant forms of GFAP found in patients - again, they form Rosenthal fibers, and have a predisposition for seizures, but do not yet mimic all features of the human disease.

Current research is aimed at understanding the mechanisms by which the mutations cause disease and screening FDA-approved drugs for beneficial effects in the mouse models.

A major effort is devoted to identifying biomarkers in blood and cerebrospinal fluid to permit monitoring severity or progression of the disease and thus provide the necessary foundation for future clinical trials.