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 astrocytes, which are 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
The age of onset is quite variable, ranging from prenatal through the sixth decade. One classification system divides patients into three categories based on age of onset: infantile (0–2 years), juvenile (2–12 years), and adult (12 years). More recent classification systems have been proposed that rely more on where the lesions are in the brain and spinal cord, and consequently what types of symptoms occur. Type I patients have frontal predominance of lesions, all are early onset, and have more aggressive course of disease. Type II patients have hindbrain predominance, with onsets throughout the lifespan, and have slower progression of disease. Type I patients predominate in the literature, but this likely reflects ascertainment bias as the adult-onset patients in particular are frequently misdiagnosed with other conditions, such as Parkinson’s disease or multiple sclerosis. Typically type I patients experience a variety of developmental delays, affecting both cognitive and motor skills (such as language or walking), followed by loss of milestones, an abnormal increase in head size, and often seizures. Type II patients experience more problems with gait. Many patients have problems with excessive vomiting, difficulty swallowing, and speaking. 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%) 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 are present in every cell. How these mutations cause Alexander disease is not presently understood. In most cases the mutation is not inherited, but arises spontaneously for unknown reasons. In some families, particularly those where patients have later onsets and milder symptoms, the mutations are inherited in an autosomal dominant pattern. Not every patient with Alexander disease has an identified mutation in GFAP, so that there may be other genetic or perhaps even non-genetic causes that have yet to be discovered.
At present, we are actively engaged in developing accurate animal models of Alexander disease as platforms for research. Mice engineered to carry mutations in GFAP identical to those found in Alexander disease patients also develop Rosenthal fibers, have sub-clinical seizure activity, and experience deficits in learning and memory. In addition, appears that accumulation of GFAP levels above a “toxic” threshold is a key step in disease, and in the mouse models can lead to early death.
Current Waisman Center research is aimed at understanding the mechanisms by which the mutations cause disease, and identifying other genetic loci that influence severity. In addition, we are testing drugs that reduce GFAP accumulation as potential therapeutics, and are attempting to identify biomarkers in blood or CSF that would permit monitoring of severity or progression.