Alexander disease, often shortened to AxD, is a rare leukodystrophy that impacts specialized cells known as astrocytes.
In addition to myelin degeneration, AxD is marked by a combination of irregularities built up in the astrocytes, which form clumps known as Rosenthal fibers.
While not unique to AxD, Rosenthal fibers are especially notable in this disease due to their abundance and placement throughout the white matter and around the blood vessels of the central nervous system (CNS). The
presence of these structures in combination with the deterioration of myelin causes secondary issues in other types of cells throughout the nervous system.
AxD is most often caused by a genetic mutation that impacts the production of an important protein found in astrocytes. This filamentous protein is known as glial fibrillary acidic protein (GFAP), and mutations on its gene (found on chromosome 17) account for over 90% of cases of AxD.
The precise location of these mutations can vary from patient to patient, but precisely how they cause AxD is not yet understood. AxD is considered a “gain-of-function” disorder, as the mutation causes an overproduction of abnormal proteins; this overproduction leads to secondary reactions throughout the nervous system, including a potentially toxic effect on the astrocytes themselves.
A small percentage of patients have been found to have no identifiable GFAP mutation, which could indicate an additional cause of the disease that has not yet been studied or discovered.
A diagnosis of AxD is made through a combination of factors, including physical symptoms, brain imaging, and genetic testing. Once a healthcare provider has detected signs or symptoms of a white matter disorder, an MRI (magnetic resonance imaging) is conducted to examine changes in the brain.
If AxD is suspected, a blood test is run to check for genetic mutations which would confirm a diagnosis.
The most common form of genetic testing is done through a blood test! This allows medical professionals to identify any changes to the GFAP gene, which would establish AxD as the diagnosis.
While most cases of AxD are due to de novo mutations, there are also cases in which they are passed on from parent to child. This is done in an autosomal dominant pattern, meaning an affected parent has a 50% chance of passing on a mutated gene to their child.
Because the known GFAP mutation occurs on only one of the two identical genes found in each cell, only one mutated gene is needed to cause the disease. In many cases of inherited AxD, symptoms are milder and there may be a later age of onset.
Alexander disease can be broken into subtypes based on several different classification systems.
The first classification system breaks AxD into three categories, which are based strictly on the age of onset. These categories are infantile, juvenile, and adult, although some experts may include a fourth neonatal category.
The second classification system relies on the location of changes to the white matter (called lesions) and the resulting symptoms, and utilizes only two subtypes; type I and type II.
Neonatal
Infantile
Juvenile
Adult
