The prevalence of Alexander disease is estimated to be about one in one million births. About five hundred cases have been reported since the disease was first characterized. Initially, it was mostly diagnosed in infants but with advances in diagnostic techniques, it is also being observed in juveniles and adults. Individuals from all ethnic groups and sexes appear to be affected equally. Alexander disease was initially believed to be due to de novo (not inherited) genetic changes, however, more cases of inherited Alexander disease are now being observed. 

Alexander disease is caused by changes in the GFAP gene in the majority of cases. GFAP encodes a protein called glial fibrillary acidic protein. This protein is found in healthy brains, almost exclusively in cells called astrocytes. GFAP is a type of intermediate filament which are proteins involved in providing structural support and strength to cells. The exact mechanism by which GFAP mutations cause Alexander disease is unknown. It is believed that such mutations lead to the production of abnormal proteins which hinders the formation of intermediate filaments. As a result, glial fibrillary acidic protein accumulates in astrocytes which has toxic effects beyond a threshold. Rosenthal fibers are altered astrocytes with GFAP deposits found through the brain and the spinal cord. It is not yet known how this mechanism leads to the destruction of the myelin sheath, and therefore, damages the white matter.

In most cases, the mutation in GFAP is not inherited and occurs at a stage of development after conception. However, in some cases, the condition may be inherited from parents and run in the family. When inherited, Alexander disease is an autosomal dominant condition meaning that inheriting one defective gene from one of the parents is adequate to cause the disease. Rarely, Alexander disease occurs in individuals with a functional GFAP gene which indicates this disease is caused by factors that are yet unknown. 

Depending on the age of onset, the extent and the location of the brain and spinal cord damage differ. Therefore, symptoms of Alexander disease vary depending on the form of the condition.

Neonatal form

The onset of symptoms in the neonatal form is from birth to thirty days of age. This form of Alexander disease causes rapid developmental regression or the loss of acquired function. Developmental regression is difficult to identify at such a young age but may present as a loss of sucking. Other symptoms include frequent seizures, hydrocephalus, or the abnormal buildup of a protective fluid called cerebrospinal fluid in the brain. The neonatal form of Alexander disease leads to severe motor and intellectual disability and even death within two years.

Infantile form

The onset of symptoms in the infantile form of Alexander disease is from thirty days to two years of age. This form is associated with delays and regression in physical, mental, and behavioral development. Other symptoms include seizures, progressive enlargement of the head, hydrocephalus or the abnormal buildup of a protective fluid called cerebrospinal fluid in the brain, uncoordinated movement (ataxia), muscle stiffness that makes mobility difficult (spasticity), difficulty swallowing, breathing, coughing, and speaking, and excessive vomiting. 

Juvenile form

The onset of symptoms of juvenile Alexander disease is between the ages of two and twelve. Symptoms include gradual intellectual regression, excessive vomiting, difficulty swallowing, breathing, and speaking, uncoordinated movement (ataxia), muscle stiffness or spasticity, particularly in lower limbs, seizures, and the gradual enlargement of the head.

Adult form

The adult form of Alexander disease is the mildest and the rarest form of this condition. The onset of symptoms can be any time from early teens to late in life. Some individuals with disease-causing changes in GFAP gene may even remain asymptomatic. Individuals affected by this form rarely show developmental delay or regression. Although in some cases, intellectual decline may happen over time, mimicking Parkinson's disease. Other symptoms are uncoordinated movement (ataxia), muscle stiffness (spasticity), and a rhythmic, jerky movement of the soft palate or the muscular part at the back of the roof of the mouth. Affected individuals may also experience difficulty swallowing and speaking, and short episodes of repetitive, uncontrolled movement of the eyes (nystagmus).

Because the symptoms of Alexander disease can be non-specific and similar to many other conditions, the diagnosis of Alexander disease may rest on the exclusion of other possible diseases for which there are definitive tests. The diagnosis of Alexander disease may be suspected when associated symptoms are observed. There are Magnetic Resonance Imaging (MRI) criteria that can help diagnose Alexander disease. A diagnosis of Alexander disease is confirmed if abnormal changes in the GFAP gene are identified. However, a functional GFAP does not completely rule out Alexander disease since a small percentage of individuals with Alexander disease do not show any abnormalities in this gene. In such cases, taking a small brain sample might be required to identify Rosenthal fibers. Notably, Rosenthal fibers are not specific to Alexander disease. Therefore, the diagnosis of this condition in individuals without a confirmed genetic cause depends on the presence of the associated clinical and neuroimaging findings, the presence of Rosenthal fibers, as well as the exclusion of other possible conditions.

The first test performed for the diagnosis of Alexander disease is often an MRI. An MRI is an imaging technique that uses magnetic fields and radio waves to visualize internal organs of the body including the brain. Healthcare professionals may use an MRI to identify damage to the white matter or other structures of the brain which can be suggestive of Alexander disease. An MRI might be less useful in diagnosing late-onset Alexander disease as brain damage may not be as extensive or easily noticeable in an MRI. 

Genetic testing can be performed to detect abnormalities in the GFAP gene. A sample for genetic testing may be obtained from a blood sample or a swab from the inside of the cheek. Genetic tests that may be used include sequence analysis to look for small changes in the individual building blocks of the gene or larger deletions or duplications of parts of the GFAP gene. In some cases, a multigene panel may be used to analyze GFAP and other genes of interest that may be associated with conditions other than Alexander disease that present with similar symptoms.

While the presence of GFAP gene abnormalities can confirm the diagnosis of Alexander disease, the absence of such abnormalities does not exclude Alexander disease because a number of individuals have a functional GFAP gene. In such cases, a brain biopsy may be necessary. A brain biopsy can be done as an open procedure by making an incision in the skull to remove a small sample from the surface of the brain. It can also be done using a needle to access areas that are deeper inside the brain. Once the sample is obtained, it is examined under a microscope to confirm the presence of Rosenthal fibers. 

There are currently no specific treatments available for Alexander disease. Management is symptomatic and supportive, depending on the needs of the affected individual. Management may include physical and occupational therapy, medication to control seizures, and speech therapy. Secondary complications can also be prevented or delayed by early recognition of certain symptoms. For example, early recognition and management of spinal problems such as an abnormal curvature of the spine (scoliosis) can prevent and delay long-term complications.

There are other therapeutic approaches under investigation to reduce the production or deposition of GFAP or to reduce the effects of the accumulation of toxic amounts of GFAP. However, nothing has been approved yet.

The prognosis of Alexander disease depends on the form of the condition. Individuals affected by the neonatal form often experience the poorest outlook with severe disability and death within the first two years of life. Children affected by the infantile form usually do not survive beyond early teens. Individuals with the juvenile form may survive to their 20s-30s. The adult form is the mildest form with a slower progression and variable prognosis. Individuals with this form of Alexander disease may survive up to decades after the onset of symptoms and some may experience very mild to no symptoms at all.

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