Causes of Alexander disease

Most cases of Alexander disease are caused by a mutation in the GFAP gene, which directs the body’s production of a glial fibrillary acidic protein (GFAP). At normal levels, GFAP supports the brain’s white matter (the myelin sheath). The mutation of this gene in Alexander disease causes this protein to accumulate. Instead of helping maintain the brain’s white matter, the extra GFAP does the opposite, killing other cells and damaging the myelin.

In most cases, the gene mutation associated with Alexander disease is not inherited from a parent. It is simply a random mutation and is new in the person who develops the syndrome.

In some cases, Alexander disease is inherited, from a similarly affected parent. In those cases, the disease is inherited in an autosomal dominant fashion.

A small number of patients with symptoms and brain images that indicate Alexander disease do not show an identifiable change on the GFAP gene. This suggests there may be other causes of the disease that we do not yet understand.

Signs and symptoms of Alexander disease

The symptoms and the progress of Alexander disease differ depending on when the disease first appears.

When the disease first appears before birth (early-onset or neonatal form), symptoms are usually seen soon after birth. These symptoms can include:

• Seizures
• Fluid buildup in the brain, with high levels of protein in the cerebrospinal fluid (CSF)
• Severe motor and intellectual impairment

When the disease first appears before age 4 (type I Alexander disease), symptoms can include:

• Seizures
• Enlarged brain and head
• Stiffness in the arms or legs
• Delayed intellectual development
• Delayed physical development
• Recurrent vomiting and difficulties with weight gain

When the disease first appears after the age of 4 (type II Alexander disease), symptoms can include:

• Speech problems
• Difficulty swallowing
• Poor coordination
• Scoliosis
• Recurrent vomiting and difficulties with weight gain

When Alexander disease first appears in the teenage years or in adulthood, symptoms are similar to type II, but with a wider variation in the rate at which the disease progresses.

Testing and diagnosis

Diagnosis of Alexander disease is made based on the physical symptoms, imaging of the brain and the results of genetic tests.

• Magnetic resonance imaging (MRI) of the brain is a key diagnostic tool, as it can detect patterns in brain tissue that are characteristic of Alexander disease.
• Genetic testing can identify changes in the GFAP gene associated with Alexander disease. This analysis is done from a blood sample.
• Neuropsychological testing can assess cognitive function. A series of tests may be administered to find out how the condition is affecting your child’s ability to reason, concentrate, solve problems and remember.

Treatment for Alexander disease

There is no known cure for Alexander disease, but treatment is available to manage symptoms and improve quality of life.

At Children’s Hospital of Philadelphia, your child’s care will be coordinated by our Leukodystrophy Center. Our multidisciplinary team provides advanced diagnostic testing, comprehensive clinical care, and the latest treatments available while we continue to seek new therapeutic options.

Clinical trials may also be an option. Your doctor can help you learn more about these studies. You can also find a list of ongoing studies at www.clinicaltrials.gov.

Follow-up care

Children with Alexander disease need regular monitoring by neurologists. Their ongoing therapy will include other medical subspecialists as needed to address their individual symptoms and adapt treatment to their changing needs. Your child’s care will be geared towards providing the highest possible quality of life and to address any symptoms that cause discomfort.