Alexander disease: Year of the Zebra 2025

Alexander disease is a rare neurological disorder that primarily affects the white matter of the brain.

If we look at a cross section of the brain, we can easily distinguish between two tissue types.

First is white matter, which is the area responsible for transmitting signals between different brain regions, and gray matter.

Gray matter contains nerve cell bodies. White brain matter is made up of bundles of axons, which are projections of nerve cells that carry impulses.

Axons are covered in myelin, a fatty insulating layer that helps speed up electrical signals.

The production of myelin depends on glial cells called oligodendrocytes, with support from astrocytes—which are glial cells that have processes coming off their cell body, giving them a star-shaped appearance.

Astrocytes influence when and where myelin is produced; they provide nutrients to sustain myelin production; and release signaling molecules that can either promote repair or contribute to myelin damage.

In Alexander disease, mutations in the GFAP gene lead to the abnormal accumulation of proteins within astrocytes, disrupting their function. Astrocyte dysfunction triggers the breakdown of myelin and progressive white matter loss, resulting in neurological impairment.

Alexander disease can typically be classified into three main types depending on the age of onset. The most common is the infantile-onset form, which typically manifests before age 2. Infants often present with macrocephaly, or an enlarged head circumference, and have seizures.

They may also experience neurodevelopmental delays, including motor, language, and cognitive development. Affected infants typically face progressive deterioration, with death occurring before age 10 in most cases.

The juvenile-onset form appears between ages 2 and 12 and generally progresses more slowly. Affected individuals often develop signs of cognitive decline, muscle spasticity, slurred speech, and loss of coordination, such as difficulty walking, keeping balance, sitting up straight, or using their arms.

Seizures may occur, though less frequently than in the infantile form, and are often triggered by mild illnesses.