Alexander disease is a leukodystrophy, a group of more than 15 rare genetic disorders that cause progressive degeneration of the white matter of the brain due to imperfect growth or destruction of the myelin sheath, the fatty covering that insulates nerve fibers in the brain and spinal cord and promotes rapid transmission of nerve impulses. Without myelin, nerve cells cease to function and eventually die. As myelin deteriorates in leukodystrophies such as Alexander disease, nervous system function is impaired. The leukodystrophies are often referred to as “demyelinating” diseases.
Most cases of Alexander disease are diagnosed before age 2 and are described as the infantile form of the disease. Signs and symptoms of the infantile form typically include an enlarged brain and head size (megalencephaly), seizures, stiffness in the arms and/or legs (spasticity), intellectual disability and developmental delay. Less frequently, onset occurs later in childhood (the juvenile form) or in adulthood. Rarely, a neonatal form of Alexander disease occurs within the first month of life and is associated with severe intellectual disability and developmental delay, a buildup of fluid in the brain (hydrocephalus) and seizures.
Alexander disease is also characterized by abnormal protein deposits known as Rosenthal fibers. These deposits are found in specialized cells called astroglial cells, which support and nourish other cells in the brain and spinal cord (central nervous system).
Juvenile Alexander Disease is characterized by difficulty with talking and swallowing and the inability to cough. There may also be weakness and spasticity of the extremities, particularly the legs. Unlike in the infantile form of the disease, mental ability and head size may be normal. Age of onset is usually between the ages of 4 and 10. Survival can extend several years following onset of symptoms, with occasional longer survival into middle age.
The course of the disease may involve signs of swallowing or speech difficulty, vomiting, ataxia and/or spasticity. Mental function often slowly declines, although in some cases the intellectual skills remain intact.
Pathologically, whereas the infantile form of Alexander disease generally affects the brain, the juvenile form generally leads to changes in the brain stem, rather than the brain. There are many Rosenthal fibers evident (as they are in infantile Alexander Disease), but the lack of myelin is less prominent than in the infantile form.
Adult-onset Alexander Disease is the rarest form of the disease, and is also also generally the most mild. Onset can be anywhere from the late teens to very late in life. In older patients, ataxia (impaired coordination) often occurs and difficulties in speech articulation, swallowing and sleep disturbances may occur. Symptoms can be similar to those of the juvenile form, although the course of disease may also be so mild that symptoms are not noticed and goes undiagnosed until an autopsy reveals the presence of Rosenthal fibers. Symptoms, when apparent, may resemble multiple sclerosis or a tumor.
The most common leukodystrophies include Canavan disease, Krabbe disease, metachromatic Leukodystrophy (MLD), Childhood Ataxia with Central Nervous System Hypomyelination (CACH), Alexander disease and Refsum disease.