Alexander Disease

Alexander disease is a rare genetic disorder that progressively damages the nervous system, causing the protective coating around nerve fibers in the brain to deteriorate over time and leading to serious neurological problems.

Table of contents

• What is Alexander disease?
• Types of Alexander disease
• Symptoms and signs
• Causes and risk factors
• What happens in the brain
• Diagnosis
• Treatment and management
• Outlook and life expectancy
• How common is Alexander disease?

Alexander’s disease, ALX, AxD, Demyelinogenic leukodystrophy, Dysmyelinogenic leukodystrophy, Fibrinoid degeneration of astrocytes, Leukodystrophy with Rosenthal fibers

What is Alexander disease?

Alexander disease is a rare genetic disorder that progressively damages the nervous system. It is a type of leukodystrophy, which is a group of conditions that affect the white matter of the brain. White matter is a network of nerve fibers in the brain that helps nerve cells communicate.^[1][2]

These diseases damage the myelin sheath, which surrounds and protects the nerve cells in the brain and spinal cord and speeds transmission of messages between cells. Myelin is a fatty substance that conducts signals throughout your body. Without healthy myelin, communication breaks down, causing serious symptoms.^[1][2]

The disease was first documented in 1949 by W. Stewart Alexander, who treated a 15-month-old infant presenting with an enlarged head, fluid buildup in the brain, seizures, and developmental delays.^[3][4]

Alexander disease is a progressive and often fatal disease. The condition worsens over time and can be life-threatening for certain age groups. People with Alexander disease can begin to show symptoms at any time in life, though most cases first appear in infants or young children. In rare cases, the disease is found before a baby is born.^[1][2]

Types of Alexander disease

Healthcare providers determine the type of Alexander disease based on when symptoms show up. The timing of onset often relates to the severity of the disease, with earlier onset generally correlating with more severe symptoms.^[2][3]

The four main types are:

• Neonatal Alexander disease: It develops during the first month of life. This form is associated with severe disability or death within two years.^[2][3]
• Infantile Alexander disease: It affects children before age 2. This is the most common type and has an onset during the first two years of life. Children affected by the infantile form may survive weeks to several years.^[2][3][6]
• Juvenile Alexander disease: Symptoms may appear between ages 2 and 13, but they’re most common between ages 4 and 10. This form is less common than the infantile type.^[2][6]
• Adult-onset Alexander disease: It can develop any time during adulthood, starting after the late teen years. This is the rarest form. When the disease begins after 4-5 years (juvenile and adult forms), survival is variable and can even reach 30 years of age and more.^[2][3][6]

Symptoms and signs

Symptoms vary depending on the age when they start. Alexander disease is a progressive condition, which means symptoms tend to get worse over time.^[2]

Neonatal and infantile symptoms

Symptoms of neonatal and infantile types include:^[1][2][4]

• Developmental delays (like walking or speech delays)
• Loss of developmental milestones
• Growth faltering or failure to thrive
• Hydrocephalus (buildup of fluid in the brain)
• Megalencephaly (abnormal increase in head size or enlarged brain)
• Seizures
• Spasms, stiff muscles or involuntary muscle movements (spasticity)

Juvenile-onset symptoms

Symptoms of the juvenile type include:^[2][4][6]

• Difficulty swallowing and speaking
• Frequent or recurrent vomiting
• Front-to-back and side-to-side spine curvature (kyphoscoliosis)
• Muscle problems (like weakness, pain or spasms, often in the legs)
• Poor coordination and loss of motor control
• Slowed mental functioning (not all cases affect this)

Adult-onset symptoms

The symptoms of adult-onset may include those from juvenile onset, along with:^[2][4]

• Tremors
• Sleep disturbances
• Problems with balance, coordination and movements (ataxia)

Symptoms are usually milder for the adult type. The symptoms sometimes mimic those of Parkinson’s disease or multiple sclerosis, or may present primarily as a psychiatric disorder.^[4][6]

Causes and risk factors

Most cases of Alexander disease are caused by a mutation in the GFAP gene, which directs the body’s production of 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.^[1][5]

The GFAP gene was identified in the region of chromosome 17q21. This gene normally produces proteins that link together to form filaments, which help support and strengthen cells in the nervous system.^[2][3]

Instead of helping maintain the brain’s white matter, the extra GFAP does the opposite, killing other cells and damaging the myelin. Recent discoveries show that approximately 90 percent of individuals with Alexander disease have a mutation in the GFAP gene.^[1][11]

Inheritance pattern

Alexander disease usually happens randomly. A new genetic variant most often causes it without any history of the condition in your biological family history. In most cases, the gene mutation associated with Alexander disease is not inherited from a parent. It is simply a random mutation.^[1][2]

The disease is inherited in an autosomal dominant manner. This means that you only need one copy of the genetic variant to develop symptoms. In rare cases, you may inherit it from your biological family. Rarely, an affected person inherits the mutation from one affected parent.^[2][3][5]

Risk factors

Anyone can develop this disease. The disease occurs in both males and females, and there are no ethnic, racial, geographic, or cultural/economic differences in its distribution.^[6][7]

If you have a family history of this condition or another type of leukodystrophy, a genetic counselor can help you understand the risk of passing on the condition to future children.^[2]

What happens in the brain

Alexander disease is caused by a mutation in the GFAP gene that codes for the glial fibrillary acidic protein. It represents the only known example of a genetic disorder affecting astrocyte cells. Astrocytes are specialized cells that support and nourish other cells in the brain and spinal cord.^[3][5]

With this condition, abnormal clumps of proteins called Rosenthal fibers build up in astrocyte cells where they don’t belong. These fibers damage myelin, the protective coating around nerve fibers. When a signal disruption happens, nerve communication stops working effectively, leading to symptoms.^[1][2][5]

The destruction of white matter is accompanied by the formation of Rosenthal fibers, which are abnormal protein deposits that accumulate in astrocytes in the brain. Rosenthal fibers are sometimes found in other disorders, but not in the same amount or area of the brain that are featured in Alexander disease.^[4][6]

• Brain
• Spinal cord
• Central nervous system
• White matter

Diagnosis

Because the genetic defect in Alexander disease is known, genetic testing on a blood sample can be used to diagnose most cases of Alexander disease. A suggestive diagnosis can also be made from the clinical symptoms.^[7]

The diagnosis can be made based on clinical and imaging features. After the diagnosis is suspected, genetic testing is usually done for confirmation.^[3]

Common diagnostic approaches include:

• Clinical evaluation of symptoms
• Imaging studies (such as MRI scans) to examine the brain
• Genetic testing to identify mutations in the GFAP gene
• Examination for enlarged head size
• Assessment of developmental delays and neurological function

A small number of people thought to have Alexander disease do not have identifiable mutations in GFAP, which leads researchers to believe that there may be other genetic or perhaps even non-genetic causes of Alexander disease.^[11]

Treatment and management

There is no cure for Alexander disease, nor is there a standard course of treatment. Treatment of Alexander disease is largely supportive and symptomatic.^[3][6]

Treatment approaches may include:

• Anticonvulsants for seizures
• Physical therapy to help with muscle stiffness and coordination
• Occupational therapy to enhance comfort, mobility, and daily routines
• Speech therapy for communication difficulties
• Management of swallowing difficulties
• Treatment of hydrocephalus if present
• Nutritional support for growth and feeding problems

Healthcare providers can help manage symptoms to slow their progression.^[2]

Emerging treatments

For the first time, a potential therapy called zilganersen is in clinical trials. This investigational antisense oligonucleotide is designed to stop the excess GFAP that accumulates because of disease-causing variants in the GFAP gene, with the goal of slowing or stabilizing disease progression. The FDA granted fast track designation to zilganersen, with topline data anticipated in the second half of 2025.^[14]

Current research is aimed at understanding the mechanisms by which the mutations cause disease, developing better animal models for the disorder, and exploring potential strategies for treatment.^[11]

Outlook and life expectancy

The prognosis for individuals with Alexander disease is generally poor, though it varies significantly depending on the age of onset.^[6]

Life expectancy varies by type:

• Neonatal type: Related to severe disability or death within two years^[3]
• Infantile form: Most children with the infantile form do not survive past the age of 6. Children affected by the infantile form (within 2-4 years of age) survive weeks to several years.^[3][6]
• Juvenile and adult forms: These have a slower, more lengthy course. When the disease begins after 4-5 years (juvenile and adult forms), survival is variable and can even reach 30 years of age and more.^[3][6]

Generally, the progression of the disease varies with its time of onset. Typically, the early onset of the disease correlates with an increase in severity.^[1][3]

How common is Alexander disease?

Alexander disease is an extremely rare condition. The prevalence of Alexander disease is unknown, but the disease is estimated to occur in 1 in 1 million people in the United States. About 500 cases have been reported since the disorder was first described in 1949.^[5][14]