Alexander disease

Alexander disease is a neurological condition that affects the white matter of the brain and spinal cord and belongs to a group of disorders called leukodystrophies. Variants in the GFAP gene, which encodes the glial fibrillary acidic protein found in astrocytes, disrupt normal support functions for nerve cells and lead to the disease. Symptoms usually begin in infancy or early childhood, although a later-onset form can appear in teenagers and adults. The exact number of people affected worldwide is not well established, but Alexander disease is considered very uncommon. Because it can appear at any age and progress at different rates, recognizing the condition early is important for planning care.

Alexander disease primarily affects the central nervous system, and neurological changes often draw medical attention first. Many infants present with an unusually large head size, called macrocephaly or megalencephaly, and may later develop spasticity that makes muscles stiff and movements awkward. Cerebellar involvement contributes to ataxia, so children can appear unsteady or have difficulty coordinating their limbs. Cognitive and developmental challenges are common; intellectual disability and slowing or loss of skill acquisition may be observed as the disease evolves. Seizures, palatal tremor, pendular nystagmus, and dysarthria further reflect broad brain involvement. Over time, additional signs such as hyperreflexia, Babinski sign, and abnormal pyramidal tract findings indicate progression. Some individuals experience sleep disturbance, fatigue, or episodes of nausea and vomiting. Skeletal issues, including scoliosis and frontal bossing, can emerge, and microcoria or other eye movement abnormalities may be noted during examinations. Not all individuals experience every feature, and severity varies considerably. Even within the same family, the type and progression of symptoms can differ, highlighting the broad clinical spectrum of this condition.

Alexander disease results from pathogenic variants in the GFAP gene. GFAP provides instructions for producing glial fibrillary acidic protein, a structural component of astrocytes that helps maintain the integrity of nerve tissue. When the protein is altered, astrocytes cannot perform their supportive roles effectively, leading to widespread dysfunction of brain white matter. The condition is inherited in an autosomal dominant pattern, meaning a single altered copy of GFAP is sufficient to cause disease. An affected individual has a 50 percent chance of passing the variant to each child. Family members who are concerned about their risk are encouraged to speak with a genetic counselor, who can discuss testing options and implications for future pregnancies. Severity and specific symptoms can vary even among relatives who share the same genetic change, an example of variable expressivity.

Currently, management focuses on supportive care and symptom management. Physical, occupational, and speech therapies help preserve mobility and communication skills. Antiseizure medications may be prescribed when seizures occur, and nutritional support can address feeding difficulties or failure to thrive. Because Alexander disease can affect several body systems, long-term care is typically coordinated by a multidisciplinary team that may include neurologists, rehabilitation specialists, nutritionists, and mental health professionals. Regular surveillance is an essential part of long-term care, helping to identify potential complications such as scoliosis progression, sleep problems, or worsening spasticity before they become serious. Patients should discuss individual treatment and monitoring plans with their healthcare team to determine which strategies are most appropriate for their specific situation. Genetic counseling is recommended for families to review inheritance, testing of relatives, and reproductive options.

The course of Alexander disease is highly variable. Some children experience gradual neurological decline, while others have periods of relative stability followed by slower progression. Early onset is generally associated with more significant developmental impact, but even within the same clinical form, outcomes differ widely. Respiratory complications, feeding difficulties, and progressive motor impairment can affect quality of life, yet supportive therapies and attentive monitoring can help many individuals maintain function longer and participate in daily activities. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialized centers and patient support networks, and genetic counseling can guide future planning.

Several clinical trials are currently investigating new treatments for Alexander disease, reflecting growing research interest in modifying the underlying astrocyte pathology. Approaches under study include molecular therapies aimed at reducing toxic GFAP accumulation and strategies to enhance astrocyte function. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility and enrollment considerations.