Alexander disease

Brain of a 4-year-old boy with Alexander disease

Alexander disease

Alexander disease is a rare, progressive neurodegenerative disorder that primarily affects the central nervous system. It is classified under the group of leukodystrophies, which are disorders characterized by the destruction of white matter in the brain. The disease is caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), leading to the formation of abnormal protein aggregates known as Rosenthal fibers within astrocytes. These abnormalities impair the function of astrocytes, which are crucial for maintaining neuronal health, leading to progressive neurological decline.

Clinical Features

Alexander disease presents in different forms, classified based on the age of onset and severity:

• Infantile Form:
• The most common and severe form, manifesting within the first two years of life.
• Symptoms include:
• Developmental delay and intellectual disability.
• Macrocephaly (enlarged head size) due to accumulation of abnormal astrocytic filaments.
• Seizures and spasticity.
• Dysphagia (difficulty swallowing).
• Progressive white matter destruction leading to leukodystrophy.

• Juvenile Form:
• Onset occurs between ages 2 and 13 years.
• Symptoms include:
• Progressive ataxia (loss of coordination).
• Dysarthria (difficulty speaking).
• Dysphagia (swallowing difficulties).
• Cognitive impairment and behavioral abnormalities.
• Progressive muscle weakness.

• Adult Form:
• The rarest and mildest form, with onset after adolescence.
• Symptoms can mimic those of multiple sclerosis or Parkinson’s disease.
• Features include:
• Mild spasticity.
• Tremors and rigidity.
• Psychiatric disturbances, such as depression or psychosis.

Pathophysiology

Alexander disease results from mutations in the GFAP gene, leading to the accumulation of Rosenthal fibers—abnormal aggregates of glial fibrillary acidic protein within astrocytes. These fibers impair astrocyte function, disrupting their roles in:

• Maintaining the blood-brain barrier.
• Regulating ion homeostasis in the brain.
• Supporting neuronal metabolism and synaptic function.

This dysfunction leads to progressive demyelination, the hallmark of leukodystrophies. The loss of myelin disrupts neural signal transmission, resulting in the neurological symptoms observed in Alexander disease.

Diagnosis

The diagnosis of Alexander disease is based on a combination of clinical features, neuroimaging findings, and genetic testing.

• Neuroimaging:
• Magnetic Resonance Imaging (MRI) shows:
• Extensive white matter abnormalities, especially in the frontal lobes.
• Basal ganglia and brainstem involvement.
• Rosenthal fibers accumulation.

• Genetic Testing:
• Identification of mutations in the GFAP gene confirms the diagnosis.
• Testing is particularly useful in cases with atypical presentations.

Management

Currently, there is no cure for Alexander disease. Treatment is primarily supportive and focuses on managing symptoms:

• Seizure Control:
• Antiepileptic drugs are used to reduce seizure frequency.

• Physical and Occupational Therapy:
• Helps maintain motor function and prevent muscle contractures.

• Nutritional Support:
• In advanced cases, feeding tubes may be required to prevent malnutrition.

• Speech Therapy:
• Assists with communication difficulties and dysphagia management.

Research into targeted therapies, including gene therapy and pharmacological interventions to reduce GFAP accumulation, is ongoing.

Prognosis

The prognosis of Alexander disease varies depending on the age of onset:

• Infantile form: Often leads to severe neurological disability and early mortality, typically within the first decade of life.
• Juvenile form: Generally progressive but slower than the infantile form.
• Adult form: Milder symptoms and a more prolonged disease course.

See Also

• Leukodystrophy
• Astrocyte
• Demyelination
• Neuromuscular disorders

External Links

• National Organization for Rare Disorders - Alexander Disease
• MedlinePlus - Alexander Disease
• NCBI Bookshelf - Alexander Disease

NIH genetic and rare disease info

• NIH info on Alexander disease

Alexander disease is a rare disease.

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