Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein, a type III intermediate filament protein expressed in astrocytes.
Introduction
- Definition: Alexander disease is a progressive disorder of cerebral white matter caused by a heterozygous pathogenic variant in the GFAP gene.
- Clinical Spectrum: The disease spans neonatal, infantile, juvenile, and adult forms, each with distinct clinical presentations.
- Inheritance: Autosomal dominant, typically de novo mutations, though familial cases have been reported.
Clinical Findings by Age Group
Neonatal Form
- Onset: Within the first 30 days of life.
- Neurologic Manifestations:
- Weak suck and feeding difficulties.
- Hypotonia, hyperexcitability, and myoclonus.
- Developmental failure or regression (may manifest as loss of the sucking reflex).
- Generalized, frequent, and/or intractable seizures.
- Elevated CSF protein levels.
Infantile Form
- Gastroesophageal reflux.
- Vomiting.
- Failure to thrive.
Children:
- Megalencephaly with frontal bossing or disproportionate head growth.
- Risk of hydrocephalus due to aqueductal stenosis.
- Distinction:
- Megalencephaly: Increased brain parenchyma volume.
- Macrocephaly: Head circumference >2 SD above the mean, which may result from megalencephaly or other causes (e.g., hydrocephalus, thickened skull).
Juvenile Form
- Severe cognitive, language, and motor delay without spasticity or ataxia.
Adults
- Rapid progression leading to severe disability or death, typically within two years.
Brain MRI Findings
A multi-institutional retrospective survey suggests four of the following five criteria can establish an MRI-based diagnosis of Alexander disease and guide genetic testing:
- Onset: Infancy or childhood.
- Developmental Course:
- Developmental delay or plateau.
- Variable acquisition of milestones (e.g., some achieve ambulation and phrases, others do not).
- Dysarthria common in individuals with expressive language.
Age-Specific MRI Findings
Neonatal Form
- Often less frequent and severe than in the neonatal form.
- Frequently triggered by illness.
Infantile Form