Lecture Notes

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

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