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.
• Gastrointestinal Manifestations:
  • Gastroesophageal reflux.
  • Vomiting.
  • Failure to thrive.
• Key Features:
  • 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).
• Neurologic Exam:
  • Severe cognitive, language, and motor delay without spasticity or ataxia.
• Prognosis:
  • Rapid progression leading to severe disability or death, typically within two years.

Infantile Form

• 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.
• Seizures:
  • Often less frequent and severe than in the neonatal form.
  • Frequently triggered by illness.
• Key Features:
  • Frontal bossing and megalencephaly are not universal.
  • Macrocephaly may develop years after initial manifestations.
  • Developmental regression may occur after seizures or mild head trauma.
• Prognosis:
  • Variable progression:
    • Loss of gross/fine motor and language skills in some.
    • Slow disease course spanning decades in others.

Children:

• Developmental delay (slow milestone attainment or failure to achieve later milestones).
• Seizures.
• Megalencephaly.
• Gradual intellectual decline and loss of function.
• Regression following mild head injury or seizure.
• Dysarthria (in children who develop speech).
• Failure to thrive.

Juvenile Form

• Onset: Childhood or adolescence.
• Early Features:
  • Milder than infantile form:
    • Mild language delay.
    • Voice changes (hypophonia, nasal speech) may precede other neurologic features.
• Common Features:
  • Vomiting and failure to thrive.
  • Scoliosis and autonomic dysfunction.
  • Anorexia, sometimes misdiagnosed as an eating disorder.
  • Delayed physical growth (short stature).
• Progression:
  • Progressive scoliosis and medullary/cervical cord atrophy over time.
• Key Insights:
  • Some cases present with isolated brain stem lesions, resolving spontaneously before progressing to atrophy.

Adults

• Onset: Adolescence or adulthood.
• Neurologic Features:
  • Bulbar/Pseudobulbar Signs:
    • Palatal myoclonus, dysphagia, dysarthria, slurred speech.
  • Motor Signs:
    • Gait abnormalities.
    • Pyramidal signs (spasticity, hyperreflexia, positive Babinski sign).
  • Cerebellar Signs:
    • Ataxia, nystagmus, dysmetria.
  • Other Features:
    • Sleep apnea.
    • Diplopia and extraocular motility disorders.
    • Autonomic dysfunction (e.g., pollakiuria, constipation, orthostatic hypotension).
• Progression:
  • Variable:
    • Hemiparesis/hemiplegia with relapsing/remitting course.
    • Slowly progressive quadriparesis/quadriplegia.
• Variable Expressivity:
  • Mildly affected parents or siblings of individuals with GFAP pathogenic variants may show few or no symptoms but have MRI abnormalities.