Alexander disease

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By Raphael Schiffmann MD

Alexander disease is also known as or subsumes Dysmyelinogenic leukodystrophy with megalobarencephaly, Fibrinoid leukodystrophy, Leukodystrophy with diffuse Rosenthal fiber formation, and Megalencephaly associated with hyaline pan-neuropathy. -ed.

Alexander disease is a leukodystrophy that may occur at any age. Following the identification of mutations in the glial fibrillary acidic protein (GFAP) gene as the cause of Alexander disease, an increasing number of adult patients have been identified. The disease is caused by a combination of the formation of characteristic aggregates, called Rosenthal fibers, and the sequestration of the protein chaperones alpha B-crystallin and HSP27 into Rosenthal fibers. Phosphorylated TPD-43 accumulates in astrocytes, suggesting a common mechanism with amyotrophic lateral sclerosis. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis. Cerebrospinal fluid GFAP levels are an important disease biomarker.

Key points

  • Alexander disease is an autosomal dominant glial cell disease caused most often by heterozygous de novo mutations in the GFAP gene.
  • Alexander disease is a leukodystrophy in young children but may present as a glial tumor in older patients and adults.
  • In children in particular, a large head or an MRI with specific abnormalities, including spinal cord injury, should suggest the diagnosis.
  • Based on the age of onset and the location of the GFAP mutation, one can divide Alexander disease in 2 subtypes with distinct average life expectancy.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited