Alexander disease is a disorder of cortical white matter that predominantly affects infants and children and usually results in death within ten years after onset. The infantile form comprises about 51% of affected individuals, the juvenile form about 23%, and the adult form about 24%. A neonatal form is also recognized. The neonatal form leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability, severe white-matter abnormalities, involvement of the basal ganglia and cerebellum, and elevated CSF protein concentration. The infantile form presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly and frontal bossing, seizures, hyperreflexia and pyramidal signs, ataxia, and hydrocephalus secondary to aqueductal stenosis. Affected children survive weeks to several years. The juvenile form usually presents between ages four and ten years, occasionally in the mid-teens. Findings can include bulbar/pseudobulbar signs, ataxia, gradual loss of intellectual function, seizures, megalencephaly, and breathing problems. Survival ranges from the early teens to the 20s-30s. The adult form is the most variable.
Diagnosis of Alexander disease is based on MRI findings. Prior to the availability of molecular genetic testing the diagnosis was confirmed by the detection of astrocytic inclusion bodies (Rosenthal fibers) on brain histology. GFAP, which encodes glial fibrillary acidic protein, is the only gene in which mutation is currently known to cause Alexander disease.
Alexander disease is inherited in an autosomal dominant manner. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent is affected or has a mutation in GFAP, the risk to the sibs of inheriting the GFAP mutation is 50%. Sibs of a proband with unaffected parents are at low risk for Alexander disease; however, the possibility of germline mosaicism exists. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member.