The value of clinical and MRI criteria in the diagnosis of Alexander disease was determined by using GFAP gene sequencing as the confirmatory assay in 13 patients with variable ages of onset in a study at Children’s National Medical Center, Washington, DC and other centers. Genomic DNA was screened for mutations in the GFAP gene, and 12 (92%) tested positive. Seven of the 12 presented in infancy (ages 2 to 18 nonths) with megalencephaly, seizures, failure to thrive, and delayed development. Five were juvenile-onset (ages 5 to 9 years) with variable symptoms, 2 being asymptomatic and the remainder with severe symptoms, including growth failure, sleepiness, and vomiting. Both groups showed progression of megalencephaly with increasing age, bulbar signs, spasticity, cognitive deficits, and developmental delay. MRI showed diffuse, symmetrical white matter abnormality in the frontal regions, sparing subcortical U-fibers. GFAP gene mutation analysis should be included in the initial diagnostic evaluation of infants or young children presenting with megalencephaly and predominantly frontal leukoencephalopathy on MRI. Gene analysis may now take the place of brain biopsy histological examination for diagnostic Rosenthal fibers. 
COMMENT. Infantile onset Alexander disease is characterized by megalencephaly, developmental delay, spasticity, and seizures, and juvenile onset cases have brainstem signs, spasticity, with or without megalencephaly or seizures. The diagnosis is strongly suspected when the MRI shows white matter changes predominating in frontal cortical regions. The histological hallmark of Alexander disease is the finding of Rosenthal fibers, astrocytic cytoplasmic inclusions. GFAP gene mutation analysis may preclude the necessity for brain biopsy.
A novel mutation in glial fibrillary acidic protein (GFAP) gene is reported in a 13-year-old boy diagnosed with juvenile Alexander disease.