Alexander disease

Alexander disease has always been considered a classic leukodystrophy (the term literally meaning abnormal white matter nutrition, but usually used more broadly to indicate any hereditary or metabolic white matter abnormality). Although rare (the true incidence is not yet known), the disease is always included in the differential diagnosis when encountering an infant with macrocephaly, delayed development, and an abnormal neuroimaging study primarily affecting the frontal lobes. Confirmation of the diagnosis previously required brain biopsy or autopsy, and demonstration of protein aggregates known as Rosenthal fibers within the cytoplasm of astrocytes. MRI criteria for diagnosis, as refined by van der Knaap et al.,¹ noted additional features besides frontal white matter defects (a periventricular rim with high signal on T1-weighted images and low signal on T2-weighted images, abnormalities of the basal ganglia and thalami, brainstem abnormalities, and contrast enhancement of particular gray and white matter structures) and are now highly reliable benchmarks for clinical practice. The realization that mutations in the astrocyte intermediate filament GFAP are responsible for nearly all cases transformed the clinical approach for the most common, infantile, form. …