Leukodystrophies are a group of rare, hereditary disorders characterized by abnormal myelination.  Each leukodystrophy is caused by abnormalities in one or more genes leading to abnormal production of myelin (hypomyelination) or destruction (demyelination). Leukodystrophies are also classified by the region of the brain or in some cases peripheral nerves that are affected.

Alexander Disease is a leukodystrophy characterized by a confluent pattern of demyelination. It is caused by autosomal dominant gain-of-function mutation in the GFAP (glial fibrillary acidic protein) gene. GFAP serves an intermediate filament protein of mature astrocytes; incorrect formation of the protein can lead to astrocyte cytoskeletal collapse and abnormal protein aggregation. Clinically, this can lead to innumerable neurologic manifestations in the affected individual. Alexander Disease predominantly affects neonates, infants, children and rarely adults.

We describe a familial cohort of adult-onset Alexander Disease associated with a c.758C>G (p.A253G) mutation of GFAP.  This mutation has previously been described in neonates. In this case series we describe the clinical and radiologic features of three sisters with adult-onset symptoms.  The first patient is a 53-year-old female who presented with progressive myelopathy and later developed bulbar symptoms. Her 51-year-old sister developed progressive, bilateral leg weakness and gait disturbance.  She progressed to have profound cognitive dysfunction.  The MRI features include T2 hyperintensities with atrophy in the midbrain and upper cervical spine with peripheral rim brainstem and periventricular garlands.