Ataxia and autonomic dysfunction as presenting symptoms in late-onset Alexander disease.

Abstract

Alexander disease (AD) is a rare leukodystrophy first described in 1949 with infantile, juvenile, or adult-onset Alexander disease (AOAD).1 The pathophysiologic hallmark of AD is the presence of corkscrew-shaped intracytoplasmic eosinophilic inclusions in astrocytes (Rosenthal fibers) on histologic examination.2 A noninvasive diagnosis is possible since the discovery of the corresponding gene ( GFAP ) encoding the glial fibrillary acidic protein in 2001.3 An autosomal dominant transmission with 100% penetrance has been described, but many patients with AD have de novo mutations not found in either parent.3-6 Disease progression, clinical phenotype, and imaging findings in AD differ enormously according to the age at onset (AAO). The phenotype in the poor prognostic infantile AD (AAO <2 years) (seizures, cognitive decline, development deficit, and megalencephaly) is associated with white matter abnormalities predominantly in the frontal lobe but also in the basal ganglia, thalamus, and brainstem. In juvenile AD (AAO 2 years to mid-teens), the phenotype may consist of coordination, swallowing, and speech difficulties with a slower progression. In the slow progressive AOAD, which is sometimes associated with a palatal myoclonus or tremor,4 involvement of the brainstem or spinal cord reflects both the phenotype and MRI.4,5,7