Unusual presentations and intrafamilial phenotypic variability in infantile onset Alexander disease

Alexander disease is an hereditary leukodystrophy related to mutations of GFAP. Classically AxD was divided in infantile, juvenile, and adult subgroups. Recent data suggested considering only two subtypes: type I (infantile onset with lesions extending to the cerebral hemispheres); type II (adult onset with primary involvement of subtentorial structures). We report two related and one unrelated patients presenting with a peculiar association of clinical and neuroradiological features. GFAP analysis disclosed the presence of one novel and two previously reported mutations. Our patients underline the importance of considering AxD in patients with bulbar symptoms and autonomic dysfunction even if MRI shows only posterior fossa abnormalities, supporting the hypothesis of a third type of AxD sharing features of both type I and type II. The evidence of an intrafamilial phenotypic variability suggests the possible role of still unknown factors influencing the effect of GFAP mutation and determining the phenotype.