To explore imaging phenotypes in juvenile- and adult-onset Alexander Disease (AxD).

AxD can be divided into Type I (onset <4 years) and Type II (juvenile or adult-onset) disease. The classic MRI characteristics for AxD include extensive frontally predominant white matter T2 hyperintensity, periventricular rim with high signal on T1-weighted images, basal ganglia, thalami, and brainstem abnormalities, and contrast enhancement. Type II AxD includes atypical MRI features such as brainstem, cerebellar, and spinal cord atrophy, and predominance of posterior WM abnormalities. However, further MRI phenotyping in Type II disease has not been described.

Participants in an AxD prospective natural history study with MRI scans available for analysis at the Children’s Hospital of Philadelphia were included. A neuroradiologist blinded to clinical data reviewed the baseline MRI scans for each subject and completed a detailed case report form, which included 23 variables capturing signal or tissue abnormality in distinct brain regions. Subjects were divided into imaging subtypes based on clear and recurring patterns.

The baseline scans for 57 AxD individuals (mean age 10.7 ± 16 years) were reviewed; 15 had clinical symptoms characteristic of Type II disease. Two phenotypes in this group emerged. The brainstem lesional group (N=8) had T2 hyperintensities in the brainstem in the absence of diffuse frontal disease. Basal ganglia and periventricular signal abnormalities were present but not universal. The remaining 7 subjects had predominant medullary, cerebellar, and cervical cord atrophy in the absence of other identifiable features of AxD.

MRI pattern recognition in leukodystrophies is critical for timely diagnosis and allows for targeted genetic testing.