General description

Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene, leading to the formation of Rosenthal fibers composed of GFAP, αB-crystallin, and heat shock proteins in astrocytes. The disease is classified into three clinical types: infantile, juvenile, and adult, based on the age of onset and clinical progression.

Alexander disease is primarily caused by GFAP gene mutations, with 97% of cases showing these mutations. The accumulation of abnormal GFAP aggregates is believed to be a key factor in the disease's pathology, affecting astrocyte function by inhibiting molecular chaperones and proteasome function.

• Infantile type: This is the most common and severe form, typically presenting in infancy with seizures, macrocephaly, developmental delays, and hydrocephalus or increased intracranial pressure. Most cases have poor outcomes, with many patients dying by the age of 2-3.
• Juvenile type: Onset occurs during childhood or later, with symptoms such as muscle weakness, spastic paralysis, and bulbar symptoms. Progression is generally slower compared to the infantile type, and familial cases are more frequent, with some asymptomatic individuals.
• Adult type: Symptoms vary widely and can include spastic paraplegia, bulbar or pseudobulbar palsy, palatal myoclonus, cerebellar ataxia, and dementia. Unlike the infantile type, macrocephaly is not typically seen in adult cases.

The definitive diagnosis of Alexander disease is made by detecting Rosenthal fibers in brain tissue. Elevated levels of αB-crystallin and heat shock proteins in the cerebrospinal fluid further support the diagnosis, as these are components of the Rosenthal fibers.

Radiographic features

Infantile type

MRI shows bilateral symmetric abnormal signals in the frontal lobes. T2WI reveals bilateral hyperintensity, while T1WI shows bilateral hypointensity, except in the periventricular white matter, where T2WI demonstrates hypointensity and T1WI displays hyperintensity, known as the 'periventricular rim.' Contrast enhancement is observed in this periventricular rim. A characteristic imaging finding in Alexander disease is ring enhancement around the frontal horns of the lateral ventricles.

On CT, there is diffuse hypoattenuation in the white matter and hyperattenuation in the periventricular rim, reflecting the accumulation of Rosenthal fibers.

In MRI, Alexander disease is diagnosed based on the presence of four typical imaging findings:

1. High signal intensity on T2-weighted images in the cerebral white matter, predominantly in the frontal regions.
2. A periventricular rim, which appears as high attenuation on CT and shows signal shortening on both T1- and T2-weighted images.
3. Swelling or high signal intensity on T2-weighted images in the basal ganglia and thalamus.
4. High signal intensity on T2-weighted images particularly affecting the midbrain and medulla.
5. Abnormal contrast enhancement in areas such as the periventricular region, frontal lobe white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, or brainstem.

Juvenile type

Imaging studies reveal findings similar to the infantile type, typically showing abnormalities in the brainstem.

Adult type

In adult-onset Alexander disease, there is no abnormality in the cerebral white matter, but significant atrophy and T2WI/FLAIR hyperintensity of the medulla and cervical spinal cord is present, while the pons remains preserved, creating a characteristic 'tadpole appearance.'

FLAIR shows hyperintensity in the pia mater of the medulla, occasionally extending to the pons and midbrain. T2WI and FLAIR occasionally show hyperintensity in the middle cerebellar peduncles and dentate nuclei.

These findings may also be observed in Adult polyglucosan body disease (APBD).