General description

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant disease. Recent studies have revealed that mutations in the colony stimulating factor 1 receptor (CSF1R) gene are prevalent among patients, suggesting that microglial dysfunction may be primary in ALSP.

Initially, Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids (HDLS) and Familial Pigmentary Orthochromatic Leukodystrophy (POLD) were considered separate diseases. However, recent studies have revealed that mutations in the CSF1R gene cause both conditions, leading to their unification under the term Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP).

Clinical manifestations

The primary clinical manifestations of ALSP include depressive mood, anxiety, abnormal behavior, and memory disturbance, typically starting in the 40s. A key characteristic of this disease is its rapid progression, leading to symptoms such as spastic paralysis, ataxia, parkinsonism, and loss of executive function, ultimately resulting in individuals becoming bed-bound within 5 years.

Radiographic features

White matter calcification

In ALSP, CT scans may occasionally reveal calcifications primarily located in the periventricular white matter.

Cerebral white matter hyperintensity

MRI findings in ALSP include bilateral hyperintensities in T2WI and FLAIR sequences affecting the parietotemporal white matter. Additionally, diffusion restriction is noted bilaterally and asymmetrically within the deep white matter of the cerebral hemispheres. It is important to note that the areas of diffusion restriction are often smaller than the corresponding T2WI hyperintense lesions, suggesting these may represent regions of ongoing degeneration. Specifically, MRI also shows bilateral hyperintensity in T2WI and FLAIR affecting the posterior limb of the internal capsule and the pyramidal tract of the brainstem.

Corpus callosum atrophy and T2WI/FLAIR hyperintensity

Further imaging studies in ALSP demonstrate atrophy in both cerebral and cerebellar parenchyma. In addition, atrophy of corpus callosum accompanied by T2WI/FLAIR hyperintensity is observed.

Differential diagnosis

The clinical manifestations and imaging findings of ALSP strongly resemble those of Leukoencephalopathy caused by autosomal recessive mutations in the mitochondrial alanyl-tRNA synthetase gene (AARS2 leukoencephalopathy).

However, there are notable differences in imaging characteristics; for instance, white matter calcifications, often observed in ALSP, are not typically seen in AARS2 leukoencephalopathy.

Unique to AARS2 leukoencephalopathy among leukodystrophies is the exclusive occurrence of ovarian failure, highlighting its distinct association with reproductive health issues.

The onset of AARS2 leukoencephalopathy typically occurs in individuals in their 20s to 30s, whereas ALSP generally manifests later, with onset usually in the 40s.