Report of A Family with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) Without Mutations in CSF1R, AARS1 or AARS2

Background: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare neurodegenerative disorder with characteristic clinicopathological features. Identification of pathogenic mutations in CSF1R, AARS1, and AARS2 genes led to increased recognition and diagnosis of the ALSP. Objectives: This paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for CSF1R, AARS1, and AARS2 mutations. Methods: The index case was a 30-year-old male who presented with gait difficulty, followed by cognitive decline and incontinence. Results: Neurological examination evidenced progressive dementia, dysarthria, spasticity, parkinsonism, and severe gait disturbances. Brain MRI showed confluent white matter abnormalities with scattered foci of restricted diffusion, and atrophy of the corpus callosum. He was suspected of ALSP; however, the extensive genetic work-up did not find pathogenic mutation. He died at 33 years, and brain autopsy was performed. He had myelin staining pallor and axonal swellings, spheroids, and pigmented glia in affected white matter. His father developed similar symptoms in his early 40s and died at 46 years. Neuropathological examination also confirmed ALSP diagnosis. We found two similar cases in the literature with typical ALSP features but negative for CSF1R mutation; however, none were tested for AARS1 and AARS2 mutations. Conclusions: We draw attention to a new entity within the ALSP disease spectrum that needs further investigation. As the disease-modifying therapy is already available for ALSP-CSF1R, there is a strong need to identify the genetic cause of patients such as these in the ALSP spectrum, enabling research toward implementing effective treatment.