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

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 Objectives: This paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for 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 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-