Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

Abstract

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

Chitotriosidase is a biomarker for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia

“…Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as CSF1R‐related leukoencephalopathy or Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), is a devastating disease characterised by rapidly progressive cognitive decline and motor impairment. First symptoms typically evolve in the fourth or fifth decade and include memory deficits, neuropsychiatric symptoms, and motor involvement 1–3 . Patients are often demented and wheelchair‐bound as early as 3 years after disease onset, and mean survival is 7 years 2 …”

“…First symptoms typically evolve in the fourth or fifth decade and include memory deficits, neuropsychiatric symptoms, and motor involvement. [1][2][3] Patients are often demented and wheelchair-bound as early as 3 years after disease onset, and mean survival is 7 years. 2 ALSP is an autosomal-dominant genetic disorder, implying a 50% risk of inheriting the disease for all first degree relatives.…”

The Primary Microglial Leukodystrophies: A Review

“…Since not all ALSP cases have been genetically identified, we cannot ignore the possibility that mutations in other genes might be causative of ALSP variants, whether or not linked to microglia. Recent clinical reviews have focused on the diagnosis of adult leukodystrophies, and particularly on “microglial leukoencephalopathies” [ 198 , 199 , 200 ]. Hematopoietic stem cell transplantation has been used in a few clinical trials with variable results [ 110 , 199 , 201 , 202 , 203 , 204 ].…”

“…Recent clinical reviews have focused on the diagnosis of adult leukodystrophies, and particularly on “microglial leukoencephalopathies” [ 198 , 199 , 200 ]. Hematopoietic stem cell transplantation has been used in a few clinical trials with variable results [ 110 , 199 , 201 , 202 , 203 , 204 ]. More specific attempts to treat CSF1R-microglial encephalopathy are focused on microglial-based therapies [ 205 ].…”

Rapidly progressive dementias — leukodystrophies as a potentially treatable cause

“…ALSP is caused by dominant variants in CSF1R, which lead to cognitive and motor decline, usually starting in the fourth or fifth decade of life (although onset in the third decade has been reported). Mean survival after diagnosis is 6.8 years, although both more rapid and more protracted forms have been reported 7 . Patients with ALSP are sometimes diagnosed with other forms of dementia, such as frontotemporal dementia, before the correct diagnosis is established.…”