神経軸索スフェロイド形成を伴う遺伝性びまん性白質脳症

Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.

We report the first autopsy-proven case of colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy harboring the CSF1R mutation c.2320T>C (p.Cys774Arg). The patient, a man in his 40s, exhibited progressive neuropsychiatric symptoms with predominant frontal white matter lesions and corpus callosum atrophy. Neuropathological examination revealed frontal-predominant demyelination with a relatively low number of axonal spheroids compared with typical cases, as well as the absence of intracranial calcifications. In addition, prominent cerebral amyloid angiopathy was observed despite an APOE ε3/ε3 genotype. These findings expand the clinicopathological spectrum of CSF1R-related leukoencephalopathy and highlight variability in pathological features associated with different CSF1R mutations.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant neurodegenerative disorder caused by CSF1R variants, which lead to microglial dysfunction and progressive white matter degeneration. This study identified CSF1R variants in three unrelated Chinese patients with HDLS. We identified heterozygous CSF1R variants (NM_001288705.3) in three unrelated Chinese patients with HDLS: c.2522 A > C/p.(Tyr841Ser), c.2442 + 1G > A/p.?, and c.2546_2548del/p.(Phe849del). While the former two variants were categorized as likely pathogenic under the American College of Medical Genetics and Genomics framework, the latter (c.2546_2548del) was classified as a variant of uncertain significance due to insufficient evidence at the time of analysis. All patients exhibited cognitive decline, personality changes, and motor symptoms. Brain MRI showed characteristic diffuse white matter hyperintensities, restricted diffusion, corpus callosum atrophy, and brain atrophy. Symptoms progressed in Patient 1 (c.2522 A > C p.(Tyr841Ser)) and Patient 3 (c.2546_2548del p.(Phe849del)) despite standard symptomatic treatments. Clinical status remained relatively stable in Patient 2 (c.2442 + 1G > A/p.?) following allogeneic hematopoietic stem cell transplantation (HSCT). These findings expand the molecular and clinical spectrum of CSF1R in Chinese populations and highlight the diagnostic value of genetic sequencing in adult-onset leukoencephalopathies. Establishing a precise molecular diagnosis is crucial, as allogeneic HSCT remains a potentially disease-modifying therapy for patients with CSF1R-related leukoencephalopathy. Further longitudinal studies are warranted to evaluate the long-term efficacy of HSCT and to explore emerging targeted therapeutic strategies.

INTRODUCTION: Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, progressive, fatal neurodegenerative disorder caused by pathogenic CSF1R gene variants, resulting in microglial dysfunction and neurodegeneration. In patients with CSF1R-ALSP, brain magnetic resonance imaging (MRI) shows early white matter lesions followed by brain atrophy accompanied by progressive cognitive, neuropsychiatric, and motor dysfunction. However, the natural history (NH) of this disease is not yet fully understood. METHODS: This study examined clinical features, brain MRI findings, and fluid biomarkers in a cohort of 16 symptomatic adults from Germany with genetically confirmed CSF1R-ALSP using a retrospective chart review to evaluate changes in symptoms and imaging during disease progression. RESULTS: In this cohort, median age of symptom onset was 45 years and disease duration varied widely (2‒15 years). The most common presenting clinical symptoms were cognitive impairment (81% of patients) and aphasia (63% of patients), which progressed rapidly over 24 months of observation. Scores for the Montreal Cognitive Assessment and the Barthel Index of independence in performing activities of daily living declined sharply during the observational period. MRI data showed white matter degeneration and brain atrophy accompanied by increased ventricular volume with significant annual progression. Significant correlations were observed between key volumetric MRI measures and clinical outcome assessments of cognition and functional independence. CONCLUSION: This retrospective study provides qualitative and quantitative data from the clinical setting for further characterization of the NH of CSF1R-ALSP, a rare neurological disorder with significant unmet medical need. Data will inform the design of and endpoint selection for future NH studies and interventional clinical trials, which will be central to the development of safe and efficacious therapies for CSF1R-ALSP. Further, it will guide clinicians less familiar with the disease in providing patients and caregivers with appropriate support and information about CSF1R-ALSP.

CSF1R-related disorder (CSF1R-RD) is a rare neurodegenerative disorder linked to mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. Over 200 mutations and diverse clinicoradiographic phenotypes have been described thus far. This case series presents three patients with two CSF1R mutations (I827N and S840C) of which the S840C mutation is novel. We detail their clinical presentations, diagnostic evaluations, and the autopsy findings for one case associated with the I827N mutation, offering new insights into the pathology of this disease.