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

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.

INTRODUCTION: Hereditary diffuse leukoencephalopathy with spheroids (HDLS), caused by CSF1R mutations, is a rare autosomal dominant leukodystrophy characterized by rapid neurological decline. Hematopoietic stem cell transplantation (HSCT) is a promising treatment, but the risk of post-transplant complications such as invasive fungal disease (IFD) remains underexplored. Microglial dysfunction in CSF1R-related disorder (CRD) may further impair host immune defense. METHODS: We describe a Chinese male with a non-hotspot CSF1R mutation (c.2443-1G>C) who underwent allogeneic HSCT. A multidisciplinary team (MDT), including clinical pharmacists, implemented an individualized pharmacological strategy for antifungal management, guided by immune status, infection risk, pharmacokinetics, and next-generation pathogen diagnostics. RESULTS: Despite prophylaxis with voriconazole and levofloxacin, the patient developed febrile neutropenia and otitis media by day +16. Empirical meropenem therapy was ineffective, prompting escalation to teicoplanin and caspofungin. Pulmonary infection developed; targeted sequencing of bronchoalveolar lavage identified Aspergillus flavus. Antifungal therapy was intensified with voriconazole, resulting in clinical resolution by day +70. Treatment was maintained with good response. DISCUSSION: This case demonstrates the complexity of managing IFD in CSF1R-related disorder patients after HSCT. The interplay between systemic immunosuppression and intrinsic microglial dysfunction may heighten infection susceptibility. Precision antifungal therapy guided by multidisciplinary team expertise and pharmacological monitoring may improve outcomes in this rare and high-risk population.