RARE DISEASE
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
Synonyms: ALSP, Autosomal dominant leukoencephalopathy with neuroaxonal spheroids, FPSG, Familial dementia, Neumann type, Familial progressive subcortical gliosis, GPSC, HDLS, Hereditary diffuse leukoencephalopathy with spheroids, POLD, Pigmentary orthochromatic leukodystrophy, Subcortical gliosis of Neumann
Synonyms: ALSP, Autosomal dominant leukoencephalopathy with neuroaxonal spheroids, FPSG, Familial dementia, Neumann type, Familial progressive subcortical gliosis, GPSC, HDLS, Hereditary diffuse leukoencephalopathy with spheroids, POLD, Pigmentary orthochromatic leukodystrophy, Subcortical gliosis of Neumann
Synonyms: ALSP, Autosomal dominant leukoencephalopathy with neuroaxonal spheroids, FPSG, Familial dementia, Neumann type, Familial progressive subcortical gliosis, GPSC, HDLS, Hereditary diffuse leukoencephalopathy with spheroids, POLD, Pigmentary orthochromatic leukodystrophy, Subcortical gliosis of Neumann
Drug discovery
1
drug
With orphan designation
Overview
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive autosomal dominant neurodegenerative disorder caused by CSF1R gene mutations. It manifests in adulthood (mean onset ~43 years) with cognitive decline, neuropsychiatric symptoms, and motor dysfunction (parkinsonism, spasticity), progressing to severe disability and death within ~6-8 years. Diagnosis relies on MRI showing frontal-predominant white matter lesions, corpus callosum thinning, and genetic confirmation. No disease-modifying therapies exist, with care focused on symptom management [1][3][8].
Burden
Median survival: 6-8 years post-symptom onset, with late-stage patients requiring full-time care [1][8]
Caregivers report significant emotional/financial strain due to progressive cognitive/motor decline [1]
Economic burden: High hospitalization rates and loss of productivity in affected adults (prime working age) [1][8]
Therapies
Symptomatic management: Physical/occupational therapy, antidepressants, and antispasmodics [3][5]
Investigational approaches: Hematopoietic stem cell transplantation trials (preliminary data), microglia-targeted therapies in preclinical stages [5][8]
No approved disease-modifying treatments; misdiagnosis delays care in 68.5% of cases [5][8]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
49 drug discovery papers about Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
49 drug discovery papers about Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-25 | The ILLUMINATE natural history study in colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
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.
2026-05-18 | Clinical and genetic characteristics of CSF1R-related leukoencephalopathy: a retrospective analysis of three cases.
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.
2026-05-08 | Microglia beyond boundaries: Paradigm shifts in origin, distribution, state diversity, and therapeutic regeneration.
Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the "microglial lineage," which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.
2026-02-06 | CSF1R-related leukoencephalopathy presenting with early apathy, hypoactivity, and cognitive flattening: a case report of a diagnostic challenge.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant leukodystrophy primarily caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene, characterized by progressive cognitive and motor decline. We present a case of a 42-year-old Chinese woman with a rapidly progressive syndrome featuring prominent apathy, cognitive impairment, and hypoactivity. Brain magnetic resonance imaging (MRI) revealed extensive confluent white matter hyperintensities (Fazekas grade 3) predominantly in frontal and parietal lobes, cerebral atrophy, and thinning of the corpus callosum. Comprehensive genetic testing identified a heterozygous missense mutation in the CSF1R gene (c.2342C > T, p.Ala781Val), located within the tyrosine kinase domain, confirming the Diagnosis of HDLS. This case highlights early apathy and hypoactivity as red-flag manifestations of CSF1R-related leukoencephalopathy in a 42-year-old woman with rapidly progressive cognitive decline. The atypical presentation, initially mimicking psychiatric or demyelinating disease, underscores the need to consider CSF1R sequencing when encountering early-onset cognitive or behavioral deterioration with unexplained white-matter changes, thereby facilitating timely diagnosis and genetic counseling.
2025-12-15 | Case Report: A pharmacist-led precision therapy framework for managing invasive fungal infection in CSF1R-Related leukoencephalopathy post Allo-HSCT.
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. 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. 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. 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.
2026-07-25 | The ILLUMINATE natural history study in colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
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.
2026-05-18 | Clinical and genetic characteristics of CSF1R-related leukoencephalopathy: a retrospective analysis of three cases.
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.
2026-05-08 | Microglia beyond boundaries: Paradigm shifts in origin, distribution, state diversity, and therapeutic regeneration.
Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the "microglial lineage," which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.
2026-02-06 | CSF1R-related leukoencephalopathy presenting with early apathy, hypoactivity, and cognitive flattening: a case report of a diagnostic challenge.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant leukodystrophy primarily caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene, characterized by progressive cognitive and motor decline. We present a case of a 42-year-old Chinese woman with a rapidly progressive syndrome featuring prominent apathy, cognitive impairment, and hypoactivity. Brain magnetic resonance imaging (MRI) revealed extensive confluent white matter hyperintensities (Fazekas grade 3) predominantly in frontal and parietal lobes, cerebral atrophy, and thinning of the corpus callosum. Comprehensive genetic testing identified a heterozygous missense mutation in the CSF1R gene (c.2342C > T, p.Ala781Val), located within the tyrosine kinase domain, confirming the Diagnosis of HDLS. This case highlights early apathy and hypoactivity as red-flag manifestations of CSF1R-related leukoencephalopathy in a 42-year-old woman with rapidly progressive cognitive decline. The atypical presentation, initially mimicking psychiatric or demyelinating disease, underscores the need to consider CSF1R sequencing when encountering early-onset cognitive or behavioral deterioration with unexplained white-matter changes, thereby facilitating timely diagnosis and genetic counseling.
2025-12-15 | Case Report: A pharmacist-led precision therapy framework for managing invasive fungal infection in CSF1R-Related leukoencephalopathy post Allo-HSCT.
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. 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. 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. 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.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
1 orphan drug designation for Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
iluzanebart | antibodies | FDA | 2022-07-27 | — | Vigil Neuroscience, Inc. |
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