Hereditary Diffuse Leukoencephalopathy with Spheroids

Mendelian MONDO:0800027 Pathograph 2 Show in embeddings browser leukodystrophy CSF1R-related disorder

Hereditary diffuse leukoencephalopathy with spheroids (HDLS), also known as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) or CSF1R-related leukoencephalopathy, is a rare, progressive white-matter neurodegenerative disease most commonly caused by heterozygous, typically autosomal dominant, pathogenic variants in CSF1R. CSF1R encodes the colony-stimulating factor 1 receptor, which is predominantly expressed on microglia, the resident brain macrophages. Impaired CSF1R signaling produces microglial dysfunction and a primary microgliopathy that drives demyelination, axonal degeneration with axonal spheroids, and accumulation of pigmented glia in cerebral white matter. Patients typically present in their 40s-50s with a frontotemporal-dementia-like phenotype, neuropsychiatric and personality changes, parkinsonism, pyramidal signs, gait disturbance, and seizures, progressing to a bedridden, vegetative state.

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2
Pathophys.
11
Phenotypes
2
Pathograph
1
Genes
4
Medical Actions
2
Trials
7
References
1
Deep Research
⚙

Pathophysiology

2
Impaired Microglial CSF1R Signaling
CSF1R encodes the colony-stimulating factor 1 receptor, a receptor tyrosine kinase expressed predominantly on microglia. Disease-causing variants cluster in the tyrosine kinase domain and impair CSF-1-stimulated receptor autophosphorylation, producing partial loss of CSF1R function (haploinsufficiency). Because CSF1R is a crucial mediator of microglial proliferation, survival, and differentiation, impaired signaling causes microglial dysfunction that initiates the disease.
microglial cell CL:0000129
macrophage colony-stimulating factor signaling pathway GO:0038145 ↓ DECREASED
macrophage colony-stimulating factor receptor activity GO:0005011 ↓ DECREASED
Downstream
White Matter Degeneration with Axonal Spheroids Microglial dysfunction from impaired CSF1R signaling drives downstream white-matter neurodegeneration with axonal spheroids and pigmented glia.
Show evidence (2 references)
PMID:22197934 SUPPORT In Vitro
"In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function."
The discovery paper shows that HDLS-causing CSF1R mutations abolish CSF-1-stimulated autophosphorylation, establishing partial loss of CSF1R function as the molecular lesion.
PMID:22197934 SUPPORT Human Clinical
"As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis."
Links impaired CSF1R signaling to microglial dysfunction as the central pathogenic mechanism.
White Matter Degeneration with Axonal Spheroids
As a primary microgliopathy, microglial dysfunction from impaired CSF1R signaling drives white-matter neurodegeneration. Pathology shows primary axonopathy followed by demyelination, with characteristic axonal spheroids and pigmented glia in affected cerebral white matter. In the Csf1r+/- mouse model, microgliosis and microglial transcriptomic alterations indicative of oxidative stress and demyelination are central, with elevated cerebral CSF-2 (GM-CSF) signaling implicated; monoallelic CSF2 deletion rescues most deficits, and elevated CSF2 is confirmed in human ALSP brains.
microglial cell CL:0000129 ⚠ ABNORMAL oligodendrocyte CL:0000128
myelination GO:0042552 ↓ DECREASED
Show evidence (5 references)
PMID:30429277 SUPPORT Human Clinical
"Primary axonopathy followed by demyelination was suggested by pathology."
Describes the neuropathologic sequence of axonal degeneration preceding demyelination in CSF1R-related leukoencephalopathy.
PMID:30429277 SUPPORT Human Clinical
"Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies"
Establishes the disease as a primary microgliopathy driven by microglial CSF1R dysfunction.
PMID:32130903 SUPPORT Model Organism
"monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r+/- mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination"
Mouse model evidence that unbalanced CSF-1R/CSF-2 signaling drives microgliosis and demyelination, with rescue by lowering CSF-2.
+ 2 more references
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hereditary Diffuse Leukoencephalopathy with Spheroids Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Musculoskeletal 1
Spasticity Spasticity HP:0001257
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22934315 SUPPORT Human Clinical
"Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk."
GeneReviews describes spasticity and rigidity as part of the neurodegenerative progression.
Nervous System 7
Cognitive impairment Cognitive impairment HP:0100543
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:36559271 SUPPORT Human Clinical
"Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%)."
Cohort data: cognitive impairment was the most common initial manifestation (43% of patients), establishing it as a core early feature.
Personality and behavioral changes Personality changes HP:0000751
Show evidence (1 reference)
PMID:22197934 SUPPORT Human Clinical
"an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
Lists personality and behavioral changes among the variable clinical presentations of HDLS.
Depression Depression HP:0000716
Show evidence (1 reference)
PMID:22197934 SUPPORT Human Clinical
"including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
Depression is listed among the variable clinical presentations of HDLS.
Parkinsonism Parkinsonism HP:0001300
Show evidence (1 reference)
PMID:22197934 SUPPORT Human Clinical
"including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
Parkinsonism is listed among the variable clinical presentations of HDLS.
Gait disturbance Gait disturbance HP:0001288
Show evidence (1 reference)
PMID:36559271 SUPPORT Human Clinical
"Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%)."
Gait problems were the second most frequent initial manifestation in the HSCT cohort.
Seizures Seizure HP:0001250
Show evidence (1 reference)
PMID:22197934 SUPPORT Human Clinical
"including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
Seizures are listed among the variable clinical presentations of HDLS.
Cerebral white matter abnormality Abnormal cerebral white matter morphology HP:0002500
Show evidence (1 reference)
PMID:30429277 SUPPORT Human Clinical
"On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks."
White matter abnormalities are a hallmark imaging feature of CSF1R-related leukoencephalopathy.
Other 3
Dementia Frontotemporal dementia HP:0002145
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:30429277 SUPPORT Human Clinical
"Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs."
Establishes frontotemporal-dementia-like cognitive decline as the typical presentation.
Thin corpus callosum Thin corpus callosum HP:0033725
Show evidence (1 reference)
PMID:30429277 SUPPORT Human Clinical
"thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks"
Corpus callosum thinning is listed as an imaging hallmark.
Cerebral calcification Cerebral calcification HP:0002514
Show evidence (1 reference)
PMID:30429277 SUPPORT Human Clinical
"thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks"
Brain calcifications are listed as an imaging hallmark of the disease.
🧬

Genetic Associations

1
CSF1R (Causative)
Gene: CSF1R hgnc:2433 relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant Autosomal recessive
Show evidence (2 references)
PMID:22197934 SUPPORT Human Clinical
"We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS."
Identifies CSF1R tyrosine-kinase-domain mutations as the cause of HDLS in 14 families.
PMID:22934315 SUPPORT Human Clinical
"Late-onset CSF1R-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner"
GeneReviews confirms autosomal dominant inheritance for the typical late-onset form.
💊

Medical Actions

4
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantation MAXO:0001479
HSCT is an emerging disease-modifying therapy increasingly offered to patients with CSF1R-ALSP, aiming to replace dysfunctional CSF1R-mutant microglia/brain macrophages with donor-derived cells. Outcomes are variable: gait problems as the predominant manifestation and younger age at transplant predict better outcomes, whereas a high burden of cognitive symptoms predicts worse outcomes.
Show evidence (3 references)
PMID:36559271 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP."
Documents HSCT as an emerging therapy increasingly used in CSF1R-ALSP.
PMID:36559271 PARTIAL Human Clinical
"gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT."
Outcomes are variable and depend on phenotype/timing, so HSCT benefit is partial and patient-dependent.
PMID:31840744 SUPPORT Human Clinical
"Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche."
Provides the mechanistic rationale for HSCT in ALSP: donor-derived myeloid cells with wild-type CSF1R engraft the brain and repopulate the dysfunctional microglial niche. The two-patient series showed MRI stabilization and partial clinical stabilization at >2 years.
Supportive and Multidisciplinary Care
Action: supportive care MAXO:0000950
Mainstay management is multidisciplinary supportive care, including neurology, neuropsychological rehabilitation, physical, occupational, and speech-language therapy, psychotherapy, social support, and genetic counseling. Sedatives, antipsychotics, and other medications that decrease alertness or increase fall risk should be used cautiously in individuals with gait problems and cognitive decline.
Show evidence (2 references)
PMID:22934315 SUPPORT Human Clinical
"Multidisciplinary care by specialists in neurology, psychotherapy, neuropsychological rehabilitation, physical therapy, occupational therapy, speech-language therapy, social services for family support, and genetic counseling."
GeneReviews specifies multidisciplinary supportive care as the management approach.
PMID:22934315 SUPPORT Human Clinical
"sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously"
GeneReviews "Agents/circumstances to avoid": caution with sedatives and antipsychotics in patients with gait problems and cognitive decline.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling is recommended given autosomal dominant (and, for biallelic early-onset disease, autosomal recessive) inheritance; predictive and prenatal/preimplantation genetic testing are possible once the familial CSF1R variant is known.
Show evidence (1 reference)
PMID:22934315 SUPPORT Human Clinical
"predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for CSF1R-related disorder are possible"
GeneReviews supports genetic counseling and predictive/prenatal testing once the familial variant is identified.
iPSC-Derived Microglia Transplantation (experimental)
Action: cellular therapy MAXO:0000016
An emerging, preclinical microglia-replacement strategy. Transplantation of human iPSC-derived microglial (iMG) progenitors into a microglia-deficient (Csf1r FIRE-enhancer-deleted) ALSP mouse model restores a homeostatic microglial signature and prevents axonal spheroids, white-matter abnormalities, reactive astrocytosis, and brain calcifications. CRISPR-corrected ALSP-patient-derived iMG can reverse pre-existing pathology, supporting iMG transplantation as a candidate disease-modifying therapy. Not yet in human use.
Show evidence (2 references)
PMID:38897209 SUPPORT Model Organism
"transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications"
Preclinical proof of concept that iMG transplantation prevents ALSP-like neuropathology in the FIRE mouse model.
PMID:38897209 SUPPORT Model Organism
"transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies"
Transplantation of CRISPR-corrected patient-derived iMG into the ALSP mouse model reverses established pathology, supporting gene-corrected autologous microglia replacement as a therapeutic avenue.
🔬

Clinical Trials

2
NCT05677659 PHASE_II TERMINATED
The Ignite Study: a Phase 2, open-label study of iluzanebart (VGL101), a TREM2 agonist monoclonal antibody, in CSF1R-mutation-confirmed ALSP patients, evaluating safety, tolerability, and effects on imaging and disease-progression biomarkers. The trial was subsequently terminated (status reflected on ClinicalTrials.gov).
Target Phenotypes: Abnormal cerebral white matter morphology HP:0002500 Cognitive impairment HP:0100543
Show evidence (1 reference)
clinicaltrials:NCT05677659 SUPPORT
"This is a multicenter, open-label study to assess the safety and tolerability of iluzanebart (also referred to as VGL101) in subjects with documentation of a gene mutation in the CSF1R gene for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)"
Documents a Phase 2 trial of the TREM2 agonist iluzanebart (VGL101) in genetically confirmed ALSP patients.
NCT04503213 ENROLLING_BY_INVITATION
Longitudinal observational study at Mayo Clinic assessing the effect of hematopoietic stem cell transplantation on symptoms of CSF1R-related leukoencephalopathy.
Target Phenotypes: Cognitive impairment HP:0100543
Show evidence (1 reference)
clinicaltrials:NCT04503213 SUPPORT
"The purpose of this study is to measure the effect of Hematopoietic Stem Cell Transplantation (HSCT) on symptoms of CSF1R-related Leukoencephalopathy."
Observational study tracking outcomes of HSCT, the leading disease-modifying intervention, in CSF1R-related leukoencephalopathy.
{ }

Source YAML

click to show 
name: Hereditary Diffuse Leukoencephalopathy with Spheroids
creation_date: "2026-06-04T00:00:00Z"
category: Mendelian
synonyms:
- ALSP
- HDLS
- Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
- CSF1R-related leukoencephalopathy
disease_term:
  preferred_term: Hereditary diffuse leukoencephalopathy with spheroids
  term:
    id: MONDO:0800027
    label: leukoencephalopathy, diffuse hereditary, with spheroids 1
parents:
  - leukodystrophy
  - CSF1R-related disorder
description: >
  Hereditary diffuse leukoencephalopathy with spheroids (HDLS), also known as
  adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
  (ALSP) or CSF1R-related leukoencephalopathy, is a rare, progressive
  white-matter neurodegenerative disease most commonly caused by heterozygous,
  typically autosomal dominant, pathogenic variants in CSF1R. CSF1R encodes the
  colony-stimulating factor 1 receptor, which is predominantly expressed on
  microglia, the resident brain macrophages. Impaired CSF1R signaling produces
  microglial dysfunction and a primary microgliopathy that drives demyelination,
  axonal degeneration with axonal spheroids, and accumulation of pigmented glia
  in cerebral white matter. Patients typically present in their 40s-50s with a
  frontotemporal-dementia-like phenotype, neuropsychiatric and personality
  changes, parkinsonism, pyramidal signs, gait disturbance, and seizures,
  progressing to a bedridden, vegetative state.

references:
  - reference: PMID:22934315
    title: "CSF1R-Related Disorder."
    tags:
      - GeneReviews
  - reference: PMID:22197934
    title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
  - reference: PMID:30429277
    title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
  - reference: PMID:32130903
    title: "Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling."
  - reference: PMID:31840744
    title: "Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia."
  - reference: PMID:36559271
    title: "Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes."
  - reference: PMID:38897209
    title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."

pathophysiology:
- name: Impaired Microglial CSF1R Signaling
  description: >
    CSF1R encodes the colony-stimulating factor 1 receptor, a receptor tyrosine
    kinase expressed predominantly on microglia. Disease-causing variants
    cluster in the tyrosine kinase domain and impair CSF-1-stimulated receptor
    autophosphorylation, producing partial loss of CSF1R function
    (haploinsufficiency). Because CSF1R is a crucial mediator of microglial
    proliferation, survival, and differentiation, impaired signaling causes
    microglial dysfunction that initiates the disease.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: macrophage colony-stimulating factor signaling pathway
    term:
      id: GO:0038145
      label: macrophage colony-stimulating factor signaling pathway
    modifier: DECREASED
  molecular_functions:
  - preferred_term: macrophage colony-stimulating factor receptor activity
    term:
      id: GO:0005011
      label: macrophage colony-stimulating factor receptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function."
    explanation: >
      The discovery paper shows that HDLS-causing CSF1R mutations abolish
      CSF-1-stimulated autophosphorylation, establishing partial loss of CSF1R
      function as the molecular lesion.
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis."
    explanation: >
      Links impaired CSF1R signaling to microglial dysfunction as the central
      pathogenic mechanism.
  downstream:
  - target: White Matter Degeneration with Axonal Spheroids
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Microglial dysfunction from impaired CSF1R signaling drives downstream
      white-matter neurodegeneration with axonal spheroids and pigmented glia.
    evidence:
    - reference: PMID:30429277
      reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies"
      explanation: >
        Establishes that microglial CSF1R dysfunction is the upstream driver of
        the downstream white-matter neurodegeneration, supporting this causal edge.

- name: White Matter Degeneration with Axonal Spheroids
  description: >
    As a primary microgliopathy, microglial dysfunction from impaired CSF1R
    signaling drives white-matter neurodegeneration. Pathology shows primary
    axonopathy followed by demyelination, with characteristic axonal spheroids
    and pigmented glia in affected cerebral white matter. In the Csf1r+/- mouse
    model, microgliosis and microglial transcriptomic alterations indicative of
    oxidative stress and demyelination are central, with elevated cerebral CSF-2
    (GM-CSF) signaling implicated; monoallelic CSF2 deletion rescues most
    deficits, and elevated CSF2 is confirmed in human ALSP brains.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
    modifier: ABNORMAL
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:30429277
    reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary axonopathy followed by demyelination was suggested by pathology."
    explanation: >
      Describes the neuropathologic sequence of axonal degeneration preceding
      demyelination in CSF1R-related leukoencephalopathy.
  - reference: PMID:30429277
    reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies"
    explanation: >
      Establishes the disease as a primary microgliopathy driven by microglial
      CSF1R dysfunction.
  - reference: PMID:32130903
    reference_title: "Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r+/- mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination"
    explanation: >
      Mouse model evidence that unbalanced CSF-1R/CSF-2 signaling drives
      microgliosis and demyelination, with rescue by lowering CSF-2.
  - reference: PMID:32130903
    reference_title: "Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also show elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients, demonstrating that the mechanisms identified in the mouse model are functional in humans."
    explanation: >
      Confirms in human ALSP brains the elevated CSF-2 signaling implicated in
      the mouse model, supporting human relevance of the mechanism.
  - reference: PMID:38897209
    reference_title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP"
    explanation: >
      A Csf1r-FIRE-enhancer-deficient (microglia-depleted) mouse recapitulates
      nearly all hallmark ALSP pathologies, confirming that loss of microglial
      CSF1R function is sufficient to drive the white-matter neurodegeneration.

phenotypes:
- category: Neurologic
  name: Dementia
  description: >
    Progressive cognitive decline with a frontotemporal-dementia-like phenotype
    is the typical presenting feature, usually beginning in the 40s-50s.
  phenotype_term:
    preferred_term: Frontotemporal dementia
    term:
      id: HP:0002145
      label: Frontotemporal dementia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30429277
    reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs."
    explanation: >
      Establishes frontotemporal-dementia-like cognitive decline as the typical
      presentation.

- category: Neurologic
  name: Cognitive impairment
  description: >
    Cognitive impairment is the most frequent initial manifestation across
    CSF1R-ALSP cohorts.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36559271
    reference_title: "Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%)."
    explanation: >
      Cohort data: cognitive impairment was the most common initial
      manifestation (43% of patients), establishing it as a core early feature.

- category: Neuropsychiatric
  name: Personality and behavioral changes
  description: >
    Personality changes, behavioral disturbance, and neuropsychiatric symptoms
    are common early features, often resembling psychiatric disease.
  phenotype_term:
    preferred_term: Personality changes
    term:
      id: HP:0000751
      label: Personality changes
  evidence:
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
    explanation: >
      Lists personality and behavioral changes among the variable clinical
      presentations of HDLS.

- category: Neuropsychiatric
  name: Depression
  description: Depression is a recognized clinical presentation of HDLS.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
    explanation: >
      Depression is listed among the variable clinical presentations of HDLS.

- category: Neurologic
  name: Parkinsonism
  description: >
    Extrapyramidal features including parkinsonism are common motor
    manifestations.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
    explanation: >
      Parkinsonism is listed among the variable clinical presentations of HDLS.

- category: Neurologic
  name: Spasticity
  description: >
    Pyramidal involvement with spasticity and rigidity develops as the disease
    progresses; most affected individuals eventually become bedridden.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk."
    explanation: >
      GeneReviews describes spasticity and rigidity as part of the
      neurodegenerative progression.

- category: Neurologic
  name: Gait disturbance
  description: >
    Gait problems are a common initial manifestation and, when predominant,
    indicate a milder phenotype with better response to HSCT.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:36559271
    reference_title: "Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%)."
    explanation: >
      Gait problems were the second most frequent initial manifestation in the
      HSCT cohort.

- category: Neurologic
  name: Seizures
  description: Epilepsy/seizures occur as part of the phenotypic spectrum.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes"
    explanation: >
      Seizures are listed among the variable clinical presentations of HDLS.

- category: Neuroradiologic
  name: Cerebral white matter abnormality
  description: >
    Brain MRI shows abnormal cerebral white matter, a defining radiologic
    feature of the disease.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:30429277
    reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks."
    explanation: >
      White matter abnormalities are a hallmark imaging feature of
      CSF1R-related leukoencephalopathy.

- category: Neuroradiologic
  name: Thin corpus callosum
  description: >
    Thinning of the corpus callosum is a characteristic imaging hallmark.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:30429277
    reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks"
    explanation: >
      Corpus callosum thinning is listed as an imaging hallmark.

- category: Neuroradiologic
  name: Cerebral calcification
  description: >
    Brain (white matter) calcifications are a hallmark imaging feature.
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  evidence:
  - reference: PMID:30429277
    reference_title: "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks"
    explanation: >
      Brain calcifications are listed as an imaging hallmark of the disease.

genetic:
- name: CSF1R
  gene_term:
    preferred_term: CSF1R
    term:
      id: hgnc:2433
      label: CSF1R
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >
      Late-onset disease is typically caused by a heterozygous CSF1R variant
      inherited in an autosomal dominant manner.
    evidence:
    - reference: PMID:22934315
      reference_title: "CSF1R-Related Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Late-onset CSF1R-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner"
      explanation: >
        GeneReviews confirms autosomal dominant inheritance for the typical
        late-onset form caused by a heterozygous CSF1R variant.
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >
      Early-onset disease is typically caused by biallelic CSF1R variants
      inherited in an autosomal recessive manner.
    evidence:
    - reference: PMID:22934315
      reference_title: "CSF1R-Related Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early-onset CSF1R-related disorder is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner"
      explanation: >
        GeneReviews confirms autosomal recessive inheritance for early-onset
        disease caused by biallelic CSF1R variants.
  notes: >
    Heterozygous pathogenic variants in CSF1R, clustering in the tyrosine kinase
    domain, are the most common cause of ALSP/HDLS. More than 70 different
    mutations have been identified worldwide.
  evidence:
  - reference: PMID:22197934
    reference_title: "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS."
    explanation: >
      Identifies CSF1R tyrosine-kinase-domain mutations as the cause of HDLS in
      14 families.
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late-onset CSF1R-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner"
    explanation: >
      GeneReviews confirms autosomal dominant inheritance for the typical
      late-onset form.

treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >
    HSCT is an emerging disease-modifying therapy increasingly offered to
    patients with CSF1R-ALSP, aiming to replace dysfunctional CSF1R-mutant
    microglia/brain macrophages with donor-derived cells. Outcomes are variable:
    gait problems as the predominant manifestation and younger age at transplant
    predict better outcomes, whereas a high burden of cognitive symptoms
    predicts worse outcomes.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: MAXO:0001479
      label: allogeneic hematopoietic stem cell transplantation
  evidence:
  - reference: PMID:36559271
    reference_title: "Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP."
    explanation: >
      Documents HSCT as an emerging therapy increasingly used in CSF1R-ALSP.
  - reference: PMID:36559271
    reference_title: "Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT."
    explanation: >
      Outcomes are variable and depend on phenotype/timing, so HSCT benefit is
      partial and patient-dependent.
  - reference: PMID:31840744
    reference_title: "Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche."
    explanation: >
      Provides the mechanistic rationale for HSCT in ALSP: donor-derived myeloid
      cells with wild-type CSF1R engraft the brain and repopulate the dysfunctional
      microglial niche. The two-patient series showed MRI stabilization and partial
      clinical stabilization at >2 years.

- name: Supportive and Multidisciplinary Care
  description: >
    Mainstay management is multidisciplinary supportive care, including
    neurology, neuropsychological rehabilitation, physical, occupational, and
    speech-language therapy, psychotherapy, social support, and genetic
    counseling. Sedatives, antipsychotics, and other medications that decrease
    alertness or increase fall risk should be used cautiously in individuals
    with gait problems and cognitive decline.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multidisciplinary care by specialists in neurology, psychotherapy, neuropsychological rehabilitation, physical therapy, occupational therapy, speech-language therapy, social services for family support, and genetic counseling."
    explanation: >
      GeneReviews specifies multidisciplinary supportive care as the management
      approach.
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously"
    explanation: >
      GeneReviews "Agents/circumstances to avoid": caution with sedatives and
      antipsychotics in patients with gait problems and cognitive decline.

- name: Genetic Counseling
  description: >
    Genetic counseling is recommended given autosomal dominant (and, for
    biallelic early-onset disease, autosomal recessive) inheritance; predictive
    and prenatal/preimplantation genetic testing are possible once the familial
    CSF1R variant is known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for CSF1R-related disorder are possible"
    explanation: >
      GeneReviews supports genetic counseling and predictive/prenatal testing
      once the familial variant is identified.

- name: iPSC-Derived Microglia Transplantation (experimental)
  description: >
    An emerging, preclinical microglia-replacement strategy. Transplantation of
    human iPSC-derived microglial (iMG) progenitors into a microglia-deficient
    (Csf1r FIRE-enhancer-deleted) ALSP mouse model restores a homeostatic
    microglial signature and prevents axonal spheroids, white-matter
    abnormalities, reactive astrocytosis, and brain calcifications. CRISPR-corrected
    ALSP-patient-derived iMG can reverse pre-existing pathology, supporting iMG
    transplantation as a candidate disease-modifying therapy. Not yet in human use.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: cellular therapy
    term:
      id: MAXO:0000016
      label: cellular therapy
  evidence:
  - reference: PMID:38897209
    reference_title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications"
    explanation: >
      Preclinical proof of concept that iMG transplantation prevents ALSP-like
      neuropathology in the FIRE mouse model.
  - reference: PMID:38897209
    reference_title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies"
    explanation: >
      Transplantation of CRISPR-corrected patient-derived iMG into the ALSP mouse
      model reverses established pathology, supporting gene-corrected autologous
      microglia replacement as a therapeutic avenue.

clinical_trials:
- name: NCT05677659
  description: >
    The Ignite Study: a Phase 2, open-label study of iluzanebart (VGL101), a TREM2
    agonist monoclonal antibody, in CSF1R-mutation-confirmed ALSP patients,
    evaluating safety, tolerability, and effects on imaging and disease-progression
    biomarkers. The trial was subsequently terminated (status reflected on
    ClinicalTrials.gov).
  phase: PHASE_II
  status: TERMINATED
  target_phenotypes:
  - preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: clinicaltrials:NCT05677659
    reference_title: "A Phase 2 Safety, Tolerability, and Proof-of-Concept Study of VGL101 in Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia (ALSP) (The Ignite Study)"
    supports: SUPPORT
    snippet: "This is a multicenter, open-label study to assess the safety and tolerability of iluzanebart (also referred to as VGL101) in subjects with documentation of a gene mutation in the CSF1R gene for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)"
    explanation: >
      Documents a Phase 2 trial of the TREM2 agonist iluzanebart (VGL101) in
      genetically confirmed ALSP patients.
- name: NCT04503213
  description: >
    Longitudinal observational study at Mayo Clinic assessing the effect of
    hematopoietic stem cell transplantation on symptoms of CSF1R-related
    leukoencephalopathy.
  status: ENROLLING_BY_INVITATION
  target_phenotypes:
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: clinicaltrials:NCT04503213
    reference_title: "Longitudinal Assessment of CSF1R-Related Leukoencephalopathy Following Stem Cell Transplantation"
    supports: SUPPORT
    snippet: "The purpose of this study is to measure the effect of Hematopoietic Stem Cell Transplantation (HSCT) on symptoms of CSF1R-related Leukoencephalopathy."
    explanation: >
      Observational study tracking outcomes of HSCT, the leading disease-modifying
      intervention, in CSF1R-related leukoencephalopathy.
📚

References & Deep Research

References

7
PMID:22934315
CSF1R-Related Disorder.
No top-level findings curated for this source.
PMID:22197934
Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
No top-level findings curated for this source.
PMID:30429277
CSF1R-related leukoencephalopathy: A major player in primary microgliopathies.
No top-level findings curated for this source.
PMID:32130903
Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling.
No top-level findings curated for this source.
PMID:31840744
Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia.
No top-level findings curated for this source.
PMID:36559271
Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes.
No top-level findings curated for this source.
PMID:38897209
Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 58 citations 2026-06-04T00:54:19.235180

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Hereditary Diffuse Leukoencephalopathy with Spheroids
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Hereditary Diffuse Leukoencephalopathy with Spheroids covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Disease Characteristics Research Report: Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS) / CSF1R-related Leukoencephalopathy / ALSP

Executive summary

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is now generally considered part of the same clinicopathologic/genetic entity as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and historical “pigmentary orthochromatic leukodystrophy” (POLD), most commonly caused by autosomal-dominant pathogenic variants in CSF1R, a receptor tyrosine kinase essential for microglial differentiation and survival. (gelfand2020allogeneichsctfor pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 2-2) The disorder typically begins in the 40s, presents with cognitive and psychiatric/behavioral changes and progressive motor dysfunction, is frequently misdiagnosed, and progresses to severe disability and death over ~6–8 years on average. (papapetropoulos2024clinicalpresentationand pages 1-2, gelfand2020allogeneichsctfor pages 2-2) Hematopoietic stem cell transplantation (HSCT) is the principal disease-modifying approach in real-world clinical practice, with observational evidence for stabilization in selected patients when performed early enough; emerging translational work in 2024 provides strong preclinical evidence for microglia replacement (human iPSC-derived microglia transplantation) as a future therapeutic strategy. (dulski2022hematopoieticstemcell pages 1-2, chadarevian2024therapeuticpotentialof pages 1-3)

Summary table of key facts

Topic Key facts Sources / URLs
Disease names / synonyms Preferred modern umbrella terms include adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and CSF1R-related leukoencephalopathy. Historical synonyms include hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD); these are now considered part of the same CSF1R-related disease spectrum. (gelfand2020allogeneichsctfor pages 8-9, gelfand2020allogeneichsctfor pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 2-2, kim2025clinicalspectrumof pages 7-8) Gelfand et al., 2020, Brain, https://doi.org/10.1093/brain/awz390; Mickeviciute et al., 2022, J Intern Med, https://doi.org/10.1111/joim.13420; Papapetropoulos et al., 2024, Front Neurol, https://doi.org/10.3389/fneur.2024.1320663
Causal gene The principal causal gene is CSF1R (colony-stimulating factor 1 receptor). Most pathogenic variants cluster in the tyrosine kinase domain; one review/meta-analysis noted 96 CSF1R mutations in ~200 families, while a 2025 Korean report cited at least 106 CSF1R mutations reported worldwide. (kim2025clinicalspectrumof pages 6-7, mickeviciute2022neuroimagingphenotypesof pages 2-2, kim2025clinicalspectrumof pages 2-3) Mickeviciute et al., 2022, https://doi.org/10.1111/joim.13420; Kim et al., 2025, https://doi.org/10.1038/s41598-024-84665-w
Inheritance Usually autosomal dominant. Disease is typically caused by loss-of-function CSF1R variants, although mechanistic debate remains regarding haploinsufficiency vs dominant-negative effects for some alleles. (papapetropoulos2024clinicalpresentationand pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 2-2, chadarevian2024therapeuticpotentialof pages 13-15) Papapetropoulos et al., 2024, https://doi.org/10.3389/fneur.2024.1320663; Mickeviciute et al., 2022, https://doi.org/10.1111/joim.13420; Chadarevian et al., 2024, https://doi.org/10.1016/j.neuron.2024.05.023
Typical age of onset Mean age at symptom onset in a literature cohort of 291 patients was 43.2 ± 11.6 years; reported range 18–78 years. In a 2025 Korean cohort, mean onset was 47.5 years (range 37–63); CSF1R-mutation carriers had median onset 45.0 vs 63.0 years in non-carriers. Women showed slightly earlier onset (40 vs 43 years, p=0.041) in imaging meta-analysis. (papapetropoulos2024clinicalpresentationand pages 1-2, kim2025clinicalspectrumof pages 6-7, kim2025clinicalspectrumof pages 2-3, mickeviciute2022neuroimagingphenotypesof pages 1-1) Papapetropoulos et al., 2024, https://doi.org/10.3389/fneur.2024.1320663; Kim et al., 2025, https://doi.org/10.1038/s41598-024-84665-w; Mickeviciute et al., 2022, https://doi.org/10.1111/joim.13420
Most common presenting symptoms In the 291-case literature analysis, the most frequent initial symptoms were cognitive impairment 47.1% and behavioral/psychiatric abnormalities 26.8%. In the 2025 Korean cohort, overall clinical features included cognitive impairment 90%, psychiatric symptoms 70%, pyramidal signs 50%, parkinsonism 50%, and epilepsy 20%. (papapetropoulos2024clinicalpresentationand pages 1-2, kim2025clinicalspectrumof pages 2-3) Papapetropoulos et al., 2024, https://doi.org/10.3389/fneur.2024.1320663; Kim et al., 2025, https://doi.org/10.1038/s41598-024-84665-w
Misdiagnosis In the 291-case literature analysis, only 24.7% were accurately diagnosed initially; 75.3% were initially mis- or undiagnosed. Frequent initial misdiagnoses included frontotemporal dementia 9.6% and multiple sclerosis 7.2%. Mean delay between symptom onset and neuroimaging was 2.3 years in an imaging meta-analysis. (papapetropoulos2024clinicalpresentationand pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 1-1) Papapetropoulos et al., 2024, https://doi.org/10.3389/fneur.2024.1320663; Mickeviciute et al., 2022, https://doi.org/10.1111/joim.13420
Key MRI / CT findings Hallmark neuroimaging features include frontoparietal confluent white-matter lesions, corpus callosum thinning/atrophy, and persistent foci of restricted diffusion on DWI/ADC. CT often shows white-matter/parenchymal calcifications, sometimes with a stepping-stone appearance along the corpus callosum. Additional findings include corticospinal tract involvement, ventricular enlargement, brain atrophy, and occasional contrast enhancement. In the Korean cohort, bilateral white-matter hyperintensities were seen in 100%, corpus callosum thinning in 77.8%, splenial involvement in 80%, and DWI restriction in 62.5% of mutation carriers. (kim2025clinicalspectrumof pages 6-7, mickeviciute2022neuroimagingphenotypesof pages 1-1, mickeviciute2022neuroimagingphenotypesof pages 9-10, mickeviciute2022neuroimagingphenotypesof pages 8-8, mickeviciute2022neuroimagingphenotypesof pages 9-9) Mickeviciute et al., 2022, https://doi.org/10.1111/joim.13420; Kim et al., 2025, https://doi.org/10.1038/s41598-024-84665-w
Survival / disease duration ALSP/HDLS is a rapidly progressive, fatal disease. Literature synthesis cited death occurring at a median of about 6–8 years from symptom onset. Untreated disease is described as typically rapidly fatal in about ~7 years in the HSCT case-report literature. A 2026 retrospective cohort reported disease duration ranging 2–15 years. (papapetropoulos2024clinicalpresentationand pages 1-2, hayer2026naturalhistoryof pages 1-2, bergner2023casereporttreatment pages 2-4) Papapetropoulos et al., 2024, https://doi.org/10.3389/fneur.2024.1320663; Bergner et al., 2023, https://doi.org/10.3389/fneur.2023.1163107; Hayer et al., 2026, https://doi.org/10.1007/s40120-026-00916-0
Treatment approach: HSCT Allogeneic hematopoietic stem cell transplantation (HSCT) is the leading disease-modifying approach used clinically, aiming to replace defective microglia with donor-derived myeloid cells. In a 15-patient retrospective HSCT study, 6/15 (40.0%) had a “good” outcome; better outcomes were associated with gait-predominant onset, younger age at HSCT, and absence of cognitive-first presentation. In a 7-patient cohort, 6/7 trended toward stabilization, though 1 died periprocedurally. Two UCSF cases were alive at 26–28 months post-HSCT with stabilization of several domains and MRI diffusion abnormalities resolving after 2 years. (gelfand2020allogeneichsctfor pages 1-1, dulski2022hematopoieticstemcell pages 1-2, dulski2022hematopoieticstemcell pages 2-4, dulski2022hematopoieticstemcell pages 6-7, tipton2021treatmentofcsf1r‐related pages 1-2, bergner2023casereporttreatment pages 2-4) Gelfand et al., 2020, https://doi.org/10.1093/brain/awz390; Dulski et al., 2022, https://doi.org/10.3390/pharmaceutics14122778; Tipton et al., 2021, https://doi.org/10.1002/mds.28734; Bergner et al., 2023, https://doi.org/10.3389/fneur.2023.1163107
Treatment approach: microglia transplantation (preclinical) A major 2024 Neuron study showed that transplantation of human iPSC-derived microglial progenitors in an ALSP mouse model prevented axonal spheroids, white-matter abnormalities, reactive astrocytosis, and calcifications, while CRISPR-corrected patient-derived microglia reversed pre-existing spheroids, astrogliosis, and calcification. This is preclinical, not yet standard clinical care, but is one of the most important recent translational advances. (chadarevian2024therapeuticpotentialof pages 1-3, chadarevian2024therapeuticpotentialof pages 5-7, chadarevian2024therapeuticpotentialof pages 11-13, chadarevian2024therapeuticpotentialof pages 7-8) Chadarevian et al., 2024, Neuron, https://doi.org/10.1016/j.neuron.2024.05.023
Clinical trial: NCT05677659 NCT05677659 — A Study of VGL101 in Patients With ALSP; sponsor Vigil Neuroscience, Inc.; Phase 2, open-label, single-group; 20 participants; intervention VGL101/iluzanebart IV every ~4 weeks for 1 year. Status: TERMINATED. Termination reason: “No beneficial effects on biomarker or clinical efficacy endpoints.” (NCT05677659 chunk 1, NCT05677659 chunk 2) ClinicalTrials.gov, 2022, https://clinicaltrials.gov/study/NCT05677659
Clinical trial: NCT05020743 NCT05020743 — Natural History Study in ALSP; sponsor Vigil Neuroscience, Inc.; observational prospective cohort; 56 participants; no intervention. Status: TERMINATED; record links termination to lack of benefit in associated VGL101 program. Primary outcome emphasized MRI ventricular volume change over serial follow-up. (NCT05020743 chunk 1) ClinicalTrials.gov, 2021, https://clinicaltrials.gov/study/NCT05020743
Clinical trial: NCT04503213 NCT04503213 — A Study to Assess CSF1R-related Leukoencephalopathy After Stem Cell Transplantation; sponsor Mayo Clinic; observational prospective study; estimated 20 participants. Status: ENROLLING BY INVITATION. Primary outcome: stability/improvement in cognitive and motor function and radiographic markers over about 5 years after HSCT. (NCT04503213 chunk 1) ClinicalTrials.gov, 2020, https://clinicaltrials.gov/study/NCT04503213

Table: This table summarizes the main clinical, genetic, imaging, prognostic, and therapeutic facts for hereditary diffuse leukoencephalopathy with spheroids / ALSP from the provided evidence. It also highlights the most relevant current clinical trials and recent preclinical therapeutic advances.

1. Disease information

1.1 What is the disease?

HDLS/ALSP is a rare, adult-onset, progressive, fatal leukoencephalopathy characterized neuropathologically by axonal spheroids and pigmented glia, and genetically most often by CSF1R pathogenic variants. ALSP is described as an autosomal dominant leukoencephalopathy caused by CSF1R mutations and unifies the spectrum previously labeled HDLS and familial POLD. (gelfand2020allogeneichsctfor pages 1-2)

1.2 Key identifiers (OMIM, Orphanet, ICD-10/ICD-11, MeSH, MONDO)

The retrieved full-text evidence did not include explicit OMIM/Orphanet/ICD/MeSH/MONDO identifiers. Synonymy and preferred terminology are well supported in the primary literature and systematic reviews, but ontology IDs should be obtained directly from curated resources (OMIM/Orphanet/MONDO/MeSH/ICD) for database population. (gelfand2020allogeneichsctfor pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 2-2)

1.3 Synonyms and alternative names

Supported synonyms and related terms include: - Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) (gelfand2020allogeneichsctfor pages 1-2) - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) (gelfand2020allogeneichsctfor pages 1-2) - Pigmentary orthochromatic leukodystrophy (POLD) (gelfand2020allogeneichsctfor pages 1-2) - CSF1R-related leukoencephalopathy (gene-based umbrella term) (mickeviciute2022neuroimagingphenotypesof pages 2-2)

1.4 Evidence source type

The clinical picture and natural history are derived largely from aggregated disease-level resources (systematic reviews of case reports/series) and retrospective cohorts; disease-modifying therapy evidence is observational (case series/cohorts), and newest mechanism-focused advances are from preclinical model systems. (papapetropoulos2024clinicalpresentationand pages 1-2, dulski2022hematopoieticstemcell pages 1-2, chadarevian2024therapeuticpotentialof pages 1-3)

2. Etiology

2.1 Disease causal factors

Primary cause: heterozygous pathogenic variants in CSF1R (colony-stimulating factor 1 receptor). CSF1R is a transmembrane receptor tyrosine kinase regulating proliferation/differentiation/survival of monocytes/macrophages and microglia. (kraya2019functionalcharacterizationof pages 1-2) Most pathogenic variants cluster in the intracellular tyrosine kinase domain and abrogate kinase activity/autophosphorylation, impairing CSF1 responsiveness and microglial maintenance. (chadarevian2024therapeuticpotentialof pages 3-5, kraya2019functionalcharacterizationof pages 5-8)

2.2 Risk factors

Genetic risk factor: carrying a pathogenic/likely pathogenic CSF1R variant in an autosomal dominant context. (papapetropoulos2024clinicalpresentationand pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 2-2) Environmental/lifestyle risk factors: none were supported by the retrieved evidence; the disease is primarily a monogenic microgliopathy.

2.3 Protective factors

Evidence for protective factors is limited and hypothesis-generating. - Pre-symptomatic immunosuppression/glucocorticoids (hypothesis + case observation): A 2021 report described an asymptomatic CSF1R mutation carrier whose long-term immunosuppression (including prednisone) was hypothesized to be protective despite “high age-related penetrance (~95% by age 60)” cited by the authors, proposing glucocorticoids might correct maladaptive microglial phenotypes through downregulation of pro-inflammatory cytokines and modulation of CSF-2/GM-CSF signaling. This is not definitive clinical evidence. (tipton2021ispresymptomaticimmunosuppression pages 3-4, tipton2021ispresymptomaticimmunosuppression pages 1-3)

2.4 Gene–environment interactions

No robust gene–environment interaction evidence was identified in the retrieved sources.

3. Phenotypes

3.1 Core phenotype spectrum (with example HPO suggestions)

ALSP/HDLS affects cognition, behavior/psychiatric status, speech, and motor systems.

Common presenting domains (systematic case literature): - Cognitive impairment as an initial symptom (47.1%). HPO: Cognitive impairment (HP:0100543), Dementia (HP:0000726). (papapetropoulos2024clinicalpresentationand pages 1-2) - Behavioral/psychiatric abnormalities as initial symptoms (26.8%). HPO: Behavioral abnormality (HP:0000708), Abnormality of mood (HP:0000712), Apathy (HP:0000741). (papapetropoulos2024clinicalpresentationand pages 1-2)

Cohort-level frequencies (Korean series of definite ALSP): - Cognitive impairment (90% overall). HPO: Cognitive impairment (HP:0100543). (kim2025clinicalspectrumof pages 2-3) - Psychiatric symptoms (70%; abulia/depression/irritability). HPO: Depression (HP:0000716), Irritability (HP:0000737), Apathy (HP:0000741). (kim2025clinicalspectrumof pages 2-3) - Pyramidal signs (50%). HPO: Spasticity (HP:0001257), Hyperreflexia (HP:0001347), Babinski sign (HP:0003487). (kim2025clinicalspectrumof pages 2-3) - Parkinsonism/extrapyramidal signs (50%). HPO: Bradykinesia (HP:0002067), Parkinsonism (HP:0001300), Rigidity (HP:0002063), Tremor (HP:0001337). (kim2025clinicalspectrumof pages 2-3) - Epilepsy (20%). HPO: Seizure (HP:0001250). (kim2025clinicalspectrumof pages 2-3)

Speech/language: - Aphasia is common (62.5% in a retrospective cohort; 63% reported at presentation). HPO: Aphasia (HP:0002381). (hayer2026naturalhistoryof pages 1-2, hayer2026naturalhistoryof pages 9-12)

3.2 Age of onset, severity, progression

  • Typical onset: mean ~43 years in a 291-case analysis (range 18–78). (papapetropoulos2024clinicalpresentationand pages 1-2)
  • In a natural-history compilation of 122 cases, mean time to incapacitation was 3.9 years and mean time to death was 6.8 years. (gelfand2020allogeneichsctfor pages 2-2)
  • Rapid progression is common; in a Korean cohort 90% became bedridden within 5 years. (kim2025clinicalspectrumof pages 2-3)

3.3 Quality-of-life / function impact

Severe functional decline is a hallmark: a 2026 retrospective cohort quantified loss of functional independence using the Barthel Index with significant annual decline, and found that by 24 months most patients had moderate/severe gait impairment and all had moderate/severe aphasia. (hayer2026naturalhistoryof pages 9-12)

4. Genetic / molecular information

4.1 Causal gene(s)

  • CSF1R is the primary causal gene for the HDLS/ALSP spectrum. (mickeviciute2022neuroimagingphenotypesof pages 2-2, kraya2019functionalcharacterizationof pages 1-2)

4.2 Variant types and functional consequences

  • Variants frequently affect the tyrosine kinase domain; mechanistically they can ablate kinase activity and impair CSF1 signaling, often interpreted as loss-of-function with possible dominant-negative effects depending on allele. (chadarevian2024therapeuticpotentialof pages 3-5, chadarevian2024therapeuticpotentialof pages 13-15)
  • A systematic review/meta-analysis reported “96 CSF1R mutations … around 200 families.” (mickeviciute2022neuroimagingphenotypesof pages 2-2)
  • A Korean referral series noted variants clustered in exons 12–21 and included pathogenic/likely pathogenic variants in the tyrosine kinase domain. (kim2025clinicalspectrumof pages 2-3)

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No strong modifier-gene, epigenetic signature, or chromosomal abnormality evidence was identified in the retrieved sources.

4.4 Suggested molecular ontology annotations

  • GO (biological process): microglial cell differentiation; regulation of microglial cell activation; phagocytosis; myelination; axonogenesis/axon maintenance; regulation of inflammatory response; lipid metabolic process. (Supported mechanistically by microglial depletion/dysfunction and myelin/lipid abnormalities described in ALSP models.) (chadarevian2024therapeuticpotentialof pages 3-5, chadarevian2024therapeuticpotentialof pages 13-15)

5. Environmental information

No consistent non-genetic environmental factors (toxins, lifestyle, infections) were supported by the retrieved evidence. Case literature may include triggers/diagnostic confounders, but causal environmental contributions were not established in the sources gathered here.

6. Mechanism / pathophysiology

6.1 Current causal chain (upstream → downstream)

Upstream trigger: CSF1R tyrosine-kinase dysfunction (typically dominant CSF1R variants) reduces CSF1R signaling required for microglial differentiation/survival. (chadarevian2024therapeuticpotentialof pages 3-5) Primary cellular pathology: microglial depletion and/or loss of homeostatic microglial programs, with chronically activated phenotypes. (chadarevian2024therapeuticpotentialof pages 3-5, chadarevian2024therapeuticpotentialof pages 13-15) Downstream tissue pathology: progressive white-matter degeneration with myelin disruption, axonal spheroids, reactive astrocytosis, lipid accumulation/dysregulation, brain calcifications, and blood–brain barrier dysfunction described in model systems and referenced in human disease context. (chadarevian2024therapeuticpotentialof pages 3-5) Clinical manifestations: cognitive/behavioral decline, aphasia, gait disorder, pyramidal/extrapyramidal signs, seizures, and loss of independence. (hayer2026naturalhistoryof pages 1-2, kim2025clinicalspectrumof pages 2-3)

6.2 2023–2024 advances (prioritized)

Microglia transplantation (preclinical, 2024): A 2024 Neuron study reported that transplantation of human iPSC-derived microglial progenitors into a microglia-deficient model prevented key ALSP-like pathologies, including axonal spheroids, white matter abnormalities, reactive astrocytosis, and calcifications, and that CRISPR-corrected patient-derived microglia reversed pre-existing spheroids, astrogliosis, and calcification. (chadarevian2024therapeuticpotentialof pages 1-3, chadarevian2024therapeuticpotentialof pages 11-13) Quantitative pathology measures (example): in hFIRE mice, axonal spheroids in hippocampus/fornix were quantified (e.g., ~54±7.9 LAMP1+ and ~34±3.4 APP+ spheroids per hippocampal field of view; engraftment returned spheroids to wild-type levels). (chadarevian2024therapeuticpotentialof pages 7-8)

6.3 Suggested cell-type ontology annotations (CL)

  • CL: microglial cell (dominant implicated CNS-resident macrophage population) (chadarevian2024therapeuticpotentialof pages 3-5)
  • Additional involved cells/tissues (downstream): astrocytes (reactive astrocytosis), oligodendrocytes/myelin (white-matter myelin disruption). (chadarevian2024therapeuticpotentialof pages 3-5)

7. Anatomical structures affected

7.1 Organ/system level

Primary involvement is the central nervous system, particularly cerebral white matter, with prominent frontoparietal involvement and corpus callosum atrophy/thinning. (mickeviciute2022neuroimagingphenotypesof pages 1-1, mickeviciute2022neuroimagingphenotypesof pages 9-10)

7.2 Tissue/cell level (UBERON + CL suggestions)

  • UBERON: cerebral white matter; corpus callosum; corticospinal tract; pons (lesion extension along corticospinal tracts has been described in pictorial examples). (mickeviciute2022neuroimagingphenotypesof pages 9-10, mickeviciute2022neuroimagingphenotypesof pages 9-9)
  • CL: microglial cell; macrophage/microglia lineage involvement is highlighted pathologically by CD68+ pigmented macrophages/microglia in biopsy/autopsy material. (kim2025clinicalspectrumof pages 6-7)

7.3 Subcellular (GO cellular component) suggestions

  • plasma membrane / receptor complex (CSF1R is a transmembrane receptor tyrosine kinase) (kraya2019functionalcharacterizationof pages 1-2)

8. Temporal development

8.1 Onset and course

  • Typically insidious adult-onset with symptom onset around early-to-mid 40s. (papapetropoulos2024clinicalpresentationand pages 1-2)
  • Rapidly progressive disease course with mean ~3.9 years to incapacitation and mean ~6.8 years to death (compiled case series). (gelfand2020allogeneichsctfor pages 2-2)

8.2 Staging and progression measures

Recent natural-history work emphasizes quantitative outcomes: - Cognitive decline: MoCA annual decline estimates and significant annual percent decrease (~−28.5% reported in a retrospective cohort model). (hayer2026naturalhistoryof pages 9-12) - Functional decline: Barthel Index annual decline (~−25% in sensitivity/Tobit models). (hayer2026naturalhistoryof pages 9-12) - Imaging progression: increasing ventricular volume and worsening MRI severity scores correlate with clinical decline. (hayer2026naturalhistoryof pages 1-2, hayer2026naturalhistoryof pages 17-19)

9. Inheritance and population

9.1 Inheritance

  • Autosomal dominant inheritance is consistently reported. (papapetropoulos2024clinicalpresentationand pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 2-2)

9.2 Epidemiology and population distribution

Population prevalence/incidence remains poorly defined, but several proportional estimates are available: - In published European cohorts, ALSP accounts for ~10% of adult-onset leukodystrophies. (gelfand2020allogeneichsctfor pages 1-2) - A Korean report cited overall adult-onset leukodystrophy prevalence ~300 per million and estimated 10–25% attributable to CSF1R-related ALSP. (kim2025clinicalspectrumof pages 6-7)

9.3 Prognosis

Median/mean survival estimates cluster around 6–8 years from symptom onset. (papapetropoulos2024clinicalpresentationand pages 1-2, gelfand2020allogeneichsctfor pages 2-2)

10. Diagnostics

10.1 Clinical suspicion and differential diagnosis

ALSP is frequently misdiagnosed: in a 291-case literature analysis, only 24.7% were initially diagnosed correctly; frequent misdiagnoses included frontotemporal dementia (9.6%) and multiple sclerosis (7.2%). (papapetropoulos2024clinicalpresentationand pages 1-2)

10.2 Imaging (real-world implementation)

Imaging is a key driver of diagnostic suspicion and subsequent CSF1R testing. - Systematic review/meta-analysis highlights typical MRI findings: frontoparietal white matter lesions, callosal thinning, and restricted diffusion foci; CT hallmark is white matter calcifications. (mickeviciute2022neuroimagingphenotypesof pages 1-1) - Recommended workup includes native brain CT and brain MRI with and without contrast; diffusion-weighted imaging is emphasized due to long-lasting diffusion restriction that can be relatively specific. (mickeviciute2022neuroimagingphenotypesof pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 8-8) - Figure/Table evidence: pictorial examples show diffusion restriction and “stepping-stone” calcifications along the corpus callosum, and Table 3 provides a recommended imaging protocol. (mickeviciute2022neuroimagingphenotypesof media a5bf8aca, mickeviciute2022neuroimagingphenotypesof media eb5e78cb)

10.3 Genetic testing

Definitive diagnosis relies on detecting a pathogenic CSF1R variant; multiple cohorts recommend CSF1R sequencing when imaging and clinical criteria suggest ALSP/HDLS. (kim2025clinicalspectrumof pages 2-3, mickeviciute2022neuroimagingphenotypesof pages 1-1)

10.4 Biomarkers

Natural-history cohorts are beginning to collect fluid biomarkers such as neurofilament light chain (NfL) and chitotriosidase; in small samples, correlations with clinical scales were not significant, indicating need for larger studies and standardization. (hayer2026naturalhistoryof pages 17-19)

11. Outcome / prognosis

ALSP/HDLS is typically rapidly progressive with severe disability and death within ~6–8 years on average. (papapetropoulos2024clinicalpresentationand pages 1-2, gelfand2020allogeneichsctfor pages 2-2) Clinical trajectories can be quantified by cognitive and functional measures (MoCA, Barthel Index) and MRI severity/volumetric progression, which correlate with clinical decline. (hayer2026naturalhistoryof pages 9-12, hayer2026naturalhistoryof pages 17-19)

12. Treatment

12.1 Pharmacotherapy

No FDA-approved disease-modifying pharmacotherapy is established in the retrieved evidence. (chadarevian2024therapeuticpotentialof pages 3-5)

12.2 HSCT (current real-world disease-modifying implementation)

Multiple observational studies support HSCT as a disease-modifying option for selected patients: - Retrospective predictor analysis (15 patients): 6/15 (40%) “good” outcomes; gait-predominant onset and younger age at HSCT predicted better outcomes; cognitive-first presentation predicted poor outcomes and cognitive worsening post-HSCT. (dulski2022hematopoieticstemcell pages 2-4, dulski2022hematopoieticstemcell pages 6-7) - Cohort report (7 patients): 6/7 trended toward stabilization; 1 periprocedural death. (tipton2021treatmentofcsf1r‐related pages 1-2) - Two-patient series with >2-year follow-up: stabilization of T2/FLAIR abnormalities within 1 year and resolution of reduced diffusion after 2 years; partial clinical stabilization despite continued parkinsonism progression. (gelfand2020allogeneichsctfor pages 1-1)

MAXO suggestions: hematopoietic stem cell transplantation; allogeneic hematopoietic stem cell transplantation; supportive physical therapy; speech therapy; seizure management. (Clinical support for HSCT and multi-domain impairment is provided by the above cohorts.) (dulski2022hematopoieticstemcell pages 1-2, kim2025clinicalspectrumof pages 2-3)

12.3 Emerging/experimental therapeutics

  • Microglia transplantation / microglia replacement (preclinical): strong 2024 Neuron evidence for prevention and reversal of pathology in a chimeric model. (chadarevian2024therapeuticpotentialof pages 1-3, chadarevian2024therapeuticpotentialof pages 11-13)

12.4 Clinical trials

  • NCT05677659 (VGL101/iluzanebart; Vigil Neuroscience; Phase 2; started 2022-12-14): terminated due to “No beneficial effects on biomarker or clinical efficacy endpoints.” (NCT05677659 chunk 1)
  • NCT05020743 (Vigil natural history; started 2021-09-13): terminated; primary outcome emphasized MRI ventricular volume change. (NCT05020743 chunk 1)
  • NCT04503213 (Mayo Clinic; started 2020-07-21): observational longitudinal assessment after HSCT; enrolling by invitation, estimated primary completion 2027-12. (NCT04503213 chunk 1)

13. Prevention

Given autosomal dominant inheritance, primary prevention is not established; practical prevention focuses on genetic counseling and cascade testing. - Secondary prevention concept: earlier recognition through characteristic imaging and prompt CSF1R genetic testing may enable earlier HSCT consideration. Misdiagnosis is common, so awareness is a prevention-like strategy for avoidable diagnostic delay. (papapetropoulos2024clinicalpresentationand pages 1-2, mickeviciute2022neuroimagingphenotypesof pages 1-1)

MAXO suggestions: genetic counseling; cascade genetic testing; surveillance MRI/CT in at-risk carriers (not formally validated in retrieved sources).

14. Other species / natural disease

No naturally occurring HDLS/ALSP-like disease in non-human species was evidenced in the retrieved sources.

15. Model organisms

Key experimental models used for mechanistic and translational research include: - Csf1r haploinsufficient and kinase-dead mouse models (reduced microglia with partial phenotypes). (chadarevian2024therapeuticpotentialof pages 3-5) - Microglia-deficient models via deletion of the Csf1r FIRE enhancer; these develop ALSP-like pathologies with aging and were used in 2024 for human microglia transplantation experiments (including humanized immunodeficient hFIRE). (chadarevian2024therapeuticpotentialof pages 3-5, chadarevian2024therapeuticpotentialof pages 5-7)

Notes on evidence limitations (important for knowledge-base curation)

  1. Ontology identifiers (OMIM/Orphanet/MONDO/MeSH/ICD): not present in the retrieved excerpts; should be programmatically fetched from the relevant ontologies. (gelfand2020allogeneichsctfor pages 1-2)
  2. Environmental risk factors and GxE: not supported in retrieved evidence.
  3. Protective factors (steroids/immunosuppression): currently hypothesis-generating and based on limited human data (case observation) plus mechanistic rationale; should be stored with low evidence strength. (tipton2021ispresymptomaticimmunosuppression pages 3-4)

References

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