Leukoencephalopathy, diffuse hereditary, with spheroids 1

Summary

Leukoencephalopathy, diffuse hereditary, with spheroids 1 (MONDO:0800027) is a disease caused by CSF1R (GenCC Strong), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include iluzanebart.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CSF1R (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 41
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy, diffuse hereditary, with spheroids 1
Mondo ID	MONDO:0800027
MeSH	C580150
OMIM	221820
Orphanet	313808
DOID	DOID:0080523
NCIT	C153289
SNOMED CT	702427005
UMLS	C5561929
MedGen	1794139
GARD	0010981
NORD	2033
Is cancer (heuristic)	no

Also known as: adult-onset leukodystrophy with neuroaxonal spheroids · Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia · adult-onset leukoencephalopathy with axonal spheroids and pigmented glia · ALSP · autosomal dominant leukoencephalopathy with neuroaxonal spheroids · CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia · CSF1R-related ALSP · dementia, familial, Neumann type · familial dementia, Neumann type · familial progressive subcortical gliosis · FPSG · gliosis, familial progressive subcortical · GPSC · HDLS · hereditary diffuse leukoencephalopathy with axonal spheroids · hereditary diffuse leukoencephalopathy with spheroids · leukoencephalopathy with neuroaxonal spheroids, autosomal dominant · leukoencephalopathy, adult-onset, with axonal spheroids and pigmented glia · leukoencephalopathy, diffuse hereditary, with spheroids · leukoencephalopathy, hereditary diffuse, with spheroids (+4 more)

Data availability: 41 ClinVar variants · 1 GenCC gene-disease record · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukoencephalopathy, diffuse hereditary, with spheroids 1

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

41 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 11 likely pathogenic, 6 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 3 pathogenic, 2 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1297008	NM_001288705.3(CSF1R):c.2344C>T (p.Arg782Cys)	CSF1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322164	NM_001288705.3(CSF1R):c.2026C>T (p.Arg676Ter)	CSF1R	Pathogenic	criteria provided, multiple submitters, no conflicts
162111	NM_001288705.3(CSF1R):c.2330G>A (p.Arg777Gln)	CSF1R	Pathogenic	criteria provided, multiple submitters, no conflicts
2575888	NM_001288705.3(CSF1R):c.2471C>T (p.Pro824Leu)	CSF1R	Pathogenic	criteria provided, single submitter
29811	NM_001288705.3(CSF1R):c.1897G>A (p.Glu633Lys)	CSF1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29813	NM_001288705.3(CSF1R):c.2381T>C (p.Ile794Thr)	CSF1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38378	NM_001288705.3(CSF1R):c.2345G>A (p.Arg782His)	CSF1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973001	NM_001288705.3(CSF1R):c.1765G>A (p.Gly589Arg)	CSF1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029947	NM_001288705.3(CSF1R):c.2503C>T (p.Gln835Ter)	CSF1R	Likely pathogenic	criteria provided, single submitter
2503453	NM_001288705.3(CSF1R):c.2377A>G (p.Lys793Glu)	CSF1R	Likely pathogenic	no assertion criteria provided
2583156	NM_001288705.3(CSF1R):c.2768A>G (p.Tyr923Cys)	CSF1R	Likely pathogenic	criteria provided, single submitter
3068555	NM_001288705.3(CSF1R):c.2339C>T (p.Ala780Val)	CSF1R	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359066	NM_001288705.3(CSF1R):c.2287G>A (p.Ala763Thr)	CSF1R	Likely pathogenic	criteria provided, single submitter
3382005	NM_001288705.3(CSF1R):c.2563C>A (p.Pro855Thr)	CSF1R	Likely pathogenic	criteria provided, single submitter
3779550	NM_001288705.3(CSF1R):c.931C>T (p.Gln311Ter)	CSF1R	Likely pathogenic	criteria provided, single submitter
3781323	NM_001288705.3(CSF1R):c.1991A>T (p.Glu664Val)	CSF1R	Likely pathogenic	criteria provided, single submitter
4531974	NM_001288705.3(CSF1R):c.2453C>A (p.Pro818His)	CSF1R	Likely pathogenic	criteria provided, single submitter
4756102	NM_001288705.3(CSF1R):c.1937T>A (p.Ile646Asn)	CSF1R	Likely pathogenic	criteria provided, single submitter
982040	NM_001288705.3(CSF1R):c.1772G>A (p.Gly591Glu)	CSF1R	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420666	NM_001288705.3(CSF1R):c.2073G>C (p.Gln691His)	CSF1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1514431	NM_001288705.3(CSF1R):c.2533C>T (p.Leu845Phe)	CSF1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1516273	NM_001288705.3(CSF1R):c.1961C>A (p.Thr654Asn)	CSF1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2415792	NM_001288705.3(CSF1R):c.2797G>A (p.Gly933Ser)	CSF1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907382	NM_001288705.3(CSF1R):c.2603T>G (p.Leu868Arg)	CSF1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1465714	NM_001288705.3(CSF1R):c.656C>A (p.Ala219Asp)	LOC111188154	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1368621	NM_001288705.3(CSF1R):c.2179A>G (p.Arg727Gly)	CSF1R	Uncertain significance	criteria provided, multiple submitters, no conflicts
1394722	NM_001288705.3(CSF1R):c.1399A>G (p.Thr467Ala)	CSF1R	Uncertain significance	criteria provided, multiple submitters, no conflicts
162129	NM_001288705.3(CSF1R):c.2562T>A (p.Asn854Lys)	CSF1R	Uncertain significance	criteria provided, multiple submitters, no conflicts
1931198	NM_001288705.3(CSF1R):c.141C>A (p.Ser47Arg)	CSF1R	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236418	NM_001288705.3(CSF1R):c.1232T>C (p.Ile411Thr)	CSF1R	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CSF1R	Definitive	Autosomal dominant	hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSF1R	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
CSF1R	Orphanet:556985	Early-onset calcifying leukoencephalopathy-skeletal dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CSF1R	HGNC:2433	ENSG00000182578	P07333	Macrophage colony-stimulating factor 1 receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSF1R	Macrophage colony-stimulating factor 1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSF1R	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSF1R	245	broad	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSF1R	4,392

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSF1R	P07333	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Other interleukin signaling	1	475.8×	0.004	CSF1R
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.004	CSF1R
Transcriptional Regulation by VENTX	1	265.6×	0.004	CSF1R

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
forebrain neuron differentiation	1	5617.3×	0.003	CSF1R
macrophage colony-stimulating factor signaling pathway	1	5617.3×	0.003	CSF1R
regulation of macrophage migration	1	4213.0×	0.003	CSF1R
cellular response to macrophage colony-stimulating factor stimulus	1	3370.4×	0.003	CSF1R
positive regulation of macrophage proliferation	1	3370.4×	0.003	CSF1R
mammary gland duct morphogenesis	1	2407.4×	0.003	CSF1R
positive regulation of protein tyrosine kinase activity	1	2106.5×	0.003	CSF1R
cell-cell junction maintenance	1	1872.4×	0.003	CSF1R
microglial cell proliferation	1	1872.4×	0.003	CSF1R
regulation of bone resorption	1	1532.0×	0.003	CSF1R
host-mediated activation of viral process	1	1404.3×	0.003	CSF1R
ruffle organization	1	1296.3×	0.003	CSF1R
positive regulation of macrophage chemotaxis	1	802.5×	0.003	CSF1R
monocyte differentiation	1	802.5×	0.003	CSF1R
olfactory bulb development	1	766.0×	0.003	CSF1R
positive regulation of cell motility	1	766.0×	0.003	CSF1R
positive regulation of tyrosine phosphorylation of STAT protein	1	732.7×	0.003	CSF1R
cellular response to cytokine stimulus	1	543.6×	0.004	CSF1R
macrophage differentiation	1	468.1×	0.005	CSF1R
regulation of MAPK cascade	1	455.5×	0.005	CSF1R
peptidyl-tyrosine phosphorylation	1	421.3×	0.005	CSF1R
positive regulation of chemokine production	1	374.5×	0.005	CSF1R
osteoclast differentiation	1	343.9×	0.005	CSF1R
positive regulation of protein phosphorylation	1	276.3×	0.006	CSF1R
hemopoiesis	1	267.5×	0.006	CSF1R
response to ischemia	1	251.5×	0.007	CSF1R
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.009	CSF1R
regulation of actin cytoskeleton organization	1	157.5×	0.010	CSF1R
protein autophosphorylation	1	145.3×	0.010	CSF1R
cytokine-mediated signaling pathway	1	130.6×	0.011	CSF1R

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CSF1R	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CSF1R	79	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	CSF1R
FEDRATINIB	4	CSF1R
AXITINIB	4	CSF1R
SORAFENIB	4	CSF1R
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R
IBRUTINIB	4	CSF1R
ENTRECTINIB	4	CSF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R
NILOTINIB	4	CSF1R
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R
PEXIDARTINIB	4	CSF1R
PAZOPANIB	4	CSF1R
NINTEDANIB	4	CSF1R
SUNITINIB	4	CSF1R
DASATINIB	4	CSF1R
QUIZARTINIB	4	CSF1R
CRIZOTINIB	4	CSF1R
MIDOSTAURIN	4	CSF1R
IMATINIB	4	CSF1R
VATALANIB	3	CSF1R
DACTOLISIB	3	CSF1R
MASITINIB	3	CSF1R
LINIFANIB	3	CSF1R
SEMAXANIB	3	CSF1R
BRIVANIB	3	CSF1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CSF1R	897	Binding:879, Functional:17, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CSF1R	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CSF1R	897

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	CSF1R
FEDRATINIB	4	CSF1R
AXITINIB	4	CSF1R
SORAFENIB	4	CSF1R
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R
IBRUTINIB	4	CSF1R
ENTRECTINIB	4	CSF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R
NILOTINIB	4	CSF1R
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R
PEXIDARTINIB	4	CSF1R
PAZOPANIB	4	CSF1R
NINTEDANIB	4	CSF1R
SUNITINIB	4	CSF1R
DASATINIB	4	CSF1R
QUIZARTINIB	4	CSF1R
CRIZOTINIB	4	CSF1R
MIDOSTAURIN	4	CSF1R
IMATINIB	4	CSF1R
VATALANIB	3	CSF1R
DACTOLISIB	3	CSF1R
MASITINIB	3	CSF1R
LINIFANIB	3	CSF1R
SEMAXANIB	3	CSF1R
BRIVANIB	3	CSF1R

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CSF1R
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05677659	PHASE2	TERMINATED	A Study of VGL101 in Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT04503213	Not specified	ENROLLING_BY_INVITATION	A Study to Assess CSF1R-related Leukoencephalopathy After Stem Cell Transplantation
NCT04925349	Not specified	RECRUITING	Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT05020743	Not specified	TERMINATED	Natural History Study in Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ILUZANEBART	2	1