| 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. (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000011) | 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. (pqac-00000002, pqac-00000003, pqac-00000006) | 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. (pqac-00000001, pqac-00000003, pqac-00000020) | 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. (pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000032) | 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%**. (pqac-00000001, pqac-00000006) | 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. (pqac-00000001, pqac-00000032) | 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. (pqac-00000002, pqac-00000032, pqac-00000033, pqac-00000037, pqac-00000039) | 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**. (pqac-00000001, pqac-00000005, pqac-00000031) | 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. (pqac-00000000, pqac-00000024, pqac-00000026, pqac-00000028, pqac-00000030, pqac-00000031) | 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. (pqac-00000016, pqac-00000017, pqac-00000019, pqac-00000021) | 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.”** (pqac-00000040, pqac-00000043) | 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. (pqac-00000042) | 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. (pqac-00000041) | 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.*