DeCure for Leukoencephalopathy, diffuse hereditary, with spheroids 1
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for leukoencephalopathy, diffuse hereditary, with spheroids 1 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLeukoencephalopathy, diffuse hereditary, with spheroids 1 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for leukoencephalopathy, diffuse hereditary, with spheroids 1 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
colony stimulating factor 1 receptor (CSF1R) — CSF1R is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet ukidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8JOT · 1.69 Å · ligand Sulfatinib (UKI). Experimental structure, not a prediction.
What the evidence adds up to
In a 2008 study of one new American family with hereditary diffuse leukoencephalopathy with spheroids (HDLS), seven affected members were identified, five deceased. Mean age at symptomatic onset was 35 years (range 20–57), mean disease duration 16 years (range 3–46). Five presented with memory disturbance and behavioural changes; two with mood disorder. Serial MRIs in the proband showed progressive, confluent, frontal-predominant leukoencephalopathy with symmetric cortical atrophy, and subtle changes were visible before symptoms began.
By 2015, mutations in the colony stimulating factor 1 receptor (CSF1R) gene had been identified as the cause of HDLS. A 29-year-old woman with a rapid course showed cognitive impairment and severe motor dysfunction; her MRI revealed spotted and confluent white matter hyperintensities on T2-weighted images involving the corticospinal tract and corpus callosum, with striking restricted diffusion in all affected areas. The authors noted that pronounced restricted diffusion might indicate more acute progression. Another 2015 report described a 32-year-old woman initially suspected of perinatal depression who developed rapid-onset depression, hypokinetic movement disorder, and cognitive decline during pregnancy; genetic testing confirmed a CSF1R mutation.
A 2019 study of Swedish type HDLS (HDLS-S), a severe adult-onset leukoencephalopathy described in a large family since 1984, found no CSF1R mutations. Instead, exome sequencing identified a p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause. Median survival in this family was less than 10 years. Brain pathology after 10 years of disease showed end-stage widespread liquefaction of the white matter, leaving only macrophages and glial cells behind a centrifugally progressing front. A 2025 case report described a woman with confirmed HDLS whose clinical picture included cognitive, affective, motor, and convulsive disorders.
What remains missing are treatments tested in controlled trials, systematic natural history data from large cohorts, and validated biomarkers to track progression. The disease is underdiagnosed, and no therapy has been shown to alter its course. Patient stratification by genetic subtype (CSF1R versus AARS) and by stage of white matter involvement may be necessary for future trial design, but funding for such studies is scarce.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2008 · 61 citations · open access
Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids
Abstract<b>Objective: </b> To report a new American family with hereditary diffuse leukoencephalopathy with spheroids (HDLS), including serial, presymptomatic and symptomatic, cranial MRIs from the proband. <b>Methods: </b> We report clinical and genealogic investigations of an HDLS family, sequential brain MRIs of the proband, and autopsy slides of brain tissue from the proband’s father. <b>Results: </b> We identified seven affected family members (five deceased). The mean age at symptomatic disease onset was 35 years (range: 20–57), and the mean disease duration was 16 years (range: 3–46). Five affected individuals initially manifested memory disturbance and behavioral changes, whereas two experienced a mood disorder as their presenting symptom. Our proband’s father had been diagnosed clinically with vascular dementia, but his brain autopsy was consistent with HDLS. The proband had a cranial MRI prior to symptom onset, with two subsequent MRIs performed during follow-up. These serial images reveal a progressive, confluent, frontal-predominant leukoencephalopathy with symmetric cortical atrophy. <b>Conclusions: </b> The proband of our newly identified hereditary diffuse leukoencephalopathy with spheroids (HDLS) kindred had subtle evidence of an incipient leukoencephalopathy on a presymptomatic cranial MRI. Conceivably, MRI may facilitate identifying affected presymptomatic individuals within known HDLS kindreds, increasing the likelihood of isolating the causative genes. <b>GLOSSARY: </b><b>DLS</b> = diffuse leukoencephalopathy with spheroids; <b>FLAIR</b> = fluid-attenuated inversion recovery; <b>HDLS</b> = hereditary diffuse leukoencephalopathy with spheroids; <b>LENAS</b> = leukoencephalopathy with neuroaxonal spheroids; <b>LFB</b> = Luxol fast blue; <b>NAL</b> = neuroaxonal leukodystrophy; <b>POLD</b> = pigmentary type of orthochromatic leukodystrophy.
Comprehensive diagnostics in a case of hereditary diffuse leukodystrophy with spheroids
AbstractBACKGROUND: Hereditary diffuse leukodystrophy with spheroids is a rare type of leukoencephalopathy. Mutations in the colony stimulating factor 1 receptor have recently been identified to be the cause of this microgliopathy. Clinical and radiological presentation can often misguide physicians during the diagnosis of patients with this underdiagnosed disease. CASE PRESENTATION: We present a 29 year-old woman with a rapid course of hereditary diffuse leukodystrophy with spheroids. She mainly showed cognitive impairment and severe motor dysfunctions. Her MRI showed spotted and confluent hyperintensities of the white matter on T2-weighted images involving the corticospinal tract as well as the corpus callosum. Further, those lesions showed striking restricted diffusion. As this restricted diffusion in all areas showing signs of leukoencephalopathy was so impressive we searched Medline for these terms and got hereditary diffuse leukodystrophy with spheroids as one of the first results. After a comprehensive diagnostic workup and exclusion of other leukoencephalopathies, stereotactic biopsy and genetic testing confirmed the diagnosis. CONCLUSION: This case points out at two important features of hereditary diffuse leukodystrophy with spheroids being spotted and/or confluent leukoencephalopathy with areas of restricted diffusion. This might help to identify more patients with this underdiagnosed disease. Moreover, the rapid clinical course in our patient raises the question whether the relatively pronounced areas of restricted diffusion are indicative of a more acute progression of the disease.
Journal of Movement Disorders · 2016 · 6 citations · open access
Suspected Perinatal Depression Revealed to be Hereditary Diffuse Leukoencephalopathy with Spheroids
AbstractEarly motor symptoms of neurodegenerative diseases often appear in combination with psychiatric symptoms, such as depression or personality changes, and are in danger of being misdiagnosed as psychogenic in young patients. We present the case of a 32-year-old woman who presented with rapid-onset depression, followed by a hypokinetic movement disorder and cognitive decline during pregnancy. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor gene, which led to the diagnosis of hereditary diffuse leukoencephalopathy with spheroids. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is probably an under-recognized disease. HDLS should be considered in patients with rapidly progressing parkinsonian symptoms and dementia accompanied by white matter lesions.
Journal of Neuropathology & Experimental Neurology · 2015 · 4 citations · open access
The First Neuropathological Studies on HDLS
AbstractI read with considerable interest the article in the Journal by Riku et al on hereditary diffuse leukoencephalopathy with spheroids (HDLS) describing the early changes in this relatively rare disease (1). Riku et al referred to the original article as a source of the primary clinical findings. In our original article, however, we presented the first 3 detailed neuropathology studies of HDLS (2). At that time, we used routine histological and histochemical techniques as well as electron microscopy. The findings of Riku et al look quite similar to ours, but the pictures are now in color. Nevertheless, the first neuropathological analyses of this …
Medical alphabet · 2025 · 0 citations · open access
Hereditary diffuse leukoencephalopathy with axonal spheroids: description of a clinical case
AbstractBackground. Hereditary diffuse leukoencephalopathy with axonal spheroids is a genetically determined mutation of the CSF1R gene with changes in the white matter of the brain. The main tests in making a diagnosis are magnetic resonance imaging (MRI) of the brain and genetic testing. С linical С ase Description . We have described a clinical case of hereditary diffuse leukoencephalopathy with axonal spheroids in a woman, confirmed by genetic studies. The clinical picture was manifested by cognitive, affective, motor disorders, and convulsive syndrome. Conclusion . Hereditary leukoencephalopathies are relatively rare diseases, understanding their pathogenesis and clinical picture has significantly expanded knowledge about neurodegenerative diseases.
An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids
AbstractAbstract Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
