DeCure for Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLeukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy maps to a 2-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 leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy 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.
What the evidence adds up to
Seven consanguineous families with biallelic missense variants in RNF220 (p.R363Q and p.R365Q) were identified as the cause of a novel leukodystrophy with ataxia, sensorineural deafness, fibrotic cardiomyopathy and hepatopathy. Mass spectrometry and co-immunoprecipitation experiments showed that RNF220 binds lamin B1, and both mutants reduced this binding. RNF220 silencing in Drosophila caused mislocalisation and aggregation of the fly lamin B1 orthologue and a neurodegenerative phenotype. Primary skin fibroblasts from patients showed nuclear abnormalities including blebs, herniations and invaginations, typical of laminopathies.
A separate report from 2006 described a large consanguineous Italian family with three patients presenting a slowly progressive ataxia and spasticity beginning between ages 2 and 3, followed by complete sensorineural deafness within two years and later restrictive cardiomyopathy. Brain MRI showed diffuse abnormal T2 signal in white matter. The critical genetic locus for that family was not identified in the abstract.
A 2022 case report described a 58-year-old patient with advanced Friedreich’s ataxia (SARA score 30/40), wheelchair-bound for 16 years, with urinary incontinence, dysarthria, neurosensorial deafness and dilated cardiomyopathy with severely reduced left ventricular ejection fraction and recurrent ventricular arrhythmias. The patient received a heart transplant after multidisciplinary discussion. Postoperative course included high-dose vasopressors, one month of hemofiltration, critical illness myopathy, several respiratory infections and delayed extubation. The patient was discharged 2.5 months after transplant and nearly five months in hospital. The authors advise careful multidisciplinary evaluation for heart transplant candidacy in such patients.
No treatment for the RNF220-related leukodystrophy has been tested. What is missing is any drug screening or preclinical model for the specific RNF220 mutations, a clear natural history study to define progression and stratify patients, and funding for translational work that could move from the genetic and cell biology findings toward a therapeutic hypothesis.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2021 · 25 citations · open access
Biallelic mutations in <i>RNF220</i> cause laminopathies featuring leukodystrophy, ataxia and deafness
AbstractLeukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in five large consanguineous nuclear families allowed us to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report these two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the underlying cause of this novel form of leukodystrophy with ataxia and sensorineural deafness that includes fibrotic cardiomyopathy and hepatopathy as associated features in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as the RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology; mutations in primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.
Journal of Cardiovascular Development and Disease · 2022 · 1 citations · open access
Should Advanced Friedreich’s Ataxia Be a Contraindication for Heart Transplantation? A Case Report of a Successful Procedure in a 58-Year-Old Patient
AbstractThe information on heart transplantation (HT) in patients with Friedreich's Ataxia (FA) is scarce, and the few published case reports are limited to young patients with mild neurological manifestations. We present the case of a 58-year-old patient with advanced FA (Scale for the Assessment and Rating of Ataxia [SARA] score 30/40), wheelchair-bound for the last 16 years and had urinary incontinence, dysarthria, and neurosensorial deafness. The patient was admitted for a refractory arrhythmic storm and had previous hypertrophic cardiomyopathy that evolved to dilated cardiomyopathy with severely reduced left ventricular ejection fraction and recurrent ventricular arrhythmias. A multidisciplinary team discussed the HT option. The patient was aware of the risks and benefits and considered worthy of the intervention, so he was listed for HT. After a successful surgical intervention, the patient had a long postoperative stay in ICU. He required a high dose of vasopressors, underwent hemofiltration for one month, suffered critical illness myopathy, had several respiratory infections and delayed tracheal extubation. Two and a half months after HT and almost five months at the hospital, the patient was successfully discharged. FA patients with severe heart conditions should be carefully evaluated by a multidisciplinary team to decide the candidacy for HT.
IDENTIFICATION OF THE CRITICAL LOCUS IN A NEW FORM OF LEUCODYSTROPHY WITH PROGRESSIVE ATAXIA, DEAFNESS, AND CARDIOMYOPATHY
AbstractObjectives: To identify the molecular genetic alteration in a new form of leukodystrophy. We recently reported a large consanguineous family from southern Italy, in which three patients presented a distinctive clinical phenotype characterized by a slowly progressive ataxia and spasticity with an onset between 2 and 3 years of age. After 5–6 years of disease evolution, patients experienced sensorineural deafness, resulting in complete hearing loss in the time-span of two years. Subsequently, they developed a restrictive cardiomyopathy. Brain MRI showed a diffuse abnormal signal of the white matter on T2.
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.
