DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for McLeod neuroacanthocytosis syndrome — 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 moduleMcLeod neuroacanthocytosis syndrome 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 mcleod neuroacanthocytosis syndrome 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
A 1994 study of one man with McLeod syndrome found caudate atrophy on cerebral imaging and reduced striatal dopamine D2-receptor binding. The authors suggested the missing gene product, possibly Kx, might be essential for striatal integrity. A 2020 study identified XK as a partner protein for VPS13A: the two form a complex in human cells, and overexpressing XK relocalises VPS13A from lipid droplets to subdomains of the endoplasmic reticulum. Two chorea-acanthocytosis-linked missense mutations in VPS13A prevented this relocalisation. The authors proposed that dysregulation of a VPS13A-XK complex is the common basis for chorea-acanthocytosis and McLeod syndrome.
Two asymptomatic or minimally symptomatic cases with documented McLeod red blood cell phenotype and confirmed XK mutations (R222G missense and IVS2+5G>A) showed minimal neurological findings at ages expected to manifest McLeod syndrome, according to a 2007 report. The authors concluded that different XK mutations may have different effects on the XK gene product and account for variable phenotype. A 2017 case report described a 60-year-old Korean man with a previously reported 5 base pair deletion in XK exon 3 (c.856_860delCTCTA) who presented with chorea, seizure, cognitive impairment, and multisystem involvement including neuropathy, myopathy, acanthocytosis, and hepatosplenomegaly.
A 2015 review of management of neuroacanthocytosis syndromes, including McLeod syndrome, found no blinded, controlled trials and only one retrospective case series describing chorea-acanthocytosis. Management remains purely symptomatic, similar in principle to Huntington's disease and Parkinson's disease. The authors recommended an integrated multidisciplinary approach. A 2007 letter reported that a patient with chorea-acanthocytosis (confirmed by serologic exclusion of McLeod syndrome) had orofacial and lingual dyskinesias, caudate atrophy, peripheral neuropathy, elevated creatinine kinase, and liver abnormalities; the patient's obsessive-compulsive symptoms were treated with citalopram, but no efficacy data were provided.
What is still missing: no controlled trials exist for any drug in McLeod syndrome; no disease-modifying therapy has been tested; the relationship between specific XK mutations and clinical severity remains unclear; and patient numbers are too small for conventional trial designs without international collaboration and dedicated funding.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Biology of the Cell · 2020 · 69 citations · open access
XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome
Abstractgene, suggesting that XK could be a partner protein for VPS13A. XK does, in fact, exhibit hallmarks of a VPS13A partner: it forms a complex with VPS13A in human cells and, when overexpressed, relocalizes VPS13A from lipid droplets to subdomains of the endoplasmic reticulum. Introduction of two different ChAc disease-linked missense mutations into VPS13A prevents this XK-induced relocalization. These results suggest that dysregulation of a VPS13A-XK complex is the common basis for ChAc and McLeod Syndrome.
AbstractMcLeod syndrome is an Xp21-linked Kell blood group variant due to lack of erythrocyte protein Kx with associated RBC membrane dysfunction such as acanthocytosis. A man with this syndrome developed chorea and slight neuropsychological impairment. He had caudate atrophy on cerebral imaging and reduced striatal dopamine D2-receptor binding on single-photon emission computed tomography. Since Xp21 was partly deleted in the patient, the missing gene product (possibly Kx) may be essential for the integrity of the striatum.
AbstractBACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.
AbstractBACKGROUND: The two core neuroacanthocytosis (NA) syndromes, chorea-acanthocytosis (ChAc) and McLeod syndrome, are progressive neurodegenerative disorders that primarily affect the basal ganglia. The characteristic phenotype comprises a variety of movement disorders including chorea, dystonia, and parkinsonism, as well as psychiatric and cognitive symptoms attributable to basal ganglia dysfunction. These disorders are symptomatically managed on a case-by-case basis, with very few practitioners seeing more than a single case in their careers. METHODS: A literature search was performed on PubMed utilizing the terms neuroacanthocytosis, chorea-acanthocytosis, and McLeod syndrome, and articles were reviewed for mentions of therapies, successful or otherwise. RESULTS: There have been no blinded, controlled trials and only one retrospective case series describing ChAc. The various therapies that have been used in patients with NA syndromes are summarized. DISCUSSION: Management remains at present purely symptomatic, which is similar in principle to other more common basal ganglia neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). However, there are some specific issues particular to NA syndromes that merit attention. An integrated multidisciplinary approach is the ideal management strategy for these complex and multifaceted neurodegenerative disorders.
Authors' Reply Obessive-compulsive Disorders Due to Neuroacanthocytosis Treated with Citalopram
AbstractCorrected by: Erratum Pharmacopsychiatry 2007; 40(03): 132-132 DOI: 10.1055/s-2007-982513 We thank R. Walker and A. Danek for their letter emphasizing that the term neuroacanthocytosis is used for distinct diseases, which can be differentiated by means of genetic tests. Our patient [ 2 ] suffered from chorea-acanthocytosis. The most prominent differential diagnosis of chorea-acanthocytosis is the McLeod syndrome, which shows a reduction of all Kell antigens and absence of Kx antigen [ 1 ] [ 3 ]. In our patient no abnormalities of Kell antigens was detected; therefore, this important differential diagnosis can be excluded. In addition to oral and perioral dyskinesias with self-mutilation of mucosa and lips, the patient had additional findings, including atrophy of caudate nuclei in brain MRI, clinical and electrophysiological signs of peripheral neuropathy, an elevated creatinine kinase and liver abnormalities (with normal serologic tests for viral causes and unspecific biopsy results). Lipoproteins were normal as was coeruloplasmin level and copper excretion. The patient had no seizures, and EEG was normal. While all of this may be found in both chorea-acanthocytosis and McLeod Syndome, the whole spectrum might be rarely present in other disorders. Serologic exclusion of McLeod syndrome led us to accept the diagnosis of chorea-acanthocytosis, especially, since in our patient the most impressive presenting symptom was his orofacial and lingual dyskinesias [ 4 ].
Journal of the Korean Neurological Association · 2017 · 1 citations · open access
The First Genetically Confirmed McLeod Syndrome in Korea
AbstractMcLeod syndrome is a rare X-linked multisystem disorder which forms the core of neuroacanthocytosis syndrome. Neurological symptoms characterized by chorea, seizure, cognitive impairment, and psychosis mostly develop around the 5-6th decades, accompanied by multisystem involvement comprising neuropathy, myopathy, acanthocytosis and hepatosplenomegaly. We hereby present a 60-year-old male who is the first genetically confirmed Korean McLeod syndrome patient. Genetic analysis of his XK gene revealed a previously reported 5 base pair deletion of exon 3 (c.856_860delCTCTA).
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.
