DeCure for Spastic paraplegia 88, autosomal dominant
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for spastic paraplegia 88, autosomal dominant — 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 moduleSpastic paraplegia 88, autosomal dominant 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 spastic paraplegia 88, autosomal dominant 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
SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Among 106 families with autosomal dominant HSP, seven families had six different SPG3A mutations, two of which were novel (T162P, C375R). In patients with onset before age 10, SPG3A was twice as frequent as SPG4 (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.
A family with pure autosomal dominant spastic paraplegia showed marked intrafamilial variability in age at onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55. A novel mutation in the SPG4 gene was found, affecting the consensus donor splice site of intron 16 and resulting in a premature termination codon at amino acid 578. The mutation segregated with disease in six patients. Another pedigree with autosomal dominant spastic paraplegia showed late onset, reduced penetrance, variable age and symptom expressivity, and a 1:1 transmission ratio from both males and females.
Two consanguineous families with complicated autosomal recessive HSP were mapped to a new locus on 8p12-p11.21. Affected individuals in one family had thin corpus callosum and mental retardation; in the other family, two of three affected individuals had epilepsy. The highest combined lod score was 7.077 at marker D8S505. Neuregulin and KIF13B genes within this interval are functional candidates. A spastic paraplegia type 7 patient with an expanded phenotype was diagnosed after discovery of pathogenic variants in SPG7.
Common forms include autosomal dominant SPG4, SPG3, and SPG31, and autosomal recessive SPG11, SPG7, and SPG15. About 80 spastic paraplegia genes have been identified, with almost 70 genes known and about 10 loci only mapped. What is still missing is systematic patient stratification by genotype and age of onset, prospective natural history data linking specific mutations to disability trajectories, and funding for trials that account for the extreme intrafamilial variability and reduced penetrance documented in these families.
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 · 2006 · 119 citations
SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years
AbstractSeven families with six different SPG3A mutations were identified among 106 with autosomal dominant hereditary spastic paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.
A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy
AbstractBACKGROUND: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. METHODS: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. RESULTS: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. CONCLUSION: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.
Intrafamilial variability in hereditary spastic paraplegia associated with an <i>SPG4</i> gene mutation
AbstractThe authors studied a family with pure autosomal dominant spastic paraplegia (ADHSP) that showed a marked intrafamilial variability in both age at onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55. They found a novel mutation in the SPG4 gene, which segregates with the disease in six patients. The mutation affects the consensus donor splice site of SPG4 intron 16, resulting in a premature termination codon at amino acid 578. The data confirm the pathologic significance of SPG4 mutations in pure ADHSP and add to the list of known SPG4 allelic variants.
Clinical Case Reports · 2017 · 12 citations · open access
Expanded phenotype in a patient with spastic paraplegia 7
AbstractKey Clinical Message Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG 7 .
Slowly progressive autosomal dominant spastic paraplegia with late onset, variable expression and reduced penetrance: a basis for diagnosis and counseling
AbstractWe have examined a pedigree in which familial spastic paraplegia (FSP) is segregating in four generations. The data show a high rate of transmission of the trait, late onset, reduced penetrance, variable age and symptom expressivity, and an autosomal dominant mode of transmission. A summary of our data together with the FSP data of other shows a 1:1 transmission from males and from females, and an overall 1:1 transmission ratio. The risks for the children of symptomatic and non-symptomatic parents are illustrated.
S S Korsakov Journal of Neurology and Psychiatry · 2019 · 5 citations
Common forms of hereditary spastic paraplegias
AbstractA group of hereditary spastic paraplegias includes about 80 spastic paraplegia genes (SPG): forms with identified (almost 70) or only mapped (about 10) genes. Methods of next generation sequencing (NGS), along with new SPG discovering, modify knowledge about earlier delineated SPG. Clinical and genetic characteristics of common autosomal dominant (SPG4, SPG3, SPG31) and autosomal recessive (SPG11, SPG7, SPG15) forms are presented.
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.
