DeCure for Lethal congenital contracture syndrome 3
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for lethal congenital contracture syndrome 3 — 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 moduleLethal congenital contracture syndrome 3 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 lethal congenital contracture syndrome 3 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
Lethal congenital contracture syndrome 3 is one of several prenatally lethal forms of arthrogryposis. A Finnish epidemiological study covering 1987–2002 identified 39 cases of lethal congenital contracture syndrome (LCCS) among 214 cases of multiple contractures, giving a prevalence of 1 in 25,250 births (0.40 per 10,000). LCCS was characterised by total fetal immobility on all ultrasound examinations from 12 weeks onward, multiple joint contractures of all four limbs, hydrops, and fetal death before the 32nd week of pregnancy. The study noted LCCS as a unique Finnish disorder and a major cause of lethal arthrogryposis in Finland.
The genetic basis of LCCS3 specifically is not addressed in these abstracts. However, related lethal congenital contracture syndrome subtypes are linked to mutations in different genes. A 2022 study identified a novel homozygous nonsense variant (c.3718C>T, p.Arg1240Ter) in the CNTNAP1 gene in a Chinese pedigree with lethal congenital contracture syndrome type 7, presenting with polyhydramnios, limb contracture, dyspnoea, and neonatal death. A 2023 report described a patient with ERBB3 deficiency who had a multisystemic syndrome including Hirschsprung disease, bilateral clubfoot, and cardiac defect; the authors noted that ERBB3 was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598) and that ERBB3 deficiency causes a complex syndrome with phenotypic variability.
Earlier work linked acetylcholine receptor δ subunit mutations to arthrogryposis multiplex congenita and a congenital myasthenic syndrome. A 2001 study reported a child with joint contractures at birth who carried heteroallelic mutations in the AChR δ subunit gene (δ756ins2 and δE59K). Expression studies showed δ756ins2 is a null mutation, while δE59K caused shorter channel activations in both fetal and adult AChR, predicting reduced fetal movement. The authors stated this was the first report associating AChR gene mutations with arthrogryposis multiplex congenita. A 1985 review noted that over 150 conditions include multiple congenital contractures and emphasised the need for a specific diagnosis to understand genetic basis and natural history.
What is still missing for LCCS3 is a specific gene identification, any clinical trial or treatment data, and a clear patient stratification that separates LCCS3 from other LCCS subtypes. No drug or intervention is mentioned in any of these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Orthopaedics and Related Research · 1985 · 143 citations
Genetic Aspects of Arthrogryposis
AbstractMultiple congenital contractures or arthrogryposis is a birth defect that occurs in approximately one in 3000 births. It can be seen in isolation or in association with other abnormalities. The etiologic and genetic basis of multiple congenital contractures is very heterogeneous. In order to understand the genetic basis and natural history of a specific case, a specific diagnosis must be made. Over 150 conditions are known in which multiple congenital contractures are a predominant sign. In this chapter, the emphasis is on a systematic differential diagnosis and consideration of empiric recurrent risk figures if a specific diagnosis cannot be reached.
Journal of Clinical Investigation · 2001 · 77 citations · open access
Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita
AbstractLimitation of movement during fetal development may lead to multiple joint contractures in the neonate, termed arthrogryposis multiplex congenita. Neuromuscular disorders are among the many different causes of reduced fetal movement. Many congenital myasthenic syndromes (CMSs) are due to mutations of the adult-specific ε subunit of the acetylcholine receptor (AChR), and, thus, functional deficits do not arise until late in gestation. However, an earlier effect on the fetus might be predicted with some defects of other AChR subunits. We studied a child who presented at birth with joint contractures and was subsequently found to have a CMS. Mutational screening revealed heteroallelic mutation within the AChR δ subunit gene, δ756ins2 and δE59K. Expression studies demonstrate that δ756ins2 is a null mutation. By contrast, both fetal and adult AChR containing δE59K have shorter than normal channel activations that predict fast decay of endplate currents. Thus, δE59K causes dysfunction of fetal as well as the adult AChR and would explain the presence of joint contractures on the basis of reduced fetal movement. This is the first report of the association of AChR gene mutations with arthrogryposis multiplex congenita. It is probable that mutations that severely disrupt function of fetal AChR will underlie additional cases.
American Journal of Medical Genetics Part A · 2006 · 74 citations
Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland—An epidemiological study
AbstractArthrogryposis multiplex congenita is a heterogeneous group of disorders characterized by multiple contractures with an estimated frequency of 1 in 3,000 births. With improving diagnostic methods, increasing numbers of fetuses with arthrogryposis are found. The pathogenetic mechanisms are relatively well known but the epidemiology and genetics of the prenatally lethal forms of arthrogryposis are less well known. In this study we collected all cases of a multiple contractures diagnosed in Finland during 1987-2002 including live born infants, stillbirths, and terminated pregnancies. Ninety-two cases of 214 suffered intrauterine demise (68 selective pregnancy terminations and 24 stillbirths) and 58 died in infancy. In 141 out of these cases the diagnosis could be included within lethal arthrogryposes, with a prevalence of 1 in 6,985 (1.43/10,000) births. Of these, 59 had spinal cord pathology at autopsy and thus were of neurogenic origin. Thirty-nine cases had lethal congenital contracture syndrome (LCCS) clinically characterized by total immobility of the fetus at all ultrasound examinations (12 weeks or later), multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd week of pregnancy. LCCS is noted as a unique Finnish disorder with a prevalence of 1 in 25,250 (0.40/10,000) births and is a major cause of lethal arthrogryposis in Finland.
Journal of Pediatric Orthopaedics · 1985 · 31 citations
GENETIC ASPECTS OF ARTHROGRYPOSIS
AbstractMultiple congenital contractures or arthrogryposis is a birth defect that occurs in approximately one in 3000 births. It can be seen in isolation or in association with other abnormalities. The etiologic and genetic basis of multiple congenital contractures is very heterogeneous. In order to understand the genetic basis and natural history of a specific case, a specific diagnosis must be made. Over 150 conditions are known in which multiple congenital contractures are a predominant sign. In this chapter, the emphasis is on a systematic differential diagnosis and consideration of empiric recurrent risk figures if a specific diagnosis cannot be reached.
The case of missing skin: Congenital Volkmann ischemic contracture
AbstractCongenital Volkmann ischemic contracture (CVIC) is an exceedingly rare neonatal compartment syndrome caused by intrauterine ischemia and external compression. It presents at birth with necrotic cutaneous lesions and neurologic impairment, typically in a distal upper extremity. Diagnosis and treatment are often delayed in neonates, leading to long-term neurologic sequelae. We present a rare case of CVIC in order to raise awareness of its presentation and management in hopes of improving outcomes.
[Analysis of CNTNAP1 gene variants in a Chinese pedigree affected with lethal congenital contracture syndrome type 7].
AbstractOBJECTIVE: To explore the genetic basis for a couple who had developed polyhydramnios during three pregnancies and given birth to two liveborns featuring limb contracture, dyspnea and neonatal death. METHODS: Whole-exome sequencing (WES) was carried out on fetal tissue and peripheral blood samples from the couple. Suspected variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor homozygous nonsense c.3718C>T (p.Arg1240Ter) variants of the CNTNAP1 gene, which were respectively inherited from its mother and father. The variant was unreported previously. According to the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PM2+PP4). CONCLUSION: The novel homozygous nonsense variants of the CNTNAP1 gene probably underlay the lethal congenital contracture syndrome type 7 (LCCS7) in this pedigree. Above finding has enabled genetic counseling and prenatal diagnosis for the family.
<i>ERBB3</i> deficiency causes a multisystemic syndrome in human patient and zebrafish
AbstractThe Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598), while a recent study reported six additional patients carrying ERBB3 variants which exhibited distinct clinical features with evident intestinal dysmotility (OMIM 243180). The potential connection between these phenotypes remains unknown, and the ERBB3-related phenotype spectrum needs to be better characterized. Here, we described a patient presenting with a multisystemic syndrome including skip segment Hirschsprung disease, bilateral clubfoot deformity, and cardiac defect. Trio-whole exome sequencing revealed a novel compound heterozygous variant (c.1914-7C>G; c.2942_2945del) in the patient's ERBB3 gene. RT-PCR and in vitro minigene analysis demonstrated that variant c.1914-7C>G caused aberrant mRNA splicing. Both variants resulted in premature termination codon and complete loss of ERBB3 function. erbb3b knockdown in zebrafish simultaneously caused a reduction in enteric neurons in the distal intestine, craniofacial cartilage defects, and micrognathia, which phenotypically mimics ERBB3-related intestinal dysmotility and some features of lethal congenital contracture syndrome in human patients. These findings provide further patient and animal evidence supporting that ERBB3 deficiency causes a complex syndrome involving multiple systems with phenotypic variability among distinct individuals.
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.
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