DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Wolcott-Rallison 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 moduleWolcott-Rallison 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 wolcott-rallison 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.
Molecular view
eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) — EIF2AK3 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 methylaminodrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4X7K · 1.8 Å · ligand 4-{2-amino-3-[5-fluoro-2-(methylamino)quinazolin-6-yl]-4-methylbenzoyl}-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one (3Z3). Experimental structure, not a prediction.
What the evidence adds up to
Wolcott-Rallison syndrome is a rare autosomal recessive condition first described in 1972, characterised by diabetes mellitus arising in early infancy and multiple epiphyseal dysplasia. A 1996 case report described an affected girl with recurrent episodes of hepatic failure, abnormal pancreatic histology at post-mortem, and congenital abnormalities of the central nervous and cardio-respiratory systems not previously described in this condition. She also had a deletion at 15q 11-12 in 65% of her cells. The syndrome is caused by defectiveness of the EIF2AK3 gene, which encodes the PKR-like endoplasmic reticulum kinase (PERK). Two novel compound heterozygous EIF2AK3 variations (c.2818C>T, p.Pro940Ser and c.2980G>C, p.Glu994Gln) were identified in a Chinese family using whole-exome sequencing; both are missense mutations located in the catalytic domain of PERK.
The syndrome has a poor prognosis, with a mean survival of 5.8 years, and the majority of children succumb in the first decade of life. A long-term follow-up report from 2021 described an 8-year-2-month-old girl with genetically proven WRS born to non-consanguineous parents, who was on a basal bolus regimen of insulin therapy for diabetes mellitus. She had features of skeletal dysplasia at 3 years and 3 months leading to short stature, but surprisingly had no episodes of hepatitis or liver dysfunction, which is frequently seen in children with WRS. The authors noted she was the oldest surviving patient with WRS reported in India and South Asia at that time. A 2024 case report from Pakistan described a patient with typical findings except skeletal dysplasia, who eventually died due to multi-organ failure; fewer than 60 cases have been described in the literature so far.
No drug treatment for Wolcott-Rallison syndrome itself is described in these abstracts. Management is limited to insulin therapy for diabetes and supportive care for associated disorders such as skeletal fractures, liver and renal dysfunction, and central hypothyroidism. The 2021 Chinese study stated that identification of EIF2AK3 variations enriched information for precise medical intervention, but no specific intervention was tested or proposed. What remains missing is any clinical trial of a disease-modifying therapy, adequate funding for natural history studies in a condition with fewer than 60 reported cases, and patient stratification that might account for the variable presence of liver dysfunction and skeletal dysplasia.
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 Genetics · 1996 · 28 citations
Wolcott‐Rallison syndrome associated with congenital malformations and a mosaic deletion 15q 11–12
AbstractWolcott-Rallison syndrome is a rare autosomal recessive condition first described in 1972. It is characterised by diabetes mellitus which arises in early infancy and multiple epiphyseal dysplasia. We describe an affected girl who had recurrent episodes of hepatic failure for which no obvious cause was found. Post-mortem examination revealed abnormal pancreatic histology and congenital abnormalities of the central nervous and cardio-respiratory systems which have not been previously described in this condition. She also demonstrated a deletion at 15q 11-12 in 65% of her cells.
Clinical Case Reports · 2019 · 8 citations · open access
Practical management in Wolcott‐Rallison syndrome with associated hypothyroidism, neutropenia, and recurrent liver failure: A case report
AbstractKey Clinical Message Wolcott‐Rallison syndrome is a rare genetic syndrome of neonatal diabetes, liver failure, and growth retardation. We present a case with a EIF2AK3 p.(Arg902Ter) mutation, additionally complicated by hypothyroidism, impaired renal function, and exocrine pancreas insufficiency, focusing on clinical management. For its optimization, thorough care of multiple organ systems is needed.
Frontiers in Pediatrics · 2021 · 5 citations · open access
Identification of Two Novel Compound Heterozygous EIF2AK3 Mutations Underlying Wolcott–Rallison Syndrome in a Chinese Family
AbstractObjective: Wolcott–Rallison syndrome is a rare autosomal recessive inheritance disorder caused by the defectiveness of eukaryotic translation initiation factor 2 alpha kinase 3 ( EIF2AK3 ), which encodes the PKR-like endoplasmic reticulum kinase (PERK). Defect in EIF2AK3 results in a permanent diabetes in early infancy or newborn period, a tendency to develop skeletal fractures and other associated disorders such as severe liver and renal dysfunction, and central hypothyroidism. Two patients with Wolcott–Rallison syndrome-like manifestations in a Chinese family and family members were genetically analyzed to identify if any variations that occurred in EIF2AK3 , which may cause Wolcott–Rallison syndrome. Methods: Whole-exome sequencing (WES) was performed to identify genetic variations, and Sanger sequencing was conducted to verify the identified variations in the family members with Wolcott–Rallison syndrome (WRS) clinical manifestations. Several bioinformatics tools were employed to predict the effect of EIF2AK3 variations on the protein function. The impact on PERK protein was analyzed by sequential analysis and evolution conservation study. Results: Two novel EIF2AK3 heterozygous single base variations (c.2818C>T and c.2980G>C) were detected in the proband. PERK has two functional domains: one is regulatory domain (aa 1–576), and the other is catalytic domain (aa 577–1,115). Both variations are missense mutations and locate in catalytic domain of PERK; c.2818C>T resulted in a residue substitution of proline for serine at amino acid site 940 (p.Pro940Ser), and variation c.2980G>C caused an amino acid change at position 994 from glutamic acid to glutamine (p.Glu994Gln). These novel missense variations may affect the physiological functions of PERK protein. Conclusions: Two novel compound heterozygous EIF2AK3 variations (c.2818C>T, p.Pro940Ser and c.2980G>C, p.Glu994Gln) were found in a Chinese family. The identification of the variations and verification of their pathogenicity extended the variation spectrum of EIF2AK3 variations causing Wolcott–Rallison syndrome and enriched valuable information for precise medical intervention for Wolcott–Rallison syndrome in China.
BMJ Case Reports · 2021 · 4 citations · open access
Long-term follow-up of a child with Wolcott-Rallison syndrome
AbstractWolcott-Rallison syndrome (WRS), the most common cause of permanent neonatal diabetes mellitus (DM) in consanguineous families, has a poor prognosis, with a mean survival of 5.8 years. Majority of children with WRS succumb to the disease in the first decade of life. We present the long-term follow-up of an 8-year-2-month-old girl with genetically proven WRS who was born to a non-consanguineous parentage. She is on basal bolus regimen of insulin therapy for DM. In addition, she was noted to have features of skeletal dysplasia at 3 years and 3 months of age, which has led to her short stature. Surprisingly, she has had no episodes of hepatitis or liver dysfunction so far, which is frequently seen in children with WRS. To the best of our knowledge, she is the oldest surviving patient with WRS reported in India and South Asia.
Problems of Endocrinology · 2015 · 2 citations · open access
Rare form of Permanent Neonatal Diabetes Mellitus (PNDM) due to novel mutation in EIF2AK3 gene (Wolcott—Rallison syndrome)
AbstractWolcott—Rallison syndrome (WRS) is a rare genetic disease inherited in autosomal recessive way. Сlinical manifestations develop in early infancy with symptoms of permanent neonatal diabetes mellitus (PNDM), skeletal dysplasia, short stature and hepatic dysfunction. The condition has poor prognosis and most patients die at a young age due to episodes of acute liver or renal failure. To date about 60 genetically proved cases of WRS have been reported worldwide. The disease is most common in countries where consanguineous marriages are frequent, such as the Saudi Arabia (60% cases of PNDM patients), India, Turkey, Pakistan and North Africa. In Russian Federation WRS patients have not been described earlier.
Sri Lanka Journal of Medicine · 2019 · 0 citations · open access
A case report of a child with Wolcott-Rallison syndrome
AbstractSri Lanka Journal of Medicine is the official journal of the Kandy Society of Medicine. It is a peer-reviewed journal currently published biannually. Original articles, reviews, brief reports, case reports, points of view, and letters to the editor, in all fields of medical science and practice are accepted for publication.The Sri Lanka Journal of Medicine is now indexed in DOAJ
The International Journal of Frontier Sciences · 2024 · 0 citations · open access
Wolcott-Rallison syndrome, A rare paediatric case report
AbstractWolcott-Rallison syndrome (WRS) is a rare autosomal recessive, neonatal or infancy onset disease that is non-autoimmune insulin-dependent diabetes and is associated with skeletal dysplasia and liver failure. It results in the death of the patient, mainly due to multi-organ failure. Less than 60 cases have been described in the literature so far. Here, we present a very rare case of WRS, which was diagnosed by genetic testing for EIF2AK3 mutations with typical findings of the disease, except skeletal dysplasia, which eventually died due to multi-organ failure. To the best of our knowledge, this is the first case report of WRS in Pakistan.
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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