DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Smith-Lemli-Opitz syndrome — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSmith-Lemli-Opitz syndrome maps to a 3-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 smith-lemli-opitz 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
thyroid stimulating hormone receptor (TSHR) — TSHR 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 2sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7UTZ · 2.4 Å · ligand (2S)-3-hydroxypropane-1,2-diyl dihexadecanoate (Z41). Experimental structure, not a prediction.
What the evidence adds up to
Smith-Lemli-Opitz syndrome is an autosomal recessive disorder of cholesterol biosynthesis. In a 1987 review from the institution where the syndrome was first described, upper urinary tract abnormalities were found in 57 per cent of children evaluated and genital abnormalities in 71 per cent. A 2018 case report describes a 3-year-old Sri Lankan boy who presented with acute adrenal crisis and circulatory collapse. He had soft dysmorphic features including microcephaly, bitemporal narrowing, upward slanting eyes, epicanthal folds, partial ptosis, broad nasal bridge, low set posteriorly rotated ears, high arched palate, and short neck, along with marked hyperpigmentation in perioral, buccal, and palmar areas. His blood glucose and serum bicarbonate were low, and serum electrolytes showed hyponatraemia with hyperkalaemia. Serum spot cortisol was low normal and 17-hydroxyprogesterone was low. He responded markedly to intravenously administered hydrocortisone.
A 2021 study of a Chinese pedigree identified two sisters with feeding difficulty, facial dysmorphism, seizures, and mental and speech retardation. A third child had feeding difficulty, poor weight gain and severe malnutrition after birth and died of unknown cause at 6 months. Genetic testing in the two sisters revealed compound heterozygous variants of the DHCR7 gene: c.127G>T (p.Val43Phe) and c.820_825del (p.Asn274_Val275del). Neither variant had been reported in literature or disease-related databases, nor in 1000G or gnomAD. The c.820_825del variant may affect the sterol-sensitive region of the DHCR7 protein, leading to deletion of two amino acids and possible truncation; the c.127G>T variant may affect the first transmembrane region. Both variants were predicted to be harmful by multiple software, and conservation analysis indicated the affected amino acids lie in a highly conserved region.
No drug treatment for the underlying cholesterol biosynthesis defect is tested in these abstracts. The 2018 case describes management of an acute adrenal crisis with hydrocortisone, but this is standard emergency care for adrenal insufficiency, not a disease-modifying intervention. What remains missing are trials of cholesterol supplementation or other metabolic therapies, systematic data on whether early diagnosis and steroid prophylaxis prevent adrenal crises, and any stratification of patients by genotype to predict which children are at highest risk of life-threatening complications.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Urology · 1987 · 32 citations
Genitourinary Abnormalities Associated with the Smith-Lemli-Opitz Syndrome
AbstractThe Smith-Lemli-Opitz syndrome is characterized by mental retardation, hypotonia, facial dysmorphism and abnormalities of the limbs, genitalia and kidneys. Since the latter 2 features have not been emphasized in the urological literature, the experience from the institution at which the syndrome was first described is reviewed and an illustrative case is reported. Upper urinary tract abnormalities were noted in 57 per cent and genital abnormalities in 71 per cent of the children evaluated.
Journal of Medical Case Reports · 2018 · 10 citations · open access
Smith–Lemli–Opitz syndrome presenting as acute adrenal crisis in a child: a case report
AbstractBACKGROUND: Smith-Lemli-Opitz syndrome is a rare autosomal recessive disorder of cholesterol biosynthesis which is characterized by multiple congenital malformations and global developmental delay. Here we report the case of a 3-year-old, previously undiagnosed, child with Smith-Lemli-Opitz syndrome presenting with acute adrenal crisis, which is an extremely rare and atypical presentation of this disease. CASE PRESENTATION: A 3-year-old Sri Lankan Sinhalese boy without evidence of infection presented with circulatory collapse. He had a normal perinatal period; however, his early infancy was complicated by poor feeding, episodes of loose stools, failure to thrive, and several episodes of unexplained drowsiness. His weight, height, and occipitofrontal circumference were well below the third percentile. He had soft dysmorphic features that included microcephaly, bitemporal narrowing, upward slanting eyes, epicanthal folds, partial ptosis, broad nasal bridge, low set posteriorly rotated ears, high arched palate, and short neck. Marked hyperpigmentation was noted in perioral, buccal, and palmar areas. His pulses were rapid and low in volume and his systolic blood pressure was low. Initial resuscitation was performed by administering multiple crystalloid fluid boluses. A septic screen was negative. His blood glucose and serum bicarbonate levels were low and serum electrolytes revealed hyponatremia with hyperkalemia. Serum spot cortisol level was low normal and 17-hydroxyprogesterone level was low. Diagnosis of Smith-Lemli-Opitz syndrome and associated adrenal crisis was made based on clinical and biochemical features. Intravenously administered hydrocortisone was commenced to which he showed a marked clinical response. CONCLUSIONS: This case describes a rare and atypical presentation of Smith-Lemli-Opitz syndrome and highlights the importance of making early and accurate syndromic diagnoses in children with dysmorphism to avoid sudden and life-threatening complications.
[Clinical features and genetic testing of a Chinese pedigree affected with Smith-Lemli-Opitz syndrome].
AbstractOBJECTIVE: To analyze the clinical features and genetic variants of two patients from a pedigree affected with Smith-Lemli-Opitz syndrome and explore their genotype-phenotype correlation. METHODS: Clinical data and family history of the pedigree were collected. Whole exome sequencing was carried out to identify the potential variants. Suspected variants were verified by Sanger sequencing of the family members. RESULTS: The proband and her sister both presented with feeding difficulty, facial dysmorphism, seizures, and mental and speech retardation. The third child of this family presented with feeding difficulty, poor weight gain and severe malnutrition after birth. He had died of unknown cause at 6 months without genetic testing. The fourth child was a healthy boy. Genetic testing showed that both the proband and her sister have carried c.127G>T (p.Val43Phe) and c.820_825del (p.Asn274_Val275del) compound heterozygous variants of the DHCR7 gene (NM_001360.2), but the fourth child carried neither of the variants. The two variants were unreported in the literature and disease-related databases, and were not included in the 1000G and gnomAD databases. The c.820_825del variant may affect the sterol-sensitive region of the DHCR7 protein, which can lead to deletion of two amino acids at positions 247 and 275, causing truncation of the DHCR7 protein. It is speculated that this may affect the stability of protein's spatial conformation, thereby decrease the activity of the enzyme. The c.127G>T variant may affect the first transmembrane region of the protein, which is involved in the transmembrane transport of proteins. Multiple software predicted it to be harmful. Conservation analysis suggested that the three amino acids all locate in a highly conserved region of the protein. In consideration of the clinical phenotype, family history and result of genetic testing, we speculated that both patients had Smith-Lemli-Opitz syndrome due to variants of the DHCR7 gene. CONCLUSION: This pedigree has enriched the phenotypic and genotypic data of Smith-Lemli-Opitz syndrome, which clarified the genetic etiology of the patients and provided a basis for genetic counseling of this pedigree.
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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