DeCure for Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase — 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 moduleHypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase 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 hypermethioninemia with deficiency of s-adenosylhomocysteine hydrolase 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
adenosylhomocysteinase (AHCY) — AHCY 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 naddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1LI4 · 2.01 Å · ligand NICOTINAMIDE-ADENINE-DINUCLEOTIDE (NAD). Experimental structure, not a prediction.
What the evidence adds up to
A single Croatian boy with S-adenosylhomocysteine hydrolase deficiency had enzyme activity approximately 3% of control in liver and 5–10% of control in red blood cells and cultured fibroblasts. Before treatment, his psychomotor development was virtually absent after five months of age. He had marked hypotonia, elevated creatine kinase and transaminases, prolonged prothrombin time, and low albumin. Brain MRI at 12.7 months showed white matter atrophy and abnormally slow myelination. Plasma methionine reached 784 microM without tyrosine elevation; S-adenosylmethionine was 30-fold elevated and S-adenosylhomocysteine 150-fold elevated. Plasma total homocysteine was only slightly elevated for an infant (14.5–15.9 microM). Leukocyte DNA was hypermethylated. Two mutations in exon 4 of the AHCY gene were identified: a maternally derived stop codon and a paternally derived missense mutation.
A second case, an eighteen-month-old female reported in 2024, was investigated for elevated transaminases, coagulopathy, cataract, hypotonia, and global developmental delay, with dysmorphic findings. She had significant methionine elevation and mild homocysteine elevation. Whole-exome sequencing revealed a homozygous novel variant in the AHCY gene and a heterozygous novel variant in the PITX3 gene. Only 19 cases of SAHH deficiency have been reported in total. The 2024 report advised a methionine-restricted diet, phosphatidylcholine, and creatine supplements, but provided no outcome data for this patient.
The 2004 report described additional pretreatment abnormalities: low plasma phosphatidylcholine and choline, and elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. No soluble inhibitor of the enzyme was found in the patient's cultured fibroblasts. The authors discussed reasons for the biochemical abnormalities and pathophysiological aspects but did not report any treatment results beyond noting that psychomotor development was virtually absent until treatment was started — without specifying what treatment was given or whether it changed the course.
What is still missing: no controlled treatment data exist for any intervention in this ultra-rare disorder. The 2024 report advises dietary and supplement strategies but provides no evidence of benefit. No trial has been designed, no funding for a natural history study or treatment trial is evident, and patient stratification by genotype or biochemical severity has not been attempted.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proceedings of the National Academy of Sciences · 2004 · 223 citations · open access
<i>S</i> -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism
AbstractWe report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 microM) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5-15.9 microM. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was approximately equal to 3% of control in liver and was 5-10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patient's cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.
S-adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism
AbstractWe report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 μM) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5–15.9 μM. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was ≈3% of control in liver and was 5–10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patient's cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.
Molecular Syndromology · 2024 · 0 citations · open access
Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene
AbstractIntroduction: S-adenosylhomocysteine hydrolase (SAHH) is one of the enzymes involved in converting methionine to homocysteine with transmethylation processes. Methyltransfer reactions are impaired in SAHH deficiency. SAHH deficiency is multisystemic and antenatal onset disorder. It is also ultra rare disease. Only 19 cases have been reported so far. Case Presentation: We report an eighteen-month-old female patient who was investigated due to elevated transaminase levels, coagulopathy, cataract, hypotonia, and global developmental delay. She also had dysmorphic findings. Significant methionine elevation and mild homocysteine elevation were detected. Other metabolic investigations and laboratory findings were unremarkable. Homozygous novel variant in the AHCY gene and heterozygous novel variant in the PITX3 gene were found by whole-exome sequencing (WES) analysis. Methionine restricted diet, phosphatidylcholine, and creatine supplements were advised. Conclusion: In this report, a case with a novel variant in the AHCY gene and prominent dysmorphic findings was reported. More SAHH deficiency cases with different findings and phenotypes will be revealed through the use of WES and genetic panels.
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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