| Knowledge-base field | Concise finding | Ontology / identifier suggestions | Key sources (year, DOI URL) | Evidence |
|---|---|---|---|---|
| Definition / inheritance | Ultra-rare **autosomal recessive** inborn error of methionine-cycle / transmethylation metabolism caused by **biallelic AHCY variants**, producing multisystem disease ranging from lethal neonatal encephalomyopathy/liver failure to mild or asymptomatic childhood presentations with later liver/muscle complications. | MONDO: not confidently confirmed here; OMIM **AHCY gene/protein record reported as 180960 in literature, but disease-specific mapping uncertain**; HPO disease grouping could include hypermethioninemia / myopathy / liver disease terms. | Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449; Barić et al. 2017, https://doi.org/10.1007/s10545-016-9972-7 | (pqac-00000001, pqac-00000007) |
| Gene / protein | **AHCY** encodes **S-adenosylhomocysteine hydrolase** (also SAHH; adenosylhomocysteinase), the key mammalian enzyme clearing SAH. | HGNC symbol: **AHCY**; protein name: S-adenosylhomocysteine hydrolase / adenosylhomocysteinase. | Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009; Vizán et al. 2021, https://doi.org/10.3389/fcell.2021.654344 | (pqac-00000000, pqac-00000009) |
| Enzyme reaction | Catalyzes hydrolysis of **S-adenosylhomocysteine (SAH)** to **adenosine + homocysteine**; reduced activity causes SAH accumulation, impaired methyltransferase flux, and disturbed SAM/SAH balance. Residual activity reported around **3%–20% of normal** in affected individuals. | GO suggestion: adenosylhomocysteinase activity; CHEBI suggestions: SAH, adenosine, homocysteine, SAM, methionine. | Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009; Motzek et al. 2016, https://doi.org/10.1371/journal.pone.0151261 | (pqac-00000002, pqac-00000008) |
| Hallmark biomarkers | Core biochemical pattern: **hypermethioninemia**, markedly elevated **SAH** and **SAM**, mild hyperhomocysteinemia in some patients, elevated **CK**, elevated aminotransferases, and low enzyme activity. Example mild pediatric case: **SAM 2426 nmol/L** (ref 55–116), **SAH 1408 nmol/L** (ref 9–45). Example homozygous adult family data: **SAH 3260 nmol/L**, **SAM 1930 nmol/L**, **methionine 528 μmol/L**. | HPO suggestions: Hypermethioninemia, Elevated circulating S-adenosylhomocysteine, Elevated circulating S-adenosylmethionine, Elevated creatine kinase, Elevated hepatic transaminases. | Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449; Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009; Barić et al. 2017, https://doi.org/10.1007/s10545-016-9972-7 | (pqac-00000004, pqac-00000000) |
| Clinical spectrum | Frequent manifestations: neonatal/infantile hypotonia, developmental delay, myopathy, liver dysfunction/failure, coagulopathy, delayed myelination or leukodystrophy, absent reflexes, cognitive/language issues, and in long-term survivors **cirrhosis/hepatocellular carcinoma**. Severity is highly variable, including **asymptomatic children** with biochemical disease. | HPO suggestions: Hypotonia, Global developmental delay, Myopathy, Leukodystrophy, Delayed myelination, Hepatic failure, Coagulopathy, Hepatocellular carcinoma. | Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449; Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009; Bas et al. 2020, https://doi.org/10.1002/ajmg.a.61489 | (pqac-00000001, pqac-00000002) |
| Major organs / systems | Primary organ involvement: **liver, skeletal muscle, central nervous system**. Secondary/late complications include hepatic cirrhosis and **hepatocellular carcinoma**. | UBERON suggestions: liver, skeletal muscle tissue, brain, cerebral white matter; CL suggestions uncertain from current evidence. | Barić et al. 2017, https://doi.org/10.1007/s10545-016-9972-7; Ramadža et al. 2022, https://doi.org/10.3389/fped.2022.847445; Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009 | (pqac-00000002, pqac-00000012) |
| Known reported variants | Reported disease-associated variants include **p.Arg49His**, **p.Arg49Cys**, **p.Tyr143Cys**, **p.Trp112Ter**, **p.Asp86Gly**, **p.Gly71Ser**, **p.Tyr328Asp**, **p.Ala89Val**, and newer presumed pathogenic variants **p.Thr57Ile** and **p.Val217Met**. Most are missense; at least one nonsense variant is reported. | Variant ontology IDs not asserted here; inheritance consistent with biallelic pathogenic / likely pathogenic germline variants. | Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009; Bas et al. 2020, https://doi.org/10.1002/ajmg.a.61489; Vugrek et al. 2009, https://doi.org/10.1002/humu.20985 | (pqac-00000002, pqac-00000013) |
| Epidemiology / patient count | Extremely rare; **2024 report states 16 patients reported globally**. A mild **South Asian / Pakistani p.Arg49His hotspot** is suggested, with allele frequency cited in the report as about **1/15,300 in South Asia vs 1/83,400 globally**; this should be treated as preliminary case-series/population-database interpretation rather than definitive prevalence. | Orphanet / MONDO IDs not confidently confirmed from current context; prevalence/incidence not established. | Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449 | (pqac-00000003, pqac-00000007) |
| Diagnosis | Recommended workup for unexplained isolated hypermethioninemia or liver-muscle-neurologic syndrome: plasma amino acids plus **SAM and SAH measurement**, CK, liver enzymes, and **molecular testing of AHCY** (single gene, panel, exome/genome depending presentation). Differential diagnosis within inherited methylation disorders is important. Newborn screening is **not currently recommended as a primary target** based on consensus guidance. | HPO / lab ontology suggestions: Hypermethioninemia, Elevated SAM, Elevated SAH; ICD/MeSH not confidently confirmed. | Barić et al. 2017, https://doi.org/10.1007/s10545-016-9972-7; Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449 | (pqac-00000001, pqac-00000006) |
| Treatment | Evidence is case-based. Main management: **methionine-restricted diet** (often with methionine-free amino acid formula). Adjuncts reported/considered: **creatine**, **phosphatidylcholine**, **N-acetylcysteine**. Biochemical and neurologic responses are variable; diet may lower methionine but often does **not normalize SAH/SAM**. **Liver transplantation** has been used in severe disease with reported biochemical and developmental improvement in at least one case. No approved gene/RNA/cell therapy and no disease-specific interventional trial identified from current search. | NCIT suggestions: Dietary modification, creatine supplementation, phosphatidylcholine supplementation, liver transplantation. | Barić et al. 2005, https://doi.org/10.1007/s10545-005-0192-9; Grubbs et al. 2010, https://doi.org/10.1007/s10545-010-9171-x; Barić et al. 2017, https://doi.org/10.1007/s10545-016-9972-7; Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449 | (pqac-00000012, pqac-00000002) |
| Prognosis | Prognosis is **highly variable**. Severe perinatal/infantile forms can be fatal within months; other patients survive into adulthood but remain at risk for progressive liver disease, myopathy, cognitive effects, and **hepatocellular carcinoma**. Long-term natural history remains poorly defined because of very small case numbers. | HPO suggestions: Early death, Liver cirrhosis, Hepatocellular carcinoma, Progressive myopathy. | Stender et al. 2015, https://doi.org/10.1016/j.ymgme.2015.10.009; Bas et al. 2020, https://doi.org/10.1002/ajmg.a.61489 | (pqac-00000002, pqac-00000001) |
| Latest 2023–2024 developments | **2024:** two asymptomatic Pakistani siblings expanded the mild phenotype and showed **diet-reversible leukodystrophy**, reinforcing concern for underdiagnosis and adult complications. **2023:** AHCY knockdown RNA-seq/cell work linked deficiency to **Wnt/LEF1-related transcriptional changes**; **C. elegans** partial-deficiency model with human-corresponding variant supported altered SAM/SAH biology and longevity effects. These mechanistic findings are experimental and not yet validated clinically. | GO suggestions: Wnt signaling pathway, regulation of transcription, methylation-related processes; model-organism mappings only. | Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449; Pavičić et al. 2023, https://doi.org/10.3390/ijms242216102; Thapa et al. 2023, https://doi.org/10.1038/s41514-023-00125-1 | (pqac-00000005, pqac-00000001) |
| Evidence gaps | No robust prevalence/incidence estimates; no controlled treatment trials; no validated genotype-specific management algorithm; penetrance and carrier frequency remain uncertain outside limited population-database observations; no established disease-specific QoL metrics; limited longitudinal biomarker-outcome correlation; no clearly documented natural disease in other species; disease identifiers across OMIM/Orphanet/MONDO require separate authoritative confirmation. | Flag as **uncertain / absent data** where noted. | Barić et al. 2017, https://doi.org/10.1007/s10545-016-9972-7; Pinto et al. 2024, https://doi.org/10.1002/jmd2.12449 | (pqac-00000001, pqac-00000012) |


*Table: This table summarizes the most actionable disease-knowledge-base facts for S-adenosylhomocysteine hydrolase deficiency, including core biology, clinical features, diagnosis, treatment, and recent developments. It emphasizes evidence-backed details, ontology suggestions where confident, and explicit uncertainty where identifiers or data are not firmly established.*