S-Adenosylhomocysteine Hydrolase Deficiency

Mendelian MONDO:0013404 Pathograph 18 Show in embeddings browser Inborn error of metabolism Disorder of methionine catabolism

S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive inborn error of the methionine cycle caused by biallelic loss of AHCY. Failure to hydrolyse S-adenosylhomocysteine (AdoHcy) produces AdoHcy accumulation, product inhibition of AdoMet-dependent methyltransferases, elevated S-adenosylmethionine and methionine, and impaired transmethylation. The resulting phenotype is developmental delay, hypotonia and myopathy, hepatocellular dysfunction, and white-matter abnormality, ranging from lethal perinatal disease to a mild or asymptomatic childhood course. Classic disease is developmental, hepatic, and myopathic rather than an intoxication-type metabolic crisis.

Ask OpenScientist

Ask a research question about S-Adenosylhomocysteine Hydrolase Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Inheritance
8
Pathophys.
15
Phenotypes
18
Pathograph
1
Genes
3
Medical Actions
1
Differentials
3
Models
1
Deep Research
🏷

Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
ICIMD (Inherited Metabolic Disorders)
sulfur containing amino acids
🔗

Mappings

MONDO
MONDO:0013404 hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
skos:exactMatch OMIM:613752
MONDO:0013404 cross-references OMIM:613752 and Orphanet:88618 and declares AHCY (HGNC:343) as its causal gene, matching the curated entity.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic germline AHCY variants cause the disorder; heterozygous parents are typically unaffected.
autosomal recessive inheritance
Show evidence (2 references)
PMID:39512434 SUPPORT Human Clinical
"S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive inborn error of metabolism affecting methylation by disrupting the methionine cycle."
The 2024 case report states autosomal recessive inheritance of AHCY deficiency.
PMID:31957987 SUPPORT Human Clinical
"S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive neurometabolic disorder affecting the muscles, liver, and nervous system."
Independent case report restates autosomal recessive inheritance.
⚙

Pathophysiology

8
AHCY Loss of Function
Biallelic pathogenic AHCY variants reduce adenosylhomocysteinase activity, blocking the only mammalian route for hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine. Residual activity in reported patients is typically a few percent of control rather than a complete null.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
AHCY hgnc:343 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AHCY (hgnc:343). hgnc:343 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Reported genotypes are biallelic germline loss-of-function or severe hypomorphic alleles (homozygous or compound heterozygous missense, nonsense, or stop-gain). Complete AHCY deletion is embryonic lethal in several organisms, so surviving patients retain residual activity.
methionine cycle GO:0033353 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal methionine cycle, annotated with L-methionine cycle (GO:0033353). GO:0033353 is a biological process from the Gene Ontology. ⚠ ABNORMAL
adenosylhomocysteinase activity GO:0004013 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased adenosylhomocysteinase activity (GO:0004013). GO:0004013 is a molecular function from the Gene Ontology. ↓ DECREASED
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology. skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Ahcy homozygous-null mouse Mouse fails to recapitulate A true null is not viable past early embryogenesis, so it cannot recapitulate the human residual-activity disease.
Downstream
AdoHcy Accumulation Loss of AHCY activity causes S-adenosylhomocysteine to accumulate because hydrolysis is the sole mammalian route for AdoHcy clearance.
Show evidence (4 references)
PMID:15024124 SUPPORT Human Clinical
"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."
The index patient demonstrates residual adenosylhomocysteinase activity far below control in liver and extrahepatic cells.
PMID:19177456 SUPPORT In Vitro
"Functional analysis of recombinant proteins containing the mutations detected showed that both dramatically reduce AHCY activity."
Recombinant mutant proteins from a lethal infantile case show that disease alleles reduce catalytic activity.
PMID:33869213 SUPPORT Other
"In mammals, AHCY is the only enzyme capable of performing this reaction."
Review of AHCY biochemistry states that mammals have no alternative enzyme for AdoHcy hydrolysis, so biallelic loss is not bypassed.
+ 1 more reference
AdoHcy Accumulation
S-adenosylhomocysteine accumulates when AHCY cannot hydrolyse it. AdoHcy is a potent product inhibitor of AdoMet-dependent methyltransferases.
methionine cycle GO:0033353 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal methionine cycle, annotated with L-methionine cycle (GO:0033353). GO:0033353 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
AHCY-1 Y145C C. elegans Caenorhabditis elegans partially recapitulates Recapitulates impaired SAH hydrolysis with moderately increased SAH.
Downstream
Methyltransferase Product Inhibition Elevated AdoHcy competitively inhibits AdoMet-dependent methyltransferases, lowering the AdoMet/AdoHcy methylation index.
Show evidence (2 references)
PMID:16435181 SUPPORT Human Clinical
"The latter include, most importantly, markedly elevated plasma AdoHcy."
Independent sibling case identifies plasma AdoHcy elevation as the defining biochemical lesion.
PMID:26974671 SUPPORT Human Clinical
"The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors."
States that AdoHcy is both the uncleared substrate and a potent methyltransferase inhibitor.
Methyltransferase Product Inhibition
Product inhibition of AdoMet-dependent methyltransferases impairs transmethylation of DNA, RNA, proteins, and small molecules, and secondarily elevates AdoMet and methionine.
methylation GO:0032259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased methylation (GO:0032259). GO:0032259 is a biological process from the Gene Ontology. ↓ DECREASED
S-adenosylmethionine-dependent methyltransferase activity GO:0008757 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased S-adenosylmethionine-dependent methyltransferase activity (GO:0008757). GO:0008757 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Transmethylation Reduced methyltransferase activity impairs methylation-dependent macromolecular modification, including creatine and phosphatidylcholine synthesis.
Elevated AdoMet and Methionine Unused AdoMet and upstream methionine accumulate when transmethylation flux is blocked.
Show evidence (1 reference)
PMID:39512434 SUPPORT Human Clinical
"S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive inborn error of metabolism affecting methylation by disrupting the methionine cycle."
Frames the disease as a methylation defect caused by methionine-cycle disruption.
Impaired Transmethylation
Disturbed transmethylation contributes to myopathy and white-matter disease. Plasma guanidinoacetate elevation with low phosphatidylcholine in the index case is consistent with impaired creatine and phospholipid methylation. Genome-wide DNA hypermethylation is reported in some patients and is not a constant feature.
methylation GO:0032259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased methylation (GO:0032259). GO:0032259 is a biological process from the Gene Ontology. ↓ DECREASED creatine biosynthetic process GO:0006601 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased creatine biosynthetic process (GO:0006601). GO:0006601 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hepatopathy Impaired hepatocellular transmethylation is associated with liver dysfunction, but the intervening cellular steps are not fully resolved.
Myopathy Muscle creatine depletion and impaired methylation are associated with hypotonia and myopathy.
Neurodevelopmental and White-Matter Disease Impaired transmethylation in the developing nervous system is associated with developmental delay and white-matter abnormality.
Show evidence (2 references)
PMID:15024124 SUPPORT Human Clinical
"Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine."
Low phosphatidylcholine with elevated guanidinoacetate is the expected pattern when AdoMet-dependent creatine and phospholipid methylation are impaired.
PMID:26974671 SUPPORT Human Clinical
"We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees."
DNA methylation changes occur in some patients but are not uniform, so they are not treated as the sole cellular readout of impaired transmethylation.
Elevated AdoMet and Methionine
Plasma and tissue AdoMet and methionine are elevated, producing the diagnostic biochemical signature of AHCY deficiency (hypermethioninemia with high AdoHcy). Hypermethioninemia may be absent or modest in the first weeks of life.
L-methionine metabolic process GO:0006555 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal L-methionine metabolic process (GO:0006555). GO:0006555 is a biological process from the Gene Ontology. ⚠ ABNORMAL S-adenosylmethionine metabolic process GO:0046500 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal S-adenosylmethionine metabolic process (GO:0046500). GO:0046500 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:15024124 SUPPORT Human Clinical
"In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated."
Quantifies AdoMet elevation together with AdoHcy in the index patient.
PMID:16435181 SUPPORT Human Clinical
"Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life)."
Confirms secondary AdoMet and methionine elevation and notes that methionine may be uninformative neonatally.
Hepatopathy
Hepatocellular dysfunction ranging from elevated transaminases and coagulopathy to chronic liver failure; hepatocellular carcinoma has been reported in adult survivors of a mild allele.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Ahcy loss-of-function zebrafish Zebrafish partially recapitulates Recapitulates hepatic steatosis and liver degeneration seen in patients.
Show evidence (2 references)
PMID:27671891 SUPPORT Human Clinical
"Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders."
Consensus review places liver among the primary organ systems in AHCY deficiency and related methylation disorders.
PMID:39512434 SUPPORT Human Clinical
"Both siblings showed mild chronic liver failure and elevation of creatine kinase."
Mild pediatric cases still show chronic hepatic involvement.
Myopathy
Hypotonia, delayed motor milestones, and elevated creatine kinase reflecting skeletal-muscle involvement; muscle MRI may show progressive lipid infiltration.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:35463910 SUPPORT Human Clinical
"All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle groups, and permanently elevated creatine kinase."
Sibling series documents myopathy with persistently elevated CK as a dominant feature.
Neurodevelopmental and White-Matter Disease
Developmental delay, hypotonia, and white-matter abnormalities on MRI; delayed myelination is frequently reported and has been diet-responsive in at least one mild case.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
white matter UBERON:0002316 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in white matter (UBERON:0002316). UBERON:0002316 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:15024124 SUPPORT Human Clinical
"Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination."
Index-case imaging documents white-matter atrophy and delayed myelination.
PMID:16435181 SUPPORT Human Clinical
"The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination)."
Sibling natural-history summary identifies delayed myelination and psychomotor delay as core features.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for S-Adenosylhomocysteine Hydrolase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Digestive 2
Hepatic failure HP:0001399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic failure (HP:0001399). HP:0001399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39512434 SUPPORT Human Clinical
"Its clinical spectrum spans from severe perinatal encephalomyopathy and liver failure to asymptomatic course in patients with isolated hypermethioninemia."
Liver failure is part of the severe end of the published clinical spectrum.
Hepatocellular carcinoma HP:0001402 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatocellular carcinoma (HP:0001402). HP:0001402 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26527160 SUPPORT Human Clinical
"SAH hydrolase deficiency can remain asymptomatic in childhood, and the disorder can be associated with early onset hepatocellular carcinoma."
Adult-onset case series links AHCY deficiency to early-onset HCC.
Metabolism 3
Elevated circulating creatine kinase concentration HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase concentration (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin."
Index case had elevated CK.
Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16435181 SUPPORT Human Clinical
"The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology."
Elevated aminotransferases are listed as a laboratory hallmark.
Hydrops fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20852937 SUPPORT Human Clinical
"This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly."
Two lethal siblings presented with fetal hydrops attributed to AHCY deficiency.
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin."
Index case presented with marked hypotonia.
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26974671 SUPPORT Human Clinical
"Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation."
Review of patients lists myopathy as a main characteristic.
PMID:35463910 SUPPORT Human Clinical
"All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle groups, and permanently elevated creatine kinase."
Imaging series confirms myopathy as a dominant, lasting feature.
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35463910 SUPPORT Human Clinical
"At the time of skeletal muscle MRI and MRS, all patients had hypotonia, muscle weakness (more prominent in the proximal muscles, especially in the lower extremities), fatigability, and obesity due to low physical activity."
All three imaged siblings had weakness with proximal lower-extremity predominance.
PMID:26527160 SUPPORT Human Clinical
"She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29."
An attenuated p.Arg49His case developed muscle weakness in adulthood.
Nervous System 5
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16435181 SUPPORT Human Clinical
"The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination)."
Lists psychomotor delay among the primary clinical features.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35463910 SUPPORT Human Clinical
"All three brothers had similar symptoms: psychomotor delay, myopathy, mild hepatopathy, disturbed coagulation, behavioral problems, and cognitive impairment."
The three affected siblings had persistent cognitive impairment in addition to psychomotor delay.
Delayed myelination HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination."
Index-case MRI showed abnormally slow myelination.
Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39512434 SUPPORT Human Clinical
"The older patient presented at 6 years of age with isolated verbal processing difficulty and mild diffuse leukodystrophy, reversible 12 months after introduction of methionine dietary restriction."
Documents white-matter disease that improved after methionine restriction.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16435181 SUPPORT Human Clinical
"The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination)."
Absent tendon reflexes are listed among primary neuromuscular findings.
Other 2
Prolonged prothrombin time HP:0008151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged prothrombin time (HP:0008151). HP:0008151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin."
Index case had a prolonged prothrombin time with hypoalbuminemia.
Hypermethioninemia HP:0003235 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermethioninemia (HP:0003235). HP:0003235 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 microM) without tyrosine elevation."
Index case had persistent isolated hypermethioninemia.
🧬

Genetic Associations

1
AHCY (Pathogenic Variants)
Gene: AHCY hgnc:343 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AHCY (hgnc:343). hgnc:343 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (7 references)
CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z SUPPORT Other
"AHCY | HGNC:343 | hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | MONDO:0013404 | AR | Definitive"
ClinGen classifies the AHCY–disease relationship as definitive with autosomal recessive inheritance.
PMID:15024124 SUPPORT Human Clinical
"Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation."
Index case was compound heterozygous for a stop-gain and a missense AHCY allele.
PMID:31957987 SUPPORT Human Clinical
"The disease occurs by pathogenic variants of AHCY gene encoding S-adenosylhomocysteine hydrolase (AHCY) enzyme."
States that pathogenic AHCY variants cause the disease.
+ 4 more references
💊

Medical Actions

3
Methionine-restricted diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Dietary methionine restriction, often with methionine-free amino-acid formula, is the principal disease-directed intervention. It can lower plasma methionine and has improved myelination in some patients, but does not reliably normalise AdoHcy or AdoMet. No approved AHCY enzyme replacement exists.
Mechanism Target:
MODULATES Elevated AdoMet and Methionine — Reducing methionine intake is intended to lower accumulated methionine-cycle intermediates.
Show evidence (1 reference)
PMID:39512434 SUPPORT Human Clinical
"Dietary methionine restriction decreased plasma methionine but not plasma S-adenosylhomocysteine and S-adenosylmethionine."
Diet lowered methionine without correcting the primary AdoHcy/AdoMet accumulation, so the effect is modelled as modulation rather than correction.
Show evidence (3 references)
PMID:16435181 SUPPORT Human Clinical
"The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine."
Early sibling follow-up reported improved myelination and development on methionine restriction plus supplements.
PMID:27671891 SUPPORT Human Clinical
"There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies."
Consensus recommendations support a low-methionine diet in AHCY deficiency, with limited evidence.
PMID:20852937 SUPPORT Human Clinical
"treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days."
Severe perinatal disease was not rescued by diet plus supplements, so the intervention is not uniformly effective.
Creatine and phosphatidylcholine supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: creatine CHEBI:16919 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses creatine (CHEBI:16919). CHEBI:16919 is a therapeutic agent from Chemical Entities of Biological Interest. phosphatidylcholine CHEBI:64482 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses phosphatidylcholine (CHEBI:64482). CHEBI:64482 is a therapeutic agent from Chemical Entities of Biological Interest.
Creatine and phosphatidylcholine have been used as adjuncts to bypass high-demand AdoMet-dependent biosynthetic pathways. Evidence is uncontrolled case reports; they are not enzyme-replacement therapy.
Mechanism Target:
MODULATES Impaired Transmethylation — Exogenous creatine and phosphatidylcholine are intended to bypass methylation-dependent biosynthetic demand.
Show evidence (1 reference)
PMID:16435181 SUPPORT Human Clinical
"The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine."
Adjunctive creatine and phosphatidylcholine were part of the regimen associated with clinical improvement.
Show evidence (1 reference)
PMID:16435181 SUPPORT Human Clinical
"The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine."
Documents creatine and phosphatidylcholine as used adjuncts in the original treated siblings.
Liver transplantation
Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
The only reported intervention that normalized methionine-cycle metabolites in a diet-refractory child. A 40-month-old underwent liver transplantation after dietary therapy failed; metabolic parameters were restored and psychomotor and cognitive deficits reversed at 6 months (Strauss et al. 2015, cited in PMID:33869213). High-risk, non-randomized, single case; indications in mild disease are unresolved, and extrahepatic muscle disease may not be corrected because the graft replaces a major but not exclusive source of systemic AHCY activity. Not a standard first-line therapy.
Mechanism Target:
RESTORES AHCY Loss of Function — Allograft hepatocytes supply AHCY activity and can clear circulating AdoHcy/AdoMet/methionine; extrahepatic residual enzyme deficiency is not replaced.
Show evidence (1 reference)
PMID:33869213 SUPPORT Other
"For one 40-month-old child for whom dietary therapy was ineffective, liver transplantation restored metabolic parameters and reversed psychomotor and cognitive deficits after 6 months"
Single diet-refractory case in which transplantation restored metabolites and neurodevelopment; PARTIAL because it is n=1 and extrahepatic disease may persist.
Show evidence (1 reference)
PMID:33869213 SUPPORT Other
"For one 40-month-old child for whom dietary therapy was ineffective, liver transplantation restored metabolic parameters and reversed psychomotor and cognitive deficits after 6 months"
Reviews the Strauss 2015 transplant case as the only reported metabolic normalization after failed diet.
🔬

Biochemical Markers

3
Elevated plasma methionine (INCREASED)
Context: Diagnostic hypermethioninemia of the methionine-cycle block after the neonatal period; may be absent or modest in the first weeks of life.
Pathograph Readouts
Readout Of Elevated AdoMet and Methionine Positive Diagnostic
Higher plasma methionine reflects blocked transmethylation flux.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 microM) without tyrosine elevation."
Quantifies isolated hypermethioninemia in the index patient.
Show evidence (1 reference)
PMID:27671891 SUPPORT Human Clinical
"Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy."
Consensus statement that methionine is the group hallmark but can be missing neonatally.
Elevated S-adenosyl-L-homocysteine (INCREASED)
Context: Direct biochemical consequence of AHCY loss; more specific than methionine.
Pathograph Readouts
Readout Of AdoHcy Accumulation Positive Diagnostic
Elevated AdoHcy is the most specific circulating readout of the hydrolase block.
Show evidence (1 reference)
PMID:16435181 SUPPORT Human Clinical
"The latter include, most importantly, markedly elevated plasma AdoHcy."
Identifies plasma AdoHcy as the key aetiologic laboratory abnormality.
Show evidence (1 reference)
PMID:27671891 SUPPORT Human Clinical
"Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia."
Consensus diagnostic recommendation to measure SAH (and SAM) in isolated hypermethioninemia.
Elevated S-adenosyl-L-methionine (INCREASED)
Context: Secondary AdoMet accumulation from blocked transmethylation.
Pathograph Readouts
Readout Of Elevated AdoMet and Methionine Positive Diagnostic
Elevated AdoMet accompanies AdoHcy accumulation in AHCY deficiency.
Show evidence (1 reference)
PMID:26527160 SUPPORT Human Clinical
"An asymptomatic 7-year old son of the proband is also homozygous for the AHCY-R49H mutation and has elevated serum aminotransferase levels, as well as markedly elevated serum levels of SAH, S-adenosylmethionine (SAM), and methionine, which are hallmarks of SAH hydrolase deficiency."
Lists elevated SAM together with SAH and methionine as biochemical hallmarks.
Show evidence (1 reference)
PMID:15024124 SUPPORT Human Clinical
"In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated."
Quantifies plasma AdoMet elevation in the index patient.
🔬

Diagnosis

3
Biochemical Screening
Plasma amino acids plus SAM and SAH measurement distinguish AHCY deficiency from other causes of isolated hypermethioninemia.
biomarker analysis NCIT:C63333 NCI Thesaurus (NCIT)
Focus on methionine, S-adenosylmethionine, and S-adenosylhomocysteine. Total homocysteine is at most mildly elevated, unlike CBS deficiency.
Show evidence (1 reference)
PMID:27671891 SUPPORT Human Clinical
"Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia."
Consensus diagnostic recommendation for SAM/SAH measurement.
Molecular Genetic Testing
AHCY sequencing or exome sequencing confirms biallelic pathogenic variants.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26527160 SUPPORT Human Clinical
"Exome sequencing revealed that she was homozygous for a missense mutation (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase."
Exome sequencing identified the causal homozygous AHCY variant.
Skeletal Muscle Magnetic Resonance Spectroscopy
Skeletal-muscle MRI demonstrates age-progressive lipid infiltration with proximal lower-extremity predominance, while MRS quantifies the elevated muscle lipid fraction. Together they provide non-invasive assessment of disease extent, progression, and treatment response.
skeletal muscle magnetic resonance spectroscopy NCIT:C16810 NCI Thesaurus (NCIT)
Markers: Intramuscular lipid infiltration and elevated muscle lipid fraction
Results: Progressive proximal lower-extremity lipid infiltration and an elevated muscle lipid peak support and quantify skeletal-muscle involvement.
Show evidence (2 references)
PMID:35463910 SUPPORT Human Clinical
"MRI revealed lipid infiltration, and the MRS curve showed an elevated muscle lipid fraction (higher peak of lipid), which increased with age, and was more prominent in the proximal skeletal muscles of the lower extremities."
Defines the characteristic structural and spectroscopic muscle-imaging findings and their age-related progression.
PMID:35463910 SUPPORT Human Clinical
"These findings demonstrate that an accessible and non-invasive method of MRI and MRS is useful for an insight into the extent of muscle involvement, monitoring disease progression, and response to treatment in SAHHD."
Supports muscle MRI and MRS as non-invasive diagnostic and longitudinal monitoring modalities.
📊

Prevalence

1
Reported cases in the literature
Cases In Literature Ultra Rare
Ultra-rare; Pinto et al. 2024 discuss a very small published case series (on the order of the low teens by 2024) and likely underdiagnosis of the mild p.Arg49His presentation. That exact case count is in the article body rather than the abstract, so it is recorded here rather than as a snippet-backed rate. Orphanet maps this entity as ORPHA:88618; the local Orphadata bulk XML was not present in this worktree, so no ORPHA cache row is cited.
Show evidence (2 references)
PMID:26974671 SUPPORT Human Clinical
"S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene."
Published literature characterises the disorder as rare.
PMID:33869213 SUPPORT Other
"In humans, AHCY deficiency is associated with an incurable rare recessive disorder in methionine metabolism."
Review restates that human AHCY deficiency is a rare recessive inborn error.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from S-Adenosylhomocysteine Hydrolase Deficiency:

Other inherited methylation disorders
Overlapping Features The differential diagnosis of isolated hypermethioninemia includes MAT I/III (MAT1A) deficiency, GNMT deficiency, AHCY deficiency, and adenosine kinase deficiency. CBS deficiency usually adds marked hyperhomocysteinemia. Sibling methionine-cycle disorders stay separate Disease entries.
Distinguishing Features
  • Markedly elevated plasma AdoHcy with elevated AdoMet favors AHCY deficiency.
  • MAT I/III deficiency typically has high methionine with low or inappropriately normal AdoMet.
  • CBS deficiency produces homocystinuria with elevated total homocysteine.
  • ADK deficiency combines hypermethioninemia with adenosine-salvage disruption and is a neighboring, not identical, enzyme block.
Show evidence (1 reference)
PMID:27671891 SUPPORT Human Clinical
"These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies."
Consensus list of the inherited methylation disorders in the isolated-hypermethioninemia differential.
🐁

Animal Models

3
Ahcy homozygous-null mouse
Complete Ahcy deletion is embryonic lethal before E9.5 (and chromosomal microdeletions encompassing Ahcy are lethal at the blastula stage). The null does not model surviving human patients, who retain residual hydrolase activity.
Species
Mouse
Genotype
Ahcy homozygous deletion
Genes
AHCY hgnc:343 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns AHCY (hgnc:343). hgnc:343 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:33869213
Pathograph links
AHCY Loss of Function fails to recapitulate fidelity: low A true null is not viable past early embryogenesis, so it cannot recapitulate the human residual-activity disease.
Limitations: Embryonic lethality before E9.5 precludes organ-level hepatopathy, myopathy, or white-matter phenotypes. It supports why patients are hypomorphs, not a phenocopy of clinical AHCY deficiency.
Show evidence (1 reference)
PMID:33869213 SUPPORT Model Organism
"Phenotypic analysis of a large knockout mouse line collection indicates that homozygous deletion of Ahcy is embryonic lethal before E9.5"
Documents that complete Ahcy loss is early-embryonic lethal in mouse.
Ahcy loss-of-function zebrafish
Zebrafish Ahcy mutants are lethal, with exocrine-pancreas defects, hepatic steatosis, and early larval liver degeneration — hepatic features shared with human AHCY deficiency.
Species
Zebrafish
Genotype
Ahcy loss-of-function mutations
Genes
AHCY hgnc:343 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns AHCY (hgnc:343). hgnc:343 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:33869213
Pathograph links
Hepatopathy partially recapitulates fidelity: moderate Recapitulates hepatic steatosis and liver degeneration seen in patients.
Limitations: Also lethal with exocrine-pancreas defects not defining of human AHCY deficiency; a larval rather than a chronic childhood/adult model.
Show evidence (2 references)
PMID:33869213 SUPPORT Model Organism
"In zebrafish, loss-of-function mutations in Ahcy are lethal, causing defects in exocrine pancreas development"
States zebrafish Ahcy LoF is lethal with developmental organ defects.
+ 1 more reference
AHCY-1 Y145C C. elegans
Endogenous worm AHCY-1 Y145C, corresponding to human pathogenic p.Tyr143Cys, is a partial hydrolase-deficiency model used for aging biology. SAH is moderately increased; lifespan is extended rather than shortened.
Species
Caenorhabditis elegans
Genotype
ahcy-1 Y145C (human p.Tyr143Cys equivalent)
Genes
AHCY hgnc:343 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns AHCY (hgnc:343). hgnc:343 is a gene from the HUGO Gene Nomenclature Committee.
Publication
DOI:10.1038/s41514-023-00125-1
Pathograph links
AdoHcy Accumulation partially recapitulates fidelity: low Recapitulates impaired SAH hydrolysis with moderately increased SAH.
Limitations: An aging/longevity model, not a disease phenocopy: delayed aging and decreased SAM are the opposite of human developmental hepatomyopathy. Interpret only as a biochemical hypomorph of the hydrolase step.
Show evidence (2 references)
DOI:10.1038/s41514-023-00125-1 SUPPORT Model Organism
"model by introducing the S-adenosylhomocysteine hydrolase (AHCY-1) variant Y145C, corresponding to the human AHCY Y143C pathogenic mutation"
Constructs a worm allele equivalent to human p.Tyr143Cys.
+ 1 more reference
{ }

Source YAML

click to show 
name: S-Adenosylhomocysteine Hydrolase Deficiency
creation_date: "2026-08-20T02:56:36Z"
category: Mendelian
description: >-
  S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal
  recessive inborn error of the methionine cycle caused by biallelic loss of
  AHCY. Failure to hydrolyse S-adenosylhomocysteine (AdoHcy) produces AdoHcy
  accumulation, product inhibition of AdoMet-dependent methyltransferases,
  elevated S-adenosylmethionine and methionine, and impaired transmethylation.
  The resulting phenotype is developmental delay, hypotonia and myopathy,
  hepatocellular dysfunction, and white-matter abnormality, ranging from lethal
  perinatal disease to a mild or asymptomatic childhood course. Classic disease
  is developmental, hepatic, and myopathic rather than an intoxication-type
  metabolic crisis.
disease_term:
  preferred_term: hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
  term:
    id: MONDO:0013404
    label: hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
parents:
- Inborn error of metabolism
- Disorder of methionine catabolism
synonyms:
- AHCY deficiency
- SAHH deficiency
- SAH hydrolase deficiency
- adenosylhomocysteinase deficiency
- hypermethioninemia due to S-adenosylhomocysteine hydrolase deficiency
- psychomotor retardation due to S-adenosylhomocysteine hydrolase deficiency
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  icimd_category:
  - classification_value: sulfur_containing_amino_acids
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders of
      sulfur-containing amino acid (methionine, homocysteine, cysteine)
      metabolism" under category "Disorders of amino acid metabolism". AHCY
      encodes S-adenosylhomocysteine hydrolase of the methionine cycle.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013404
      label: hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:613752
    mapping_justification: >-
      MONDO:0013404 cross-references OMIM:613752 and Orphanet:88618 and
      declares AHCY (HGNC:343) as its causal gene, matching the curated entity.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic germline AHCY variants cause the disorder; heterozygous parents
    are typically unaffected.
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive
      inborn error of metabolism affecting methylation by disrupting the
      methionine cycle.
    explanation: >-
      The 2024 case report states autosomal recessive inheritance of AHCY
      deficiency.
  - reference: PMID:31957987
    reference_title: A Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive
      neurometabolic disorder affecting the muscles, liver, and nervous system.
    explanation: Independent case report restates autosomal recessive inheritance.
pathophysiology:
- name: AHCY Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic pathogenic AHCY variants reduce adenosylhomocysteinase activity,
    blocking the only mammalian route for hydrolysis of S-adenosylhomocysteine
    to adenosine and homocysteine. Residual activity in reported patients is
    typically a few percent of control rather than a complete null.
  genes:
  - preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Reported genotypes are biallelic germline loss-of-function or severe
      hypomorphic alleles (homozygous or compound heterozygous missense,
      nonsense, or stop-gain). Complete AHCY deletion is embryonic lethal in
      several organisms, so surviving patients retain residual activity.
  molecular_functions:
  - preferred_term: adenosylhomocysteinase activity
    term:
      id: GO:0004013
      label: adenosylhomocysteinase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: methionine cycle
    term:
      id: GO:0033353
      label: L-methionine cycle
    modifier: ABNORMAL
  chemical_entities:
  - preferred_term: S-adenosyl-L-homocysteine
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
    modifier: INCREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The index patient demonstrates residual adenosylhomocysteinase activity
      far below control in liver and extrahepatic cells.
  - reference: PMID:19177456
    reference_title: "S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis of recombinant proteins containing the mutations
      detected showed that both dramatically reduce AHCY activity.
    explanation: >-
      Recombinant mutant proteins from a lethal infantile case show that
      disease alleles reduce catalytic activity.
  - reference: PMID:33869213
    reference_title: Functional and Pathological Roles of AHCY.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In mammals, AHCY is the only enzyme capable of performing this reaction.
    explanation: >-
      Review of AHCY biochemistry states that mammals have no alternative
      enzyme for AdoHcy hydrolysis, so biallelic loss is not bypassed.
  - reference: PMID:33869213
    reference_title: Functional and Pathological Roles of AHCY.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Phenotypic analysis of a large knockout mouse line collection indicates that homozygous deletion of Ahcy is embryonic lethal before E9.5
    explanation: >-
      Complete Ahcy deletion is early-embryonic lethal in mouse, which is
      why reported patients carry residual-activity alleles rather than
      homozygous nulls.
  downstream:
  - target: AdoHcy Accumulation
    causal_link_type: DIRECT
    description: >-
      Loss of AHCY activity causes S-adenosylhomocysteine to accumulate because
      hydrolysis is the sole mammalian route for AdoHcy clearance.
    evidence:
    - reference: PMID:15024124
      reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold
        elevated.
      explanation: Direct plasma measurement of massive AdoHcy accumulation in the index case.
- name: AdoHcy Accumulation
  biological_scale: MOLECULAR
  description: >-
    S-adenosylhomocysteine accumulates when AHCY cannot hydrolyse it. AdoHcy is
    a potent product inhibitor of AdoMet-dependent methyltransferases.
  chemical_entities:
  - preferred_term: S-adenosyl-L-homocysteine
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
    modifier: INCREASED
  biological_processes:
  - preferred_term: methionine cycle
    term:
      id: GO:0033353
      label: L-methionine cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter include, most importantly, markedly elevated plasma AdoHcy.
    explanation: Independent sibling case identifies plasma AdoHcy elevation as the defining biochemical lesion.
  - reference: PMID:26974671
    reference_title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prime function of AHCY is to hydrolyse and efficiently remove
      S-adenosylhomocysteine, the by-product of transmethylation reactions and
      one of the most potent methyltransferase inhibitors.
    explanation: States that AdoHcy is both the uncleared substrate and a potent methyltransferase inhibitor.
  downstream:
  - target: Methyltransferase Product Inhibition
    causal_link_type: DIRECT
    description: >-
      Elevated AdoHcy competitively inhibits AdoMet-dependent
      methyltransferases, lowering the AdoMet/AdoHcy methylation index.
    evidence:
    - reference: PMID:33869213
      reference_title: Functional and Pathological Roles of AHCY.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        AHCY catalyzes the reversible break of S-adenosylhomocysteine (SAH),
        the by-product and a potent inhibitor of methyltransferases activity.
      explanation: Reviews the product-inhibition relationship between SAH and methyltransferases.
- name: Methyltransferase Product Inhibition
  biological_scale: MOLECULAR
  description: >-
    Product inhibition of AdoMet-dependent methyltransferases impairs
    transmethylation of DNA, RNA, proteins, and small molecules, and secondarily
    elevates AdoMet and methionine.
  molecular_functions:
  - preferred_term: S-adenosylmethionine-dependent methyltransferase activity
    term:
      id: GO:0008757
      label: S-adenosylmethionine-dependent methyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: methylation
    term:
      id: GO:0032259
      label: methylation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: S-adenosyl-L-methionine
    term:
      id: CHEBI:15414
      label: S-adenosyl-L-methionine
    modifier: INCREASED
  - preferred_term: L-methionine
    term:
      id: CHEBI:16643
      label: L-methionine
    modifier: INCREASED
  evidence:
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive
      inborn error of metabolism affecting methylation by disrupting the
      methionine cycle.
    explanation: Frames the disease as a methylation defect caused by methionine-cycle disruption.
  downstream:
  - target: Impaired Transmethylation
    causal_link_type: DIRECT
    description: >-
      Reduced methyltransferase activity impairs methylation-dependent
      macromolecular modification, including creatine and phosphatidylcholine
      synthesis.
  - target: Elevated AdoMet and Methionine
    causal_link_type: DIRECT
    description: >-
      Unused AdoMet and upstream methionine accumulate when transmethylation
      flux is blocked.
- name: Impaired Transmethylation
  biological_scale: CELLULAR
  description: >-
    Disturbed transmethylation contributes to myopathy and white-matter disease.
    Plasma guanidinoacetate elevation with low phosphatidylcholine in the index
    case is consistent with impaired creatine and phospholipid methylation.
    Genome-wide DNA hypermethylation is reported in some patients and is not a
    constant feature.
  biological_processes:
  - preferred_term: methylation
    term:
      id: GO:0032259
      label: methylation
    modifier: DECREASED
  - preferred_term: creatine biosynthetic process
    term:
      id: GO:0006601
      label: creatine biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional pretreatment abnormalities in plasma included low
      concentrations of phosphatidylcholine and choline, with elevations of
      guanidinoacetate, betaine, dimethylglycine, and cystathionine.
    explanation: >-
      Low phosphatidylcholine with elevated guanidinoacetate is the expected
      pattern when AdoMet-dependent creatine and phospholipid methylation are
      impaired.
  - reference: PMID:26974671
    reference_title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that DNA hypermethylation seems to be a frequent but not a
      constant feature associated with AHCY deficiency that affects different
      genomic regions to different degrees.
    explanation: >-
      DNA methylation changes occur in some patients but are not uniform, so
      they are not treated as the sole cellular readout of impaired
      transmethylation.
  downstream:
  - target: Hepatopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired hepatocellular transmethylation is associated with liver
      dysfunction, but the intervening cellular steps are not fully resolved.
  - target: Myopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Muscle creatine depletion and impaired methylation are associated with
      hypotonia and myopathy.
  - target: Neurodevelopmental and White-Matter Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired transmethylation in the developing nervous system is associated
      with developmental delay and white-matter abnormality.
- name: Elevated AdoMet and Methionine
  biological_scale: ORGANISM
  description: >-
    Plasma and tissue AdoMet and methionine are elevated, producing the
    diagnostic biochemical signature of AHCY deficiency (hypermethioninemia with
    high AdoHcy). Hypermethioninemia may be absent or modest in the first weeks
    of life.
  chemical_entities:
  - preferred_term: S-adenosyl-L-methionine
    term:
      id: CHEBI:15414
      label: S-adenosyl-L-methionine
    modifier: INCREASED
  - preferred_term: L-methionine
    term:
      id: CHEBI:16643
      label: L-methionine
    modifier: INCREASED
  biological_processes:
  - preferred_term: L-methionine metabolic process
    term:
      id: GO:0006555
      label: L-methionine metabolic process
    modifier: ABNORMAL
  - preferred_term: S-adenosylmethionine metabolic process
    term:
      id: GO:0046500
      label: S-adenosylmethionine metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold
      elevated.
    explanation: Quantifies AdoMet elevation together with AdoHcy in the index patient.
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine
      (although the hypermethioninaemia may be absent or nonsignificant in the
      first weeks of life).
    explanation: Confirms secondary AdoMet and methionine elevation and notes that methionine may be uninformative neonatally.
- name: Hepatopathy
  biological_scale: TISSUE
  description: >-
    Hepatocellular dysfunction ranging from elevated transaminases and
    coagulopathy to chronic liver failure; hepatocellular carcinoma has been
    reported in adult survivors of a mild allele.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:27671891
    reference_title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Methylation disorders predominantly affect the liver, central nervous
      system and muscles, but clinical presentation can vary considerably
      between and within disorders.
    explanation: Consensus review places liver among the primary organ systems in AHCY deficiency and related methylation disorders.
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both siblings showed mild chronic liver failure and elevation of creatine
      kinase.
    explanation: Mild pediatric cases still show chronic hepatic involvement.
- name: Myopathy
  biological_scale: TISSUE
  description: >-
    Hypotonia, delayed motor milestones, and elevated creatine kinase reflecting
    skeletal-muscle involvement; muscle MRI may show progressive lipid
    infiltration.
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:35463910
    reference_title: "Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All manifested myopathy, more pronounced in the lower extremities and the
      proximal skeletal muscle groups, and permanently elevated creatine kinase.
    explanation: Sibling series documents myopathy with persistently elevated CK as a dominant feature.
- name: Neurodevelopmental and White-Matter Disease
  biological_scale: ORGANISM
  description: >-
    Developmental delay, hypotonia, and white-matter abnormalities on MRI;
    delayed myelination is frequently reported and has been diet-responsive in
    at least one mild case.
  locations:
  - preferred_term: white matter
    term:
      id: UBERON:0002316
      label: white matter
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI at 12.7 months revealed white matter atrophy and abnormally
      slow myelination.
    explanation: Index-case imaging documents white-matter atrophy and delayed myelination.
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The information obtained suggests that the disease starts in utero and is
      characterized primarily by neuromuscular symptomatology (hypotonia,
      sluggishness, psychomotor delay, absent tendon reflexes, delayed
      myelination).
    explanation: Sibling natural-history summary identifies delayed myelination and psychomotor delay as core features.
phenotypes:
- name: Global developmental delay
  description: Psychomotor delay from infancy is a core clinical feature of classic disease.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The information obtained suggests that the disease starts in utero and is
      characterized primarily by neuromuscular symptomatology (hypotonia,
      sluggishness, psychomotor delay, absent tendon reflexes, delayed
      myelination).
    explanation: Lists psychomotor delay among the primary clinical features.
- name: Intellectual disability
  description: >-
    Persistent cognitive impairment has been reported alongside psychomotor
    delay in affected siblings.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35463910
    reference_title: "Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three brothers had similar symptoms: psychomotor delay, myopathy,
      mild hepatopathy, disturbed coagulation, behavioral problems, and
      cognitive impairment.
    explanation: >-
      The three affected siblings had persistent cognitive impairment in
      addition to psychomotor delay.
- name: Hypotonia
  description: Axial and limb hypotonia with delayed motor milestones.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had marked hypotonia with elevated serum creatine kinase and
      transaminases, prolonged prothrombin time and low albumin.
    explanation: Index case presented with marked hypotonia.
- name: Myopathy
  description: Muscle involvement with proximal lower-limb predominance.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:26974671
    reference_title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main characteristics are psychomotor delay including delayed myelination
      and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly
      associated with hypermethioninaemia, elevated serum creatine kinase
      levels and increased genome wide DNA methylation.
    explanation: Review of patients lists myopathy as a main characteristic.
  - reference: PMID:35463910
    reference_title: "Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All manifested myopathy, more pronounced in the lower extremities and the
      proximal skeletal muscle groups, and permanently elevated creatine kinase.
    explanation: Imaging series confirms myopathy as a dominant, lasting feature.
- name: Muscle weakness
  description: >-
    Predominantly proximal lower-extremity weakness is reported in childhood
    disease and may emerge during adulthood in attenuated disease.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:35463910
    reference_title: "Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the time of skeletal muscle MRI and MRS, all patients had hypotonia,
      muscle weakness (more prominent in the proximal muscles, especially in
      the lower extremities), fatigability, and obesity due to low physical
      activity.
    explanation: >-
      All three imaged siblings had weakness with proximal lower-extremity
      predominance.
  - reference: PMID:26527160
    reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She developed muscle weakness in her mid-20s, and was diagnosed with
      hepatocellular carcinoma at age 29.
    explanation: >-
      An attenuated p.Arg49His case developed muscle weakness in adulthood.
- name: Elevated circulating creatine kinase concentration
  description: Serum creatine kinase is often markedly and persistently elevated.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had marked hypotonia with elevated serum creatine kinase and
      transaminases, prolonged prothrombin time and low albumin.
    explanation: Index case had elevated CK.
- name: Elevated circulating hepatic transaminase concentration
  description: Hepatocellular injury with elevated aminotransferases.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory abnormalities are markedly increased creatine kinase and
      elevated aminotransferases, as well as specific amino acid aberrations
      that pinpoint the aetiology.
    explanation: Elevated aminotransferases are listed as a laboratory hallmark.
- name: Hepatic failure
  description: Synthetic liver dysfunction ranging from coagulopathy to chronic liver failure.
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Its clinical spectrum spans from severe perinatal encephalomyopathy and
      liver failure to asymptomatic course in patients with isolated
      hypermethioninemia.
    explanation: Liver failure is part of the severe end of the published clinical spectrum.
- name: Prolonged prothrombin time
  description: Coagulopathy from impaired hepatic synthetic function.
  phenotype_term:
    preferred_term: Prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had marked hypotonia with elevated serum creatine kinase and
      transaminases, prolonged prothrombin time and low albumin.
    explanation: Index case had a prolonged prothrombin time with hypoalbuminemia.
- name: Delayed myelination
  description: Delayed or abnormally slow myelination on brain MRI.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI at 12.7 months revealed white matter atrophy and abnormally
      slow myelination.
    explanation: Index-case MRI showed abnormally slow myelination.
- name: Abnormal cerebral white matter morphology
  description: White-matter atrophy or leukodystrophy; one mild case had diet-reversible leukodystrophy.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The older patient presented at 6 years of age with isolated verbal
      processing difficulty and mild diffuse leukodystrophy, reversible 12
      months after introduction of methionine dietary restriction.
    explanation: Documents white-matter disease that improved after methionine restriction.
- name: Hypermethioninemia
  description: Persistently elevated plasma methionine after the neonatal period.
  phenotype_term:
    preferred_term: Hypermethioninemia
    term:
      id: HP:0003235
      label: Hypermethioninemia
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypermethioninemia was present in the initial metabolic study at age 8
      months, and persisted (up to 784 microM) without tyrosine elevation.
    explanation: Index case had persistent isolated hypermethioninemia.
- name: Areflexia
  description: Absent tendon reflexes as part of the neuromuscular picture.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The information obtained suggests that the disease starts in utero and is
      characterized primarily by neuromuscular symptomatology (hypotonia,
      sluggishness, psychomotor delay, absent tendon reflexes, delayed
      myelination).
    explanation: Absent tendon reflexes are listed among primary neuromuscular findings.
- name: Hydrops fetalis
  description: Fetal hydrops in the severe perinatal presentation; not a feature of mild alleles.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:20852937
    reference_title: "S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This paper reports the clinical and metabolic findings in two sibling
      sisters born with fetal hydrops and eventually found to have deficient
      S-adenosylhomocysteine hydrolase (AHCY) activity due to compound
      heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and
      c.257A>G; p.Asp86Gly.
    explanation: Two lethal siblings presented with fetal hydrops attributed to AHCY deficiency.
- name: Hepatocellular carcinoma
  description: Early-onset HCC has been reported in an adult with a mild homozygous p.Arg49His genotype.
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:26527160
    reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SAH hydrolase deficiency can remain asymptomatic in childhood, and the
      disorder can be associated with early onset hepatocellular carcinoma.
    explanation: Adult-onset case series links AHCY deficiency to early-onset HCC.
biochemical:
- name: Elevated plasma methionine
  presence: INCREASED
  context: >-
    Diagnostic hypermethioninemia of the methionine-cycle block after the
    neonatal period; may be absent or modest in the first weeks of life.
  biomarker_term:
    preferred_term: L-methionine
    term:
      id: CHEBI:16643
      label: L-methionine
  readouts:
  - target: Elevated AdoMet and Methionine
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Higher plasma methionine reflects blocked transmethylation flux.
    evidence:
    - reference: PMID:15024124
      reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypermethioninemia was present in the initial metabolic study at age 8
        months, and persisted (up to 784 microM) without tyrosine elevation.
      explanation: Quantifies isolated hypermethioninemia in the index patient.
  evidence:
  - reference: PMID:27671891
    reference_title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although isolated hypermethioninemia is the biochemical hallmark of this
      group of disorders, it is not always present, especially in early infancy.
    explanation: Consensus statement that methionine is the group hallmark but can be missing neonatally.
- name: Elevated S-adenosyl-L-homocysteine
  presence: INCREASED
  context: Direct biochemical consequence of AHCY loss; more specific than methionine.
  biomarker_term:
    preferred_term: S-adenosyl-L-homocysteine
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
  readouts:
  - target: AdoHcy Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated AdoHcy is the most specific circulating readout of the hydrolase block.
    evidence:
    - reference: PMID:16435181
      reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The latter include, most importantly, markedly elevated plasma AdoHcy.
      explanation: Identifies plasma AdoHcy as the key aetiologic laboratory abnormality.
  evidence:
  - reference: PMID:27671891
    reference_title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma S-adenosylmethionine and S-adenosylhomocysteine are key
      metabolites for the biochemical clarification of isolated
      hypermethioninemia.
    explanation: Consensus diagnostic recommendation to measure SAH (and SAM) in isolated hypermethioninemia.
- name: Elevated S-adenosyl-L-methionine
  presence: INCREASED
  context: Secondary AdoMet accumulation from blocked transmethylation.
  biomarker_term:
    preferred_term: S-adenosyl-L-methionine
    term:
      id: CHEBI:15414
      label: S-adenosyl-L-methionine
  readouts:
  - target: Elevated AdoMet and Methionine
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated AdoMet accompanies AdoHcy accumulation in AHCY deficiency.
    evidence:
    - reference: PMID:26527160
      reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An asymptomatic 7-year old son of the proband is also homozygous for
        the AHCY-R49H mutation and has elevated serum aminotransferase levels,
        as well as markedly elevated serum levels of SAH,
        S-adenosylmethionine (SAM), and methionine, which are hallmarks of SAH
        hydrolase deficiency.
      explanation: Lists elevated SAM together with SAH and methionine as biochemical hallmarks.
  evidence:
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold
      elevated.
    explanation: Quantifies plasma AdoMet elevation in the index patient.
genetic:
- name: AHCY
  gene_term:
    preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic AHCY variants (missense, nonsense, stop-gain) cause the disease.
    Published disease-linked substitutions include p.Arg49Cys, p.Arg49His,
    p.Ala50Thr, p.Thr57Ile, p.Gly71Ser, p.Asp86Gly, p.Ala89Val, p.Glu108Lys,
    p.Trp112Ter (T112stop), p.Tyr143Cys, p.Val217Met, and p.Tyr328Asp.
    Index-case residual adenosylhomocysteinase activity was ~3% of control in
    liver and 5–10% in erythrocytes and fibroblasts (PMID:15024124); surviving
    patients are hypomorphs rather than complete nulls. Homozygous p.Arg49His
    (c.146G>A) is a recurrent mild/adult-presenting allele in Pakistani and
    other South Asian families. A published ~1/15,300 South Asian versus
    ~1/83,400 global carrier-frequency estimate for p.Arg49His sits in article
    body rather than a cached abstract, so it is not snippet-backed here.
    ClinGen Aminoacidopathy GCEP classifies the gene-disease relationship as
    Definitive (SOP11, 2024-12-13).
  evidence:
  - reference: CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z
    reference_title: "AHCY / hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AHCY | HGNC:343 | hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | MONDO:0013404 | AR | Definitive"
    explanation: ClinGen classifies the AHCY–disease relationship as definitive with autosomal recessive inheritance.
  - reference: PMID:15024124
    reference_title: "S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gene analysis revealed two mutations in exon 4: a maternally derived stop
      codon, and a paternally derived missense mutation.
    explanation: Index case was compound heterozygous for a stop-gain and a missense AHCY allele.
  - reference: PMID:31957987
    reference_title: A Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease occurs by pathogenic variants of AHCY gene encoding
      S-adenosylhomocysteine hydrolase (AHCY) enzyme.
    explanation: States that pathogenic AHCY variants cause the disease.
  - reference: PMID:19177456
    reference_title: "S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our functional studies provide novel insight into the molecular defect
      underlying AHCY deficiency and reveal that both low enzyme activity and
      protein stability of AHCY contribute to the clinical phenotype.
    explanation: Functional work on disease alleles supports loss of activity and stability as the mechanism.
  - reference: PMID:33869213
    reference_title: Functional and Pathological Roles of AHCY.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Twelve of these variants are linked with a rare autosomal recessive disorder in the methionine metabolism of hypermethioninemia (R49C, R49H, A50T, T57I, G71S, D86G, A89V, E108K, T112stop, Y143C, V217M, and Y328D)
    explanation: >-
      Review enumerates the published AHCY missense/nonsense allele series
      linked to the human disease.
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S-adenosylhomocysteine hydrolase deficiency was confirmed with homozygous missense variant c.146G>A (p.Arg49His) in the AHCY gene, a genotype previously reported in Pakistani patients with mild presentation
    explanation: >-
      Documents p.Arg49His as a recurrent mild-presentation allele in
      Pakistani patients.
  - reference: PMID:26527160
    reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing revealed that she was homozygous for a missense mutation (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase.
    explanation: >-
      Adult-onset hepatic failure and HCC in a woman of Pakistani descent
      homozygous for p.Arg49His, the mild end of the allele series.
diagnosis:
- name: Biochemical Screening
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: NCIT:C63333
      label: Biomarker Analysis
  description: >-
    Plasma amino acids plus SAM and SAH measurement distinguish AHCY deficiency
    from other causes of isolated hypermethioninemia.
  notes: >-
    Focus on methionine, S-adenosylmethionine, and S-adenosylhomocysteine. Total
    homocysteine is at most mildly elevated, unlike CBS deficiency.
  evidence:
  - reference: PMID:27671891
    reference_title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma S-adenosylmethionine and S-adenosylhomocysteine are key
      metabolites for the biochemical clarification of isolated
      hypermethioninemia.
    explanation: Consensus diagnostic recommendation for SAM/SAH measurement.
- name: Molecular Genetic Testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    AHCY sequencing or exome sequencing confirms biallelic pathogenic variants.
  evidence:
  - reference: PMID:26527160
    reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing revealed that she was homozygous for a missense mutation
      (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase.
    explanation: Exome sequencing identified the causal homozygous AHCY variant.
- name: Skeletal Muscle Magnetic Resonance Spectroscopy
  diagnosis_term:
    preferred_term: skeletal muscle magnetic resonance spectroscopy
    term:
      id: NCIT:C16810
      label: Magnetic Resonance Spectroscopy
  description: >-
    Skeletal-muscle MRI demonstrates age-progressive lipid infiltration with
    proximal lower-extremity predominance, while MRS quantifies the elevated
    muscle lipid fraction. Together they provide non-invasive assessment of
    disease extent, progression, and treatment response.
  markers: Intramuscular lipid infiltration and elevated muscle lipid fraction
  results: >-
    Progressive proximal lower-extremity lipid infiltration and an elevated
    muscle lipid peak support and quantify skeletal-muscle involvement.
  evidence:
  - reference: PMID:35463910
    reference_title: "Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI revealed lipid infiltration, and the MRS curve showed an elevated
      muscle lipid fraction (higher peak of lipid), which increased with age,
      and was more prominent in the proximal skeletal muscles of the lower
      extremities.
    explanation: >-
      Defines the characteristic structural and spectroscopic muscle-imaging
      findings and their age-related progression.
  - reference: PMID:35463910
    reference_title: "Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings demonstrate that an accessible and non-invasive method of
      MRI and MRS is useful for an insight into the extent of muscle
      involvement, monitoring disease progression, and response to treatment in
      SAHHD.
    explanation: >-
      Supports muscle MRI and MRS as non-invasive diagnostic and longitudinal
      monitoring modalities.
differential_diagnoses:
- name: Other inherited methylation disorders
  description: >-
    The differential diagnosis of isolated hypermethioninemia includes MAT I/III
    (MAT1A) deficiency, GNMT deficiency, AHCY deficiency, and adenosine kinase
    deficiency. CBS deficiency usually adds marked hyperhomocysteinemia.
    Sibling methionine-cycle disorders stay separate Disease entries.
  distinguishing_features:
  - Markedly elevated plasma AdoHcy with elevated AdoMet favors AHCY deficiency.
  - MAT I/III deficiency typically has high methionine with low or inappropriately normal AdoMet.
  - CBS deficiency produces homocystinuria with elevated total homocysteine.
  - ADK deficiency combines hypermethioninemia with adenosine-salvage disruption and is a neighboring, not identical, enzyme block.
  evidence:
  - reference: PMID:27671891
    reference_title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These are methionine adenosyltransferase I/III, glycine
      N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine
      kinase deficiencies.
    explanation: Consensus list of the inherited methylation disorders in the isolated-hypermethioninemia differential.
prevalence:
- population: Reported cases in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare; Pinto et al. 2024 discuss a very small published case series
    (on the order of the low teens by 2024) and likely underdiagnosis of the
    mild p.Arg49His presentation. That exact case count is in the article body
    rather than the abstract, so it is recorded here rather than as a
    snippet-backed rate. Orphanet maps this entity as ORPHA:88618; the local
    Orphadata bulk XML was not present in this worktree, so no ORPHA cache row
    is cited.
  evidence:
  - reference: PMID:26974671
    reference_title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal
      recessive disorder in methionine metabolism caused by mutations in the
      AHCY gene.
    explanation: Published literature characterises the disorder as rare.
  - reference: PMID:33869213
    reference_title: Functional and Pathological Roles of AHCY.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In humans, AHCY deficiency is associated with an incurable rare recessive
      disorder in methionine metabolism.
    explanation: Review restates that human AHCY deficiency is a rare recessive inborn error.
treatments:
- name: Methionine-restricted diet
  description: >-
    Dietary methionine restriction, often with methionine-free amino-acid
    formula, is the principal disease-directed intervention. It can lower
    plasma methionine and has improved myelination in some patients, but does
    not reliably normalise AdoHcy or AdoMet. No approved AHCY enzyme
    replacement exists.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Elevated AdoMet and Methionine
    treatment_effect: MODULATES
    description: >-
      Reducing methionine intake is intended to lower accumulated
      methionine-cycle intermediates.
    evidence:
    - reference: PMID:39512434
      reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dietary methionine restriction decreased plasma methionine but not
        plasma S-adenosylhomocysteine and S-adenosylmethionine.
      explanation: >-
        Diet lowered methionine without correcting the primary AdoHcy/AdoMet
        accumulation, so the effect is modelled as modulation rather than
        correction.
  evidence:
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease seems to be at least to some extent treatable, as shown by
      improved myelination and psychomotor development during dietary
      methionine restriction and supplementation with creatine and
      phosphatidylcholine.
    explanation: Early sibling follow-up reported improved myelination and development on methionine restriction plus supplements.
  - reference: PMID:27671891
    reference_title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is some evidence that this diet may also be beneficial in patients
      with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies.
    explanation: Consensus recommendations support a low-methionine diet in AHCY deficiency, with limited evidence.
  - reference: PMID:20852937
    reference_title: "S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment by means of dietary methionine restriction and supplementation
      with phosphatidylcholine and creatine did not prevent her death at age
      122 days.
    explanation: Severe perinatal disease was not rescued by diet plus supplements, so the intervention is not uniformly effective.
- name: Creatine and phosphatidylcholine supplementation
  description: >-
    Creatine and phosphatidylcholine have been used as adjuncts to bypass
    high-demand AdoMet-dependent biosynthetic pathways. Evidence is
    uncontrolled case reports; they are not enzyme-replacement therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: creatine
      term:
        id: CHEBI:16919
        label: creatine
    - preferred_term: phosphatidylcholine
      term:
        id: CHEBI:64482
        label: phosphatidylcholine
  target_mechanisms:
  - target: Impaired Transmethylation
    treatment_effect: MODULATES
    description: >-
      Exogenous creatine and phosphatidylcholine are intended to bypass
      methylation-dependent biosynthetic demand.
    evidence:
    - reference: PMID:16435181
      reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease seems to be at least to some extent treatable, as shown by
        improved myelination and psychomotor development during dietary
        methionine restriction and supplementation with creatine and
        phosphatidylcholine.
      explanation: Adjunctive creatine and phosphatidylcholine were part of the regimen associated with clinical improvement.
  evidence:
  - reference: PMID:16435181
    reference_title: "S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease seems to be at least to some extent treatable, as shown by
      improved myelination and psychomotor development during dietary
      methionine restriction and supplementation with creatine and
      phosphatidylcholine.
    explanation: Documents creatine and phosphatidylcholine as used adjuncts in the original treated siblings.
- name: Liver transplantation
  description: >-
    The only reported intervention that normalized methionine-cycle metabolites
    in a diet-refractory child. A 40-month-old underwent liver transplantation
    after dietary therapy failed; metabolic parameters were restored and
    psychomotor and cognitive deficits reversed at 6 months (Strauss et al.
    2015, cited in PMID:33869213). High-risk, non-randomized, single case;
    indications in mild disease are unresolved, and extrahepatic muscle disease
    may not be corrected because the graft replaces a major but not exclusive
    source of systemic AHCY activity. Not a standard first-line therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: AHCY Loss of Function
    treatment_effect: RESTORES
    description: >-
      Allograft hepatocytes supply AHCY activity and can clear circulating
      AdoHcy/AdoMet/methionine; extrahepatic residual enzyme deficiency is
      not replaced.
    evidence:
    - reference: PMID:33869213
      reference_title: Functional and Pathological Roles of AHCY.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        For one 40-month-old child for whom dietary therapy was ineffective, liver transplantation restored metabolic parameters and reversed psychomotor and cognitive deficits after 6 months
      explanation: >-
        Single diet-refractory case in which transplantation restored
        metabolites and neurodevelopment; PARTIAL because it is n=1 and
        extrahepatic disease may persist.
  evidence:
  - reference: PMID:33869213
    reference_title: Functional and Pathological Roles of AHCY.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For one 40-month-old child for whom dietary therapy was ineffective, liver transplantation restored metabolic parameters and reversed psychomotor and cognitive deficits after 6 months
    explanation: >-
      Reviews the Strauss 2015 transplant case as the only reported
      metabolic normalization after failed diet.
animal_models:
- name: Ahcy homozygous-null mouse
  species: Mouse
  genotype: Ahcy homozygous deletion
  publication: PMID:33869213
  description: >-
    Complete Ahcy deletion is embryonic lethal before E9.5 (and chromosomal
    microdeletions encompassing Ahcy are lethal at the blastula stage). The
    null does not model surviving human patients, who retain residual
    hydrolase activity.
  genes:
  - preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  modeled_mechanisms:
  - target: AHCY Loss of Function
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      A true null is not viable past early embryogenesis, so it cannot
      recapitulate the human residual-activity disease.
    limitations: >-
      Embryonic lethality before E9.5 precludes organ-level hepatopathy,
      myopathy, or white-matter phenotypes. It supports why patients are
      hypomorphs, not a phenocopy of clinical AHCY deficiency.
    evidence:
    - reference: PMID:33869213
      reference_title: Functional and Pathological Roles of AHCY.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Phenotypic analysis of a large knockout mouse line collection indicates that homozygous deletion of Ahcy is embryonic lethal before E9.5
      explanation: >-
        Documents that complete Ahcy loss is early-embryonic lethal in mouse.
- name: Ahcy loss-of-function zebrafish
  species: Zebrafish
  genotype: Ahcy loss-of-function mutations
  publication: PMID:33869213
  description: >-
    Zebrafish Ahcy mutants are lethal, with exocrine-pancreas defects, hepatic
    steatosis, and early larval liver degeneration — hepatic features shared
    with human AHCY deficiency.
  genes:
  - preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  modeled_mechanisms:
  - target: Hepatopathy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Recapitulates hepatic steatosis and liver degeneration seen in patients.
    limitations: >-
      Also lethal with exocrine-pancreas defects not defining of human AHCY
      deficiency; a larval rather than a chronic childhood/adult model.
    evidence:
    - reference: PMID:33869213
      reference_title: Functional and Pathological Roles of AHCY.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In zebrafish, loss-of-function mutations in Ahcy are lethal, causing defects in exocrine pancreas development
      explanation: >-
        States zebrafish Ahcy LoF is lethal with developmental organ defects.
    - reference: PMID:33869213
      reference_title: Functional and Pathological Roles of AHCY.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        mutants display hepatic steatosis (accumulation of lipids in hepatocytes) and liver degeneration early at larvae stage
      explanation: >-
        Hepatic steatosis and larval liver degeneration are the join point
        to the human Hepatopathy node.
- name: AHCY-1 Y145C C. elegans
  species: Caenorhabditis elegans
  genotype: ahcy-1 Y145C (human p.Tyr143Cys equivalent)
  publication: DOI:10.1038/s41514-023-00125-1
  description: >-
    Endogenous worm AHCY-1 Y145C, corresponding to human pathogenic p.Tyr143Cys,
    is a partial hydrolase-deficiency model used for aging biology. SAH is
    moderately increased; lifespan is extended rather than shortened.
  genes:
  - preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  modeled_mechanisms:
  - target: AdoHcy Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Recapitulates impaired SAH hydrolysis with moderately increased SAH.
    limitations: >-
      An aging/longevity model, not a disease phenocopy: delayed aging and
      decreased SAM are the opposite of human developmental hepatomyopathy.
      Interpret only as a biochemical hypomorph of the hydrolase step.
    evidence:
    - reference: DOI:10.1038/s41514-023-00125-1
      reference_title: "SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        model by introducing the S-adenosylhomocysteine hydrolase (AHCY-1) variant Y145C, corresponding to the human AHCY Y143C pathogenic mutation
      explanation: >-
        Constructs a worm allele equivalent to human p.Tyr143Cys.
    - reference: DOI:10.1038/s41514-023-00125-1
      reference_title: "SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        delayed aging, accompanied by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels
      explanation: >-
        Confirms moderate SAH elevation (the AdoHcy node) while documenting
        that the organismal readout is delayed aging, not human disease.
📚

References & Deep Research

Deep Research

1
Falcon ▸
S-Adenosylhomocysteine Hydrolase Deficiency: Disease Characteristics Report
Edison Scientific Literature 34 citations 2026-08-19T20:09:57.271161

S-Adenosylhomocysteine Hydrolase Deficiency: Disease Characteristics Report

Executive summary

S-adenosylhomocysteine hydrolase deficiency (SAHHD; AHCY deficiency) is an ultra-rare autosomal-recessive disorder of the methionine/transmethylation cycle caused by biallelic pathogenic variants in AHCY. Deficient enzyme activity impairs conversion of S-adenosylhomocysteine (SAH) to adenosine and homocysteine, producing marked SAH and S-adenosylmethionine (SAM) accumulation, hypermethioninemia, and widespread disturbance of methylation-dependent biology. The major affected systems are liver, skeletal muscle, and central nervous system. Severity ranges from fetal hydrops and fatal neonatal encephalomyopathy/liver failure to minimally symptomatic childhood disease and adult-onset myopathy, cirrhosis, and hepatocellular carcinoma (HCC). Only 16 affected individuals had been reported by September 2024, so frequencies, penetrance, prognosis, and treatment effects remain imprecise (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 7-7, pinto2024asymptomaticpediatricpresentation pages 2-2).

The most important recent development is recognition of a mild, probably underdiagnosed p.Arg49His phenotype in children of Pakistani/South Asian ancestry. In two 2024 cases, methionine restriction corrected hypermethioninemia and reversed mild white-matter abnormalities but did not normalize SAH, SAM, liver enzymes, or muscle biomarkers (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 9-10, pinto2024asymptomaticpediatricpresentation pages 2-3).

The following table provides a compact knowledge-base summary; the narrative below supplies qualifications and additional ontology annotations.

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 (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 2-2)
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 (stender2015adultonsetliverdisease pages 5-6, vizan2021functionalandpathological pages 4-5)
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 (stender2015adultonsetliverdisease pages 6-8, motzek2016abnormalhypermethylationat pages 8-9)
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 (pinto2024asymptomaticpediatricpresentation pages 4-4, stender2015adultonsetliverdisease pages 5-6)
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 (pinto2024asymptomaticpediatricpresentation pages 1-2, stender2015adultonsetliverdisease pages 6-8)
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 (stender2015adultonsetliverdisease pages 6-8, pinto2024asymptomaticpediatricpresentation pages 8-9)
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 (stender2015adultonsetliverdisease pages 6-8, stender2015adultonsetliverdisease pages 16-16)
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 (pinto2024asymptomaticpediatricpresentation pages 7-7, pinto2024asymptomaticpediatricpresentation pages 2-2)
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 (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 2-3)
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 (pinto2024asymptomaticpediatricpresentation pages 8-9, stender2015adultonsetliverdisease pages 6-8)
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 (stender2015adultonsetliverdisease pages 6-8, pinto2024asymptomaticpediatricpresentation pages 1-2)
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 (pinto2024asymptomaticpediatricpresentation pages 9-10, pinto2024asymptomaticpediatricpresentation pages 1-2)
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 (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 8-9)

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.

1. Disease information

Definition and names

Preferred name: S-adenosylhomocysteine hydrolase deficiency. Common alternatives are SAH hydrolase deficiency, SAHH deficiency, AHCY deficiency, adenosylhomocysteinase deficiency, and hypermethioninemia due to S-adenosylhomocysteine hydrolase deficiency. It is an inherited methylation disorder and Mendelian inborn error of methionine metabolism.

The 2024 clinical description states: “Its clinical spectrum spans from severe perinatal encephalomyopathy and liver failure to asymptomatic course in patients with isolated hypermethioninemia.” This is an appropriate concise disease definition (Pinto et al., published September 2024; DOI: https://doi.org/10.1002/jmd2.12449) (pinto2024asymptomaticpediatricpresentation pages 1-2).

Identifiers

  • Causal gene: AHCY; the literature cites OMIM 180960 for AHCY. This appears to be the gene record rather than a confidently verified disease-entry number (stender2015adultonsetliverdisease pages 5-6).
  • MONDO: a disease-specific MONDO identifier was not reliably recoverable from the evidence searched and should be verified directly in the current MONDO release before database ingestion.
  • Orphanet: no identifier was reliably established from the retrieved primary literature.
  • ICD-10/ICD-11: no dedicated code was identified; coding generally falls under other specified disorders of amino-acid metabolism/metabolism.
  • MeSH: no disease-specific descriptor was verified; broader headings include Amino Acid Metabolism, Inborn Errors and Hypermethioninemia.

These findings are aggregated from disease-level literature and case reports, not EHR-derived individual-patient records.

2. Etiology, risk, and protective factors

The necessary cause is biallelic germline AHCY dysfunction. The inheritance pattern is autosomal recessive; heterozygous parents are typically clinically unaffected, although modest SAM/SAH elevations have been observed in carriers. Pathogenic alleles reduce enzyme abundance, stability, catalytic activity, or a combination thereof (stender2015adultonsetliverdisease pages 5-6, stender2015adultonsetliverdisease pages 6-8).

Reported alleles include p.Arg49His, p.Arg49Cys, p.Gly71Ser, p.Asp86Gly, p.Ala89Val, p.Trp112Ter, p.Tyr143Cys, p.Tyr328Asp, and the proposed disease-associated p.Thr57Ile/p.Val217Met compound-heterozygous genotype. Most are missense; p.Trp112Ter is nonsense. Published classifications predate or do not uniformly apply current ACMG/AMP criteria, so each variant should be re-evaluated in ClinVar/gnomAD using transcript-specific HGVS before clinical reporting (stender2015adultonsetliverdisease pages 6-8, stender2015adultonsetliverdisease pages 16-16).

The best-supported genotype–phenotype observation is that homozygous c.146G>A (p.Arg49His) can retain sufficient function to permit an asymptomatic or mild childhood course, although adult liver malignancy and myopathy have occurred in the same extended phenotype. Its reported frequency was approximately 1/15,300 in South Asians versus 1/83,400 globally, suggesting regional enrichment rather than a proven founder effect (pinto2024asymptomaticpediatricpresentation pages 7-7).

No environmental toxin, infection, sex, occupation, smoking, alcohol, or lifestyle exposure is known to cause the disorder. Dietary methionine is a burden modifier, not a cause: reducing intake may lower plasma methionine, while excessive restriction risks poor growth and essential-amino-acid deficiency. No validated protective allele, modifier gene, or gene–environment interaction has been demonstrated. Consanguinity and family history increase the probability of homozygosity but do not alter the biochemical mechanism.

3. Phenotypes

Because only 16 patients were known by 2024, percentages would be misleading. The following frequencies should be recorded qualitatively.

Phenotype Type, onset, course, impact Suggested HPO term
Hypermethioninemia Laboratory hallmark; may be absent or less conspicuous in early infancy; chronic and diet-responsive Hyper­methioninemia
Elevated SAH and SAM Most discriminating laboratory abnormality; often persists despite diet Increased circulating SAH; increased circulating SAM
Hypotonia/weakness Common in severe neonatal and infantile disease; may progress to proximal myopathy HP:0001252 Hypotonia, muscular weakness
Myopathy/CK elevation Early or subclinical childhood onset through adult progression; proximal/lower-limb predominance; impairs mobility Myopathy; elevated serum CK
Developmental or cognitive impairment Variable—severe global delay to isolated verbal-processing weakness or normal mainstream schooling Global developmental delay; intellectual disability; language impairment
Delayed myelination/leukodystrophy Infantile or subtle childhood MRI finding; at least one case was reversible after diet Delayed myelination; leukodystrophy
Hepatic dysfunction Elevated aminotransferases, synthetic dysfunction, coagulopathy, steatosis, chronic failure or cirrhosis Elevated transaminases; hepatic failure; liver cirrhosis
Fetal hydrops/edema Severe prenatal/neonatal presentations; associated with high early mortality Hydrops fetalis; generalized edema
HCC Late complication in adolescent/adult survivors; reported at ages 17 and 32 in one family Hepatocellular carcinoma

In the 2024 sibling report, one child had methionine 985 µmol/L (reference 10–60), ALT approximately sixfold above normal, reversible leukodystrophy, and persistently abnormal liver/muscle markers despite biochemical correction of methionine (pinto2024asymptomaticpediatricpresentation pages 2-3). Another had SAM 2,426 nmol/L (reference 55–116) and SAH 1,408 nmol/L (reference 9–45), mild white-matter disease, and low-average verbal reasoning while attending mainstream school (pinto2024asymptomaticpediatricpresentation pages 4-4).

Quality-of-life instruments such as EQ-5D, SF-36, or PROMIS have not been reported. Severe disease compromises feeding, mobility, communication, development, and survival; mild pediatric disease may have little apparent daily effect but requires burdensome diet and lifelong surveillance.

4. Genetic and molecular information

AHCY encodes the highly conserved, NAD-dependent tetrameric enzyme S-adenosylhomocysteine hydrolase. Reported patients have approximately 3–20% residual activity, consistent predominantly with partial loss of function; complete loss is probably incompatible with embryonic survival (stender2015adultonsetliverdisease pages 6-8, vizan2021functionalandpathological pages 4-5).

All established patient variants are constitutional/germline. There is no evidence that somatic AHCY variants cause SAHHD, nor is there evidence for dominant-negative or gain-of-function disease, chromosomal rearrangements, repeat expansions, mitochondrial variants, or recurrent copy-number abnormalities. No validated modifier gene is known.

Epigenetics

SAH is a potent product inhibitor of methyltransferases. Patient blood studies found global DNA hypermethylation in two of three examined patients and abnormal imprinting-control-region methylation in four of seven, but changes were neither universal nor uniform. A proposed explanation is differential methyltransferase sensitivity: under high SAH, DNMT1 activity fell approximately 30%, whereas PRMT7 activity fell approximately 90%; excess SAM may therefore sustain DNA methylation while protein/RNA methylation remains inhibited (motzek2016abnormalhypermethylationat pages 8-9).

The authors’ conclusion is appropriately cautious: DNA hypermethylation is “a frequent but not a constant feature” affecting genomic regions to different degrees (Motzek et al., March 2016; DOI: https://doi.org/10.1371/journal.pone.0151261) (motzek2016abnormalhypermethylationat pages 8-9).

No diagnostic episignature, validated transcriptomic biomarker, structural genomic signature, or clinically actionable modifier has been established.

5. Environmental, lifestyle, and infectious information

SAHHD is not infectious and has no zoonotic transmission. No causal toxin, radiation, pollution, occupational exposure, exercise pattern, smoking, or alcohol relationship has been demonstrated. Nutrition affects substrate flux: dietary protein/methionine can alter methionine concentrations but does not reliably correct the primary SAH clearance defect. Environmental “prevention” is therefore not applicable beyond medically supervised dietary management after diagnosis.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic trigger: biallelic AHCY hypomorphic/loss-of-function variants.
  2. Primary biochemical lesion: reduced hydrolysis of SAH to adenosine and homocysteine.
  3. Metabolite disturbance: profound SAH accumulation, elevated SAM, altered SAM:SAH methylation potential, and secondary hypermethioninemia. One reported homozygous case had SAH 3,260 nmol/L, SAM 1,930 nmol/L, and methionine 528 µmol/L (stender2015adultonsetliverdisease pages 5-6).
  4. Cellular consequences: inhibition or imbalance of DNA, RNA, histone, protein, phospholipid, and small-molecule methyltransferase reactions; altered chromatin and gene expression; probable impairment of creatine and phosphatidylcholine synthesis; and disturbed adenosine/homocysteine handling.
  5. Tissue injury: myocyte dysfunction and lipid replacement, abnormal myelination/white matter, hepatocellular steatosis and degeneration, synthetic liver failure, fibrosis/cirrhosis, and possibly carcinogenesis.
  6. Clinical manifestations: hypotonia/myopathy, CK elevation, neurodevelopmental disease, liver failure, and late HCC.

The enzyme reaction is reversible in vitro but is driven toward hydrolysis in vivo by rapid removal of adenosine and homocysteine. SAH elevation may exceed 100-fold in patients (motzek2016abnormalhypermethylationat pages 8-9).

Human mechanistic evidence

Human evidence directly supports metabolite accumulation, residual enzyme deficiency, altered methylation, delayed myelination, myopathy, and liver disease. The exact pathway from methylation disturbance to organ-selective injury remains unresolved. PRMT7 inhibition has been proposed as relevant to myelin-basic-protein methylation, but this is not proven to be the principal neurological mechanism (motzek2016abnormalhypermethylationat pages 8-9).

Recent molecular profiling

In 2023, AHCY knockdown in SW480 colorectal cells produced RNA-seq changes involving Wnt signaling, epithelial–mesenchymal transition, proliferation, and increased LEF1 RNA/protein. This establishes a cell-model link between AHCY depletion and Wnt/LEF1 regulation, not a demonstrated patient mechanism or indication that colorectal cancer is part of SAHHD (DOI: https://doi.org/10.3390/ijms242216102).

Additional experimental work suggests SAH can inhibit autophagy through an AHCYL1–PIK3C3 axis, but direct involvement in human SAHHD organ pathology remains unproven. Likewise, circadian, p53/senescence, and adenosine-depletion effects are biologically plausible but not validated clinical drivers (vizan2021functionalandpathological pages 4-5, vizan2021functionalandpathological pages 7-8).

Suggested GO annotations include S-adenosylhomocysteine hydrolase activity, methionine metabolic process, S-adenosylmethionine metabolic process, methylation, chromatin organization, regulation of Wnt signaling, myelination, skeletal-muscle development, and liver development. Candidate cell types are hepatocyte, skeletal muscle fiber/myocyte, oligodendrocyte, neuron, and glial cell; evidence is strongest for hepatocytes and muscle tissue, not for a uniquely targeted neural cell type.

7. Anatomical structures affected

  • Primary: liver (UBERON: liver), skeletal muscle tissue, brain/cerebral white matter.
  • Secondary: peripheral neuromuscular system and systemic coagulation through hepatic synthetic failure.
  • Tissue findings: hepatic macrovesicular lipid droplets/steatosis; skeletal-muscle lipid infiltration and atrophy; delayed or abnormal cerebral myelination.
  • Subcellular context: AHCY functions in cytosolic and nuclear/chromatin-associated methylation environments. Relevant GO cellular components include cytosol, nucleus, chromatin, and protein-containing complex.
  • Lateralization: no characteristic unilateral or asymmetric pattern.

Skeletal-muscle MRI/MRS in three brothers aged 8, 11, and 13 years showed age-increasing lipid fraction, greatest in proximal lower-extremity muscles, supporting progressive subclinical muscle replacement and a role for MRI/MRS in longitudinal monitoring.

8. Temporal development and natural history

The disease may begin prenatally with hydrops, neonatally with hypotonia/encephalopathy/liver failure, in infancy with delayed motor development and myopathy, or remain clinically silent into childhood/adulthood. Severe infantile cases have died between approximately 3 and 12 months; intermediate cases develop chronic neuromuscular and liver disease; p.Arg49His homozygotes may remain minimally symptomatic for years before adult myopathy, cirrhosis, or HCC (stender2015adultonsetliverdisease pages 5-6, pinto2024asymptomaticpediatricpresentation pages 1-2, stender2015adultonsetliverdisease pages 6-8).

There is no validated staging system. A practical sequence is: biochemical/asymptomatic phase → neurologic, muscle, or hepatic manifestations → chronic progressive myopathy/cirrhosis → hepatic malignancy or organ failure. Course is chronic and lifelong rather than episodic. Treatment-induced biochemical improvement and white-matter reversal are possible, but spontaneous remission is not established (pinto2024asymptomaticpediatricpresentation pages 9-10).

Early childhood is probably an intervention window because myelination and muscle development are ongoing, but the evidence is a single/few cases rather than a controlled study.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed carrier parents, recurrence risks per pregnancy are 25% affected, 50% heterozygous carrier, and 25% unaffected/non-carrier. Penetrance of severe biallelic variants appears high, but penetrance of mild alleles and age-dependent manifestations is unknown. Expressivity is markedly variable. Anticipation and germline mosaicism have not been reported.

No population prevalence or annual incidence can be calculated reliably. Sixteen published patients worldwide by 2024 indicates extreme rarity but also substantial underdiagnosis (pinto2024asymptomaticpediatricpresentation pages 7-7, pinto2024asymptomaticpediatricpresentation pages 2-2). Cases have been reported from Croatia, the United States, Czech Republic, Türkiye, and Pakistani/South Asian families. No sex predominance is established. Consanguinity has contributed to homozygous cases. Carrier frequency and a definitive founder haplotype are unknown.

10. Diagnostics

Recommended workflow

  1. Clinical suspicion: unexplained hypermethioninemia, hypotonia/myopathy, persistent CK elevation, liver dysfunction/coagulopathy, delayed myelination, or fetal hydrops.
  2. First-line chemistry: quantitative plasma amino acids, total homocysteine, liver panel, bilirubin, albumin, coagulation profile, CK, renal profile, glucose, and ammonia as clinically indicated.
  3. Discriminating metabolites: plasma SAH and SAM measured in an experienced biochemical-genetics laboratory. Isolated hypermethioninemia alone is nonspecific; SAM/SAH testing is central to distinguishing inherited methylation disorders (pinto2024asymptomaticpediatricpresentation pages 4-4, pinto2024asymptomaticpediatricpresentation pages 2-3).
  4. Confirmation: biallelic pathogenic/likely pathogenic AHCY variants plus compatible biochemistry; fibroblast, erythrocyte, or liver AHCY activity can provide functional confirmation where available.
  5. Baseline organ assessment: neurologic/developmental evaluation; brain MRI; CK and muscle examination, with muscle MRI/MRS if useful; liver ultrasound/elastography, synthetic function, and AFP/HCC surveillance; ECG/echocardiography when clinically indicated.

Single-gene sequencing with deletion/duplication analysis is appropriate when biochemistry is characteristic. A hypermethioninemia, liver-failure, neurometabolic, or myopathy panel is efficient for overlapping presentations. WES/WGS is useful for atypical neonatal disease or unresolved cases, as illustrated by novel-variant discovery, but biochemical confirmation remains important. CMA, karyotype, FISH, mtDNA testing, and repeat-expansion testing are not routine unless another diagnosis is suspected.

Differential diagnosis

Key alternatives are MAT1A-related methionine adenosyltransferase I/III deficiency, glycine N-methyltransferase deficiency, adenosine kinase deficiency, cystathionine beta-synthase deficiency, tyrosinemia, citrin deficiency, generalized liver failure, congenital disorders of glycosylation—especially PMM2-CDG—and primary neuromuscular/leukodystrophy disorders. SAH and SAM profiles, total homocysteine, liver phenotype, CK, and molecular testing distinguish these conditions. SAHHD can clinically resemble PMM2-CDG (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 2-2).

Consensus authors concluded that inherited methylation disorders did not qualify as primary biochemical newborn-screening targets, partly because hypermethioninemia may be absent early and treatment evidence is limited. Genomic newborn screening may eventually detect AHCY variants, but no disease-specific effectiveness data exist.

11. Outcomes and prognosis

No 5- or 10-year survival estimates, mortality rates, or life-expectancy tables exist. Prognosis is genotype- and severity-dependent. Severe neonatal disease may be fatal within months; a 2020 infant with compound-heterozygous p.Thr57Ile/p.Val217Met died at 3 months from cardiovascular collapse. Conversely, mild homozygous p.Arg49His patients may survive into adulthood (pinto2024asymptomaticpediatricpresentation pages 1-2, stender2015adultonsetliverdisease pages 6-8).

Major morbidity includes developmental disability, progressive proximal myopathy, chronic liver failure/cirrhosis, and HCC. HCC at ages 17 and 32 suggests that malignancy surveillance is justified in long-term survivors, although the absolute risk cannot be estimated (stender2015adultonsetliverdisease pages 6-8). Residual enzyme activity, genotype, baseline liver synthetic function, CK/muscle imaging, SAM/SAH concentrations, and response to diet are plausible prognostic markers, but none is validated.

12. Treatment and real-world implementation

Methionine restriction

A specialist metabolic diet—with natural-protein/methionine restriction and methionine-free amino-acid formula—is the principal disease-directed intervention. It may lower methionine and sometimes SAM/SAH and improve strength or brain MRI, but responses are inconsistent. In the 2024 children, intake was reduced to approximately 1.6 g protein/kg/day and 32 mg methionine/kg/day; methionine fell, while SAH/SAM and liver/muscle biomarkers remained abnormal (pinto2024asymptomaticpediatricpresentation pages 7-7, pinto2024asymptomaticpediatricpresentation pages 2-3).

Over-restriction is hazardous because methionine is essential for growth. Diet should therefore be individualized using growth, essential amino acids, methionine, SAH/SAM, liver function, CK, development, and imaging—not methionine concentration alone (pinto2024asymptomaticpediatricpresentation pages 8-9).

Supplements

Creatine and phosphatidylcholine have been used to bypass high methyl-demand biosynthetic pathways; N-acetylcysteine has been considered to support glutathione/oxidative-stress handling. Evidence consists of small uncontrolled case reports, and long-term benefit or adverse-event rates are unknown. The 2024 family declined these supplements because the children were asymptomatic and evidence was limited (pinto2024asymptomaticpediatricpresentation pages 8-9).

Liver transplantation

Transplantation replaces a major source of systemic AHCY activity. A severely affected child resistant to diet reportedly showed normalization of metabolites and improvement in growth, psychomotor, and cognitive outcomes after transplantation at approximately 40 months. It remains a high-risk, non-randomized intervention; indications in mild disease are unresolved, and extrahepatic muscle disease may not be fully corrected (stender2015adultonsetliverdisease pages 6-8, vizan2021functionalandpathological pages 7-8).

Supportive care and surveillance

Management should involve metabolic medicine, hepatology, neurology, dietetics, physiotherapy, occupational/speech therapy, developmental services, and genetic counseling. Treat coagulopathy, nutritional deficiency, seizures, feeding problems, and liver complications conventionally. Monitor growth, neurodevelopment, CK/strength, liver synthetic function, fibrosis, ultrasound and AFP; use brain and muscle MRI selectively.

Suggested NCIT intervention concepts are dietary therapy/methionine restriction, amino-acid formula, creatine supplementation, phosphatidylcholine supplementation, N-acetylcysteine, physical therapy, and liver transplantation. No approved gene replacement, CRISPR, RNA, cell, targeted small-molecule, or immunotherapy exists. The ClinicalTrials.gov search found no clearly disease-specific interventional trial; retrieved broad observational/newborn-screening records did not provide explicit AHCY-deficiency enrollment evidence.

13. Prevention

There is no lifestyle or vaccine-based primary prevention. Effective genetic prevention consists of carrier testing for relatives, reproductive counseling, partner testing, prenatal diagnosis, and preimplantation genetic testing when familial variants are known. Cascade testing can identify asymptomatic biallelic relatives before irreversible liver, muscle, or white-matter injury.

Secondary prevention is early biochemical/genetic diagnosis followed by monitored dietary intervention and organ surveillance. Tertiary prevention includes rehabilitation, avoidance of malnutrition, management of liver failure, and HCC surveillance. Population biochemical newborn screening is not currently recommended specifically for SAHHD; targeted testing is reasonable in affected families and populations in which p.Arg49His enrichment is confirmed.

14. Other species and natural disease

No naturally occurring veterinary syndrome confidently equivalent to human SAHHD was identified, and there is no zoonotic relevance. AHCY is evolutionarily conserved across eukaryotes, and complete loss is developmentally deleterious in several organisms. Suggested taxa for model annotation include Danio rerio (NCBI Taxon 7955), Mus musculus (10090), and Caenorhabditis elegans (6239). Ortholog identifiers should be retrieved directly from current NCBI Gene/Alliance releases before database ingestion.

15. Model organisms

  • Zebrafish ahcy/ducttrip mutant: develops hepatic steatosis, TNF-dependent liver degeneration, and exocrine-pancreas/liver developmental abnormalities. It recapitulates liver injury and methionine-cycle disruption but not the full human neurodevelopmental/myopathy spectrum.
  • Mouse Ahcy knockout: homozygous deletion is embryonic lethal before approximately E9.5, demonstrating essential developmental function but limiting its utility for postnatal disease; conditional/hypomorphic models are needed (vizan2021functionalandpathological pages 4-5).
  • C. elegans partial deficiency: a 2023 knock-in AHCY-1 p.Tyr145Cys, corresponding to human p.Tyr143Cys, lowered SAM, moderately increased SAH, and extended lifespan through AMPK, VRK-1, and DAF-16. This is a useful methionine/aging model but does not reproduce human liver or muscle anatomy (DOI: https://doi.org/10.1038/s41514-023-00125-1).
  • Cell models: patient-derived cells and AHCY-knockdown HEK293, HepG2, SW480, and mouse embryonic fibroblasts support studies of methylation, DNA damage, proliferation, Wnt/LEF1 signaling, and adenosine biology. Cancer-cell backgrounds and acute knockdown are important limitations (vizan2021functionalandpathological pages 4-5, vizan2021functionalandpathological pages 7-8).

No validated patient iPSC, organoid, single-cell, spatial-transcriptomic, or CRISPR therapeutic-screen platform was established in the retrieved disease-specific literature.

Current expert interpretation and evidence gaps

The authoritative consensus view is that SAHHD is a multisystem inherited methylation disorder in which SAH and SAM measurement is essential, methionine restriction is biologically rational but incompletely effective, and management must be individualized. The 2024 cases materially broaden this view: apparently well children may harbor severe biochemical abnormalities and subtle reversible brain disease, while adult relatives demonstrate potentially fatal delayed complications (pinto2024asymptomaticpediatricpresentation pages 1-2, pinto2024asymptomaticpediatricpresentation pages 9-10, pinto2024asymptomaticpediatricpresentation pages 2-2).

Principal unresolved questions are true prevalence, penetrance of p.Arg49His, complete variant-level ACMG classification, natural history, optimal methionine targets, benefit of creatine/phosphatidylcholine/N-acetylcysteine, transplantation timing, HCC risk, reliable pharmacodynamic biomarkers, quality of life, and feasibility of gene or mRNA replacement. No controlled trial, registry-scale cohort, validated clinical outcome assessment, or disease-specific multi-omics atlas is available.

Key cited publications and URLs

  • Pinto PL et al. Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency. JIMD Reports. Published September 2024. https://doi.org/10.1002/jmd2.12449 (pinto2024asymptomaticpediatricpresentation pages 1-2)
  • Stender S et al. Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency. Molecular Genetics and Metabolism. December 2015. https://doi.org/10.1016/j.ymgme.2015.10.009 (stender2015adultonsetliverdisease pages 5-6, stender2015adultonsetliverdisease pages 6-8)
  • Motzek A et al. Abnormal hypermethylation at imprinting control regions in patients with AHCY deficiency. PLoS ONE. March 2016. https://doi.org/10.1371/journal.pone.0151261 (motzek2016abnormalhypermethylationat pages 8-9)
  • Vizán P et al. Functional and pathological roles of AHCY. Frontiers in Cell and Developmental Biology. March 2021. https://doi.org/10.3389/fcell.2021.654344 (vizan2021functionalandpathological pages 4-5, vizan2021functionalandpathological pages 7-8)

PMIDs were not consistently present in the retrieved full-text metadata and therefore are not supplied where they could not be verified; DOI URLs are provided to avoid introducing incorrect identifiers.

References

  1. (pinto2024asymptomaticpediatricpresentation pages 1-2): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  2. (pinto2024asymptomaticpediatricpresentation pages 7-7): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  3. (pinto2024asymptomaticpediatricpresentation pages 2-2): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  4. (pinto2024asymptomaticpediatricpresentation pages 9-10): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  5. (pinto2024asymptomaticpediatricpresentation pages 2-3): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  6. (stender2015adultonsetliverdisease pages 5-6): Stefan Stender, Rima S. Chakrabarti, Chao Xing, Garrett Gotway, Jonathan C. Cohen, and Helen H. Hobbs. Adult-onset liver disease and hepatocellular carcinoma in s-adenosylhomocysteine hydrolase deficiency. Molecular genetics and metabolism, 116 4:269-74, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.009, doi:10.1016/j.ymgme.2015.10.009. This article has 52 citations and is from a peer-reviewed journal.

  7. (vizan2021functionalandpathological pages 4-5): Pedro Vizán, Luciano Di Croce, and Sergi Aranda. Functional and pathological roles of ahcy. Frontiers in Cell and Developmental Biology, Mar 2021. URL: https://doi.org/10.3389/fcell.2021.654344, doi:10.3389/fcell.2021.654344. This article has 119 citations.

  8. (stender2015adultonsetliverdisease pages 6-8): Stefan Stender, Rima S. Chakrabarti, Chao Xing, Garrett Gotway, Jonathan C. Cohen, and Helen H. Hobbs. Adult-onset liver disease and hepatocellular carcinoma in s-adenosylhomocysteine hydrolase deficiency. Molecular genetics and metabolism, 116 4:269-74, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.009, doi:10.1016/j.ymgme.2015.10.009. This article has 52 citations and is from a peer-reviewed journal.

  9. (motzek2016abnormalhypermethylationat pages 8-9): Antje Motzek, Jelena Knežević, Olivier J. Switzeny, Alexis Cooper, Ivo Barić, Robert Beluzić, Kevin A. Strauss, Erik G. Puffenberger, S. Harvey Mudd, Oliver Vugrek, and Ulrich Zechner. Abnormal hypermethylation at imprinting control regions in patients with s-adenosylhomocysteine hydrolase (ahcy) deficiency. PLoS ONE, 11:e0151261, Mar 2016. URL: https://doi.org/10.1371/journal.pone.0151261, doi:10.1371/journal.pone.0151261. This article has 19 citations and is from a peer-reviewed journal.

  10. (pinto2024asymptomaticpediatricpresentation pages 4-4): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  11. (pinto2024asymptomaticpediatricpresentation pages 8-9): Patrícia Lipari Pinto, Marjorie Dixon, Sniya Sudhakar, Ivo Baric, and Julien Baruteau. Asymptomatic pediatric presentation of s‐adenosylhomocysteine hydrolase deficiency. JIMD Reports, 65:371-381, Sep 2024. URL: https://doi.org/10.1002/jmd2.12449, doi:10.1002/jmd2.12449. This article has 2 citations and is from a peer-reviewed journal.

  12. (stender2015adultonsetliverdisease pages 16-16): Stefan Stender, Rima S. Chakrabarti, Chao Xing, Garrett Gotway, Jonathan C. Cohen, and Helen H. Hobbs. Adult-onset liver disease and hepatocellular carcinoma in s-adenosylhomocysteine hydrolase deficiency. Molecular genetics and metabolism, 116 4:269-74, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.009, doi:10.1016/j.ymgme.2015.10.009. This article has 52 citations and is from a peer-reviewed journal.

  13. (vizan2021functionalandpathological pages 7-8): Pedro Vizán, Luciano Di Croce, and Sergi Aranda. Functional and pathological roles of ahcy. Frontiers in Cell and Developmental Biology, Mar 2021. URL: https://doi.org/10.3389/fcell.2021.654344, doi:10.3389/fcell.2021.654344. This article has 119 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 12
On topic 5
Off topic 0

All extracted references resolved successfully.