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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Mappings

MONDO

MONDO:0013404 hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

MONDO:0013404 cross-references OMIM:613752 and Orphanet:88618 and declares AHCY (HGNC:343) as its causal gene, matching the curated entity.

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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 DIRECT BACKGROUND 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 DIRECT BACKGROUND 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.

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Discussions and Knowledge Gaps

2

How do tissue-specific methylation changes produce organ disease?

ahcy_tissue_methylation

Clinical DNA methylation measurements are restricted to blood and vary between patients and loci. The 2016 study did not perform the DNMT1 or myelin-protein methyltransferase activity experiments quoted in its discussion; those are earlier studies. No direct methylation-to-neurological-phenotype mechanism is established. Zebrafish hypomethylation and the worm SAM decrease further demonstrate model and tissue differences.

Show evidence (1 reference)

PMID:26974671 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This study was performed on DNA extracted from peripheral blood samples."

The tissue restriction prevents direct extrapolation to affected muscle or brain.

Which findings in the dual AHCY/PITX3 case are attributable to AHCY?

ahcy_dual_diagnosis

The 2024 dysmorphic case carried homozygous AHCY p.Gly348Val and heterozygous PITX3 p.Tyr144Cys, both classified by the authors as likely pathogenic. SAM, SAH and enzyme activity were not available. Cataracts were attributed to PITX3; prematurity and neonatal illness also complicate neurodevelopmental attribution. The described facial and limb findings are case observations without an established AHCY-specific gestalt. The report advises diet and supplements but documents nonadherence, not treatment efficacy. Its assertion of HCC risk in heterozygous carriers is not established by the cited single-family primary report.

Show evidence (3 references)

PMID:39634240 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"S-adenosylhomocysteine (AdoHcy), and S-adenosylmethionine (AdoMet) could not be performed."

Biochemical confirmation was unavailable in this dual-diagnosis case.

PMID:39634240 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We thought that cataract finding in our patient was explained by the genetic variant in the PITX3 gene."

The authors attribute cataract to the second molecular diagnosis.

PMID:39634240 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"However, prematurity and neonatal problems may have contributed to neurodevelopmental problems."

The source itself identifies additional developmental confounding.

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Pathophysiology

14

AHCY Loss of Function

Biallelic AHCY variants reduce adenosylhomocysteinase activity. Residual activity is demonstrated in tested patient tissues and recombinant alleles, but has not been measured for every genotype. Individual substitutions can affect activity, stability or cofactor state in assay-dependent ways.

AHCY hgnc:343

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic missense or truncating variants impair AHCY function; allele-specific activity and severity cannot be inferred from a single universal residual-activity percentage.

adenosylhomocysteinase activity GO:0004013 ↓ DECREASED

Experimental models

Recombinant p.Arg49Cys and p.Asp86Gly AHCY proteins OTHER Recombinant disease alleles reduce hydrolase activity under specified conditions.

Animal models

Ahcy-containing lethal nonagouti deletion mouse Mouse partially recapitulates Models loss of Ahcy within a larger deletion, with early embryonic death.

Downstream

AdoHcy Accumulation Reduced hydrolysis impairs SAH clearance.

Methionine Accumulation Disruption of methionine-cycle metabolism is associated with variable hypermethioninemia through unresolved intermediate flux changes.

Variable Blood DNA Hypermethylation The clinical association is reproducible in subsets; the biochemical route and tissue specificity are unresolved.

Skeletal Muscle Injury Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular events are not established.

Hepatic Injury Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular events are not established.

Hepatic Synthetic Dysfunction Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular events are not established.

Impaired Myelination Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular events are not established.

Cerebral White Matter Volume Loss Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular events are not established.

Altered Neurodevelopment Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular events are not established.

Show evidence (2 references)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT In Vitro

"Functional analysis of recombinant proteins containing the mutations detected showed that both dramatically reduce AHCY activity."

The p.Arg49Cys and p.Asp86Gly proteins had reduced activity in recombinant assays.

AdoHcy Accumulation

SAH accumulates when its AHCY-mediated hydrolysis is impaired. Marked plasma elevation is a characteristic diagnostic observation; plasma levels do not directly quantify each tissue compartment.

Experimental models

Stable AHCY knockdown in SW480 colorectal cancer cells CELL LINE AHCY knockdown increases cellular SAH in the assayed cell line.

Animal models

ducttrip Ahcy-deficient zebrafish Zebrafish partially recapitulates Whole-larval SAH is elevated in homozygous mutants.

AHCY-1 Y145C C. elegans Caenorhabditis elegans partially recapitulates Young-adult mutant worms have moderately elevated SAH.

Downstream

Methyltransferase Product Inhibition SAH binds methyltransferase SAM-binding sites and inhibits susceptible enzymes; the degree varies with enzyme and substrate conditions.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated."

The index patient had markedly elevated plasma SAH and SAM.

Methyltransferase Product Inhibition

Mechanism confidence: Established

Accumulated SAH can inhibit SAM-dependent methyltransferases. Susceptibility differs by enzyme and cellular context; the SAM:SAH ratio is an index of methylation potential rather than a measurement of every methylation reaction.

Downstream

AdoMet Accumulation Reduced SAM consumption may contribute to the observed SAM accumulation; plasma measurements do not resolve intracellular flux.

Impaired Phosphatidylcholine Synthesis Inhibition of the relevant methylation reaction is inferred from metabolite patterns, without a direct patient enzyme assay.

Impaired Creatine Synthesis Inhibition of the relevant methylation reaction is inferred from metabolite patterns, without a direct patient enzyme assay.

Show evidence (1 reference)

PMID:33869213 SUPPORT DIRECT BACKGROUND In Vitro

"SAH is structurally similar to SAM and binds with a similar range of affinity to the SAM-binding pocket of MTases, thereby inhibiting their activity in a negative feedback loop"

The review summarizes product inhibition; sensitivities vary between methyltransferases and cellular contexts.

AdoMet Accumulation

SAM is elevated in plasma in human AHCY deficiency. Reduced consumption through inhibited methylation reactions is a proposed contributor; tissue-specific fluxes are not directly established by plasma concentrations.

Show evidence (2 references)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated."

The index patient had markedly elevated plasma SAH and SAM.

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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)."

SAM and methionine accumulate, but neonatal methionine can be normal.

Methionine Accumulation

Methionine is often elevated, but may be normal in early infancy or during dietary restriction despite marked SAM and SAH abnormalities. It is not a sufficient screening or treatment-response marker by itself.

Show evidence (1 reference)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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)."

SAM and methionine accumulate, but neonatal methionine can be normal.

Impaired Phosphatidylcholine Synthesis

Mechanism confidence: Hypothetical

Low plasma phosphatidylcholine and choline suggest impaired methylation-dependent phosphatidylcholine synthesis in the index patient. Direct PEMT activity was not measured, and this does not establish the sole cause of myopathy or liver injury.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine."

Plasma metabolites suggest impaired phosphatidylcholine and creatine synthesis, but neither methyltransferase was directly assayed in the patient.

Impaired Creatine Synthesis

Mechanism confidence: Hypothetical

Elevated guanidinoacetate with variable creatine measurements suggests partial impairment of methylation-dependent creatine synthesis. Brain spectroscopy retained a creatine peak; a universal cerebral creatine-depletion syndrome is not demonstrated.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine."

Plasma metabolites suggest impaired phosphatidylcholine and creatine synthesis, but neither methyltransferase was directly assayed in the patient.

Variable Blood DNA Hypermethylation

Peripheral-blood measurements show global or imprinting-region hypermethylation in subsets of patients. In the seven-patient study, four participants were siblings; global methylation was measured in only three. No abnormal GTL2, LINE1 or Alu methylation and no consistent relation to plasma SAH were found. Differential enzyme inhibition and excess SAM are hypotheses, not directly assayed explanations.

Show evidence (2 references)

PMID:26974671 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Global DNA methylation was increased in two of three analysed patients."

Peripheral-blood DNA was globally hypermethylated in two of three tested patients; this was not a brain or muscle assay.

PMID:26974671 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Three patients showed a hypermethylation in up to five imprinted gene DMRs."

Among seven patients, including four siblings, three had variable imprinting-control-region hypermethylation. Other patients and loci were unaffected.

Skeletal Muscle Injury

Myopathy includes persistent CK elevation, proximal weakness, variable muscle-fiber degeneration and replacement by fat. The molecular route from AHCY deficiency is unresolved. Normal intramyocellular lipid in the three-brother imaging study and persistent CK elevation during phosphatidylcholine supplementation argue against treating choline deficiency as an established sole mediator.

Downstream

Myopathy Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Hypotonia Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Proximal muscle weakness Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Elevated circulating creatine kinase activity Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Areflexia Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Increased muscle fatiguability Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Skeletal muscle atrophy Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator was not experimentally isolated.

Waddling gait Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator was not experimentally isolated.

Gowers sign Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator was not experimentally isolated.

Myalgia Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator was not experimentally isolated.

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle groups, and permanently elevated creatine kinase."

Three affected brothers had persistent myopathy and elevated CK; imaging and biopsies characterize injury without resolving its molecular mediator.

Hepatic Injury

Hepatic involvement includes aminotransferase elevation and biopsy abnormalities. Transaminases can also have a muscle contribution, so they do not alone isolate hepatocyte injury. A confirmed adult patient developed hepatocellular carcinoma at age 29, but the incidence and molecular route to malignancy are unknown.

Animal models

ducttrip Ahcy-deficient zebrafish Zebrafish perturbs Larval liver injury and steatosis are improved by tnfa antisense knockdown.

Downstream

Elevated circulating hepatic transaminase concentration Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Show evidence (2 references)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin."

The index patient had muscle injury markers, aminotransferase elevation, and impaired hepatic synthetic function.

PMID:26527160 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29."

One confirmed homozygous p.Arg49His patient developed HCC; her relatives with fatal liver disease were not genetically confirmed.

Hepatic Synthetic Dysfunction

Low albumin, reduced coagulation factors and hypofibrinogenemia accompany prolonged prothrombin time. Biochemical synthetic dysfunction can occur despite few outward symptoms; it is distinct from aminotransferase elevation.

Downstream

Prolonged prothrombin time Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Hypoalbuminemia Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Hypofibrinogenemia Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Reduced factor VII activity Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Hepatic failure Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin."

The index patient had muscle injury markers, aminotransferase elevation, and impaired hepatic synthetic function.

Impaired Myelination

Delayed myelination occurs in affected infants. The responsible methyltransferase, lipid or protein abnormalities in patient brain are not established. Improvement during combined dietary treatment does not isolate a single causal pathway.

Downstream

Delayed myelination Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination."

Brain MRI showed two distinct abnormalities: loss of white-matter volume and delayed myelination.

Cerebral White Matter Volume Loss

White-matter atrophy was observed on MRI in the index patient. This structural finding is recorded separately from delayed myelination; its specific molecular mediator is unresolved.

Downstream

Cerebral white matter atrophy Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination."

Brain MRI showed two distinct abnormalities: loss of white-matter volume and delayed myelination.

Altered Neurodevelopment

Global developmental delay and cognitive or behavioral difficulties vary between patients. Some children have little clinical impairment despite substantial biochemical abnormalities. Neither blood DNA methylation nor a specific neural methyltransferase defect has been proven to explain the clinical spectrum.

Downstream

Global developmental delay Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Intellectual disability Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Developmental regression Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Microcephaly Clinical manifestation associated with this disease process; specific intervening mechanisms and individual penetrance remain unresolved.

Show evidence (2 references)

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency."

The transplant case had multisystem developmental disease before treatment; evidence is limited to the primary abstract.

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT 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.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

38

Blood 3

Prolonged prothrombin time HP:0008151

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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.

Reduced factor VII activity HP:0008169

Show evidence (1 reference)

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency."

Reported in the severely affected child before liver transplantation; the accessible primary report is abstract-only.

Hypofibrinogenemia HP:0011900

Show evidence (1 reference)

PMID:39512434 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"coagulation abnormalities, which are frequently seen in SAHH deficiency, were also present, as evidenced by a prolonged PT of 19.8 s (normal 9.6–11.8) and low fibrinogen levels of 0.8 g/L (normal 1.7–4.0)"

Low fibrinogen accompanied coagulation abnormalities in a clinically mild child.

Digestive 3

Hepatic failure HP:0001399

Show evidence (1 reference)

PMID:39512434 SUPPORT DIRECT BACKGROUND 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

Show evidence (1 reference)

PMID:26527160 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29."

One confirmed homozygous p.Arg49His patient developed HCC; her relatives with fatal liver disease were not genetically confirmed.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:39634240 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She is 3 years old and has been followed with hepatomegaly, hypotonia, global developmental delay, and persistent dysmorphic features."

Hepatomegaly occurred in a child with an author-classified likely pathogenic homozygous AHCY variant; SAM/SAH and enzyme activity were unavailable, and a second PITX3 variant confounded some features.

Eye 1

Esotropia HP:0000565

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Concomitant, convergent strabismus was noted at age 11 months."

Convergent strabismus was observed in the index infant.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency."

Reported in the severely affected child before liver transplantation; the accessible primary report is abstract-only.

Metabolism 5

Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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

Show evidence (1 reference)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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.

Hypermethioninemia HP:0003235

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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.

Hydrops fetalis HP:0001789

Show evidence (1 reference)

PMID:20852937 SUPPORT DIRECT PRIMARY RESULT 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.

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin."

Low albumin was documented in the index patient.

Musculoskeletal 7

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle groups, and permanently elevated creatine kinase."

Three affected brothers had persistent myopathy and elevated CK; imaging and biopsies characterize injury without resolving its molecular mediator.

Proximal muscle weakness HP:0003701

Show evidence (2 references)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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.

Hip dysplasia HP:0001385

Show evidence (1 reference)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The boy had mild bilateral hip dysplasia and limited leg abduction."

Mild bilateral hip dysplasia was observed in one affected infant.

Increased muscle fatiguability HP:0003750

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT 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."

Fatigability was documented in the three-brother muscle-imaging study.

Skeletal muscle atrophy HP:0003202

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Skeletal muscle MRI showed abnormal fatty infiltration, edema, and atrophy, predominantly in the proximal muscles of the lower extremities, in all three patients."

MRI demonstrated muscle atrophy with proximal lower-limb predominance in three brothers.

Gowers sign HP:0003391

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He complained of fatigability and had muscle weakness, predominantly of the lower limbs, hypotonia and hyporeflexia, waddling gait, and positive Gowers sign."

A positive Gowers sign was recorded in the younger two brothers.

Nervous System 14

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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.

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency."

The transplant case had multisystem developmental disease before treatment; evidence is limited to the primary abstract.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT 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

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination."

Index-case MRI showed abnormally slow myelination.

Leukodystrophy HP:0002415

Show evidence (1 reference)

PMID:39512434 SUPPORT DIRECT PRIMARY RESULT 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

Show evidence (1 reference)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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.

Developmental regression HP:0002376

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Subsequently, stagnation and then regression were noted."

The index infant initially progressed slowly, then stagnated and regressed after approximately five months.

Cerebral white matter atrophy HP:0012762

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination."

The index MRI showed white-matter atrophy as well as delayed myelination.

Cerebellar hypoplasia HP:0001321

Show evidence (1 reference)

PMID:27671891 SUPPORT DIRECT BACKGROUND Human Clinical

"Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination"

The consensus review describes these structural brain findings in two sisters with severe perinatal disease.

Pontine hypoplasia Hypoplasia of the pons HP:0012110

Show evidence (1 reference)

PMID:27671891 SUPPORT DIRECT BACKGROUND Human Clinical

"Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination"

The consensus review describes these structural brain findings in two sisters with severe perinatal disease.

Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

PMID:27671891 SUPPORT DIRECT BACKGROUND Human Clinical

"Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination"

The consensus review describes these structural brain findings in two sisters with severe perinatal disease.

Waddling gait HP:0002515

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He complained of fatigability and had muscle weakness, predominantly of the lower limbs, hypotonia and hyporeflexia, waddling gait, and positive Gowers sign."

Waddling gait was observed in the affected brothers.

Delayed ability to walk HP:0031936

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He started to walk unassisted at age 19 months."

The index child acquired independent walking at 19 months after treatment initiation.

Seizure HP:0001250

Show evidence (1 reference)

PMID:39634240 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had her first seizure when she was 6 months old."

A seizure was reported in one child with a likely pathogenic AHCY genotype, prematurity, neonatal sepsis and a second PITX3 variant; attribution to AHCY alone is uncertain.

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:39634240 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had no words. She had no eye contact."

The same child had no words at 18 months and severe global developmental delay; the dual genetic diagnosis and neonatal complications limit attribution.

Respiratory 1

Respiratory failure HP:0002878

Show evidence (1 reference)

PMID:27671891 SUPPORT DIRECT BACKGROUND Human Clinical

"Two sibs presented severely with fetal hydrops, insufficient liver synthetic function and muscular hypotonia leading to respiratory failure and death in early infancy."

Respiratory failure occurred in the severe perinatal sibling presentation.

Constitutional 1

Myalgia HP:0003326

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He complained of fatigability and occasional lower leg muscle aches."

The oldest brother reported occasional lower-leg muscle aches.

Growth 2

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency."

Reported in the severely affected child before liver transplantation; the accessible primary report is abstract-only.

Obesity HP:0001513

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT 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."

Obesity was observed in three brothers and attributed by the authors to low physical activity; this family does not establish disease prevalence.

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Genetic Associations

1

AHCY (Pathogenic Variants)

Gene: AHCY hgnc:343 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (6 references)

CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z SUPPORT DIRECT BACKGROUND Other

ClinGen classifies the AHCY–disease relationship as definitive with autosomal recessive inheritance.

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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:19177456 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

Functional work on disease alleles supports loss of activity and stability as the mechanism.

+ 3 more references

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Medical Actions

7

Methionine-restricted diet

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Specialist-supervised methionine restriction with adequate protein, energy and other amino acids is the main dietary intervention. Some cases show developmental or MRI improvement, but biochemical and clinical responses vary and SAM/SAH, muscle injury and coagulation abnormalities can persist. Evidence is uncontrolled; excessive restriction can compromise nutrition.

Mechanism Target:

MODULATES Methionine Accumulation — Restriction can lower plasma methionine while SAM and SAH remain elevated.

Show evidence (1 reference)

PMID:39512434 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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 DIRECT BACKGROUND 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 DIRECT PRIMARY RESULT 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 supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: creatine CHEBI:16919

Platform: Small molecule

Creatine has been given with methionine restriction and other supplements to bypass a hypothesized biosynthetic deficit. Combined-treatment case reports do not isolate its benefit, and persistent muscle disease despite treatment limits efficacy claims.

Mechanism Target:

MODULATES Impaired Creatine Synthesis — Proposed substrate replacement bypasses a methylation-dependent synthetic step; independent clinical correction of that step has not been demonstrated.

Show evidence (1 reference)

PMID:16435181 SUPPORT INDIRECT PRIMARY RESULT 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 (2 references)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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.

PMID:35789945 SUPPORT DIRECT BACKGROUND Human Clinical

"We are unable to assess the specific benefit of phosphatidylcholine and creatine supplementation as all of these patients were also on methionine-restricted diet"

The literature analysis could not isolate either supplement effect from combined therapy.

Phosphatidylcholine supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: phosphatidylcholine CHEBI:64482

Platform: Small molecule

Phosphatidylcholine has been given with methionine restriction and other supplements to bypass a hypothesized biosynthetic deficit. Combined-treatment case reports do not isolate its benefit, and persistent muscle disease despite treatment limits efficacy claims.

Mechanism Target:

MODULATES Impaired Phosphatidylcholine Synthesis — Proposed substrate replacement bypasses a methylation-dependent synthetic step; independent clinical correction of that step has not been demonstrated.

Show evidence (1 reference)

PMID:16435181 SUPPORT INDIRECT PRIMARY RESULT 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 (2 references)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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.

PMID:35789945 SUPPORT DIRECT BACKGROUND Human Clinical

"We are unable to assess the specific benefit of phosphatidylcholine and creatine supplementation as all of these patients were also on methionine-restricted diet"

The literature analysis could not isolate either supplement effect from combined therapy.

Liver transplantation

Action: Liver Transplantation NCIT:C15271

Platform: Surgery

One severely affected child underwent living-donor liver transplantation at 40 months. Over six months on an unrestricted diet, methionine and SAM normalized, SAH fell substantially, coagulation improved and developmental gains occurred. The SAM:SAH ratio remained below the control mean. This abstract-supported single case does not demonstrate complete neurological reversal, extrahepatic cure or established indications for mildly affected patients.

Mechanism Target:

MODULATES AdoHcy Accumulation — A liver graft substantially reduced circulating SAH in one child; extrahepatic AHCY deficiency is not replaced.

Show evidence (1 reference)

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52±0.19 to 1.48±0.79 mol:mol (control 4.10±2.11 mol:mol)."

A substantial SAH reduction was reported in one transplanted child.

Show evidence (2 references)

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted diet."

Single-case biochemical follow-up after transplantation; SAH fell 96%, but the ratio did not reach the control mean.

PMID:26095522 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains in gross motor, language, and social skills."

Promising short-term developmental gains are not evidence of complete reversal of disability.

Multisystem surveillance

Platform: Other

Consensus-based follow-up assesses development, muscle function, nutrition, liver synthetic function and coagulation. Serial amino acids, SAM, SAH, CK, liver tests and coagulation studies guide care. Liver imaging and alpha-fetoprotein are suggested given the reported adult HCC, without a quantified disease-specific cancer risk or proven surveillance benefit.

Show evidence (1 reference)

PMID:27671891 SUPPORT DIRECT BACKGROUND Human Clinical

"The following tests are indicated: protein status, amino acids, AdoMet, AdoHcy, liver function tests, CK, alpha-fetoprotein, coagulation tests, liver imaging, while others depend on the clinical situation."

Consensus recommendation based on sparse clinical experience; follow-up intervals depend on age and course.

Vitamin K for responsive coagulopathy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Vitamin K shortened prolonged prothrombin time in one treated child. This is a case-specific supportive response, not correction of the underlying AHCY defect.

Show evidence (1 reference)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"However, it was still frequently above the normal limit, but was responsive to vitamin K."

The preceding sentence identifies prothrombin time; responsiveness was reported in one sibling.

Respiratory and feeding support in severe infantile disease

Platform: Other

A severely affected infant required tracheostomy and gastrostomy during prolonged neonatal intensive care. These measures supported respiratory and nutritional needs; they did not prevent subsequent deterioration.

Show evidence (1 reference)

PMID:35789945 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient was hospitalized for 3.5 months in the neonatal ICU due to respiratory failure and generalized hypotonia requiring tracheostomy and gastrostomy tube placement."

Actual supportive interventions were reported in the new 2022 case.

🔬

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 Methionine Accumulation Positive Diagnostic

Elevated plasma methionine accompanies the metabolic block but can be absent in early infancy or during treatment.

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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:16435181 SUPPORT DIRECT PRIMARY RESULT 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)."

SAM and methionine accumulate, but neonatal methionine can be normal.

Elevated S-adenosyl-L-homocysteine (INCREASED)

Context: Marked circulating SAH elevation is a characteristic consequence of reduced hydrolase activity.

Pathograph Readouts

Readout Of AdoHcy Accumulation Positive Diagnostic

Elevated SAH is a characteristic circulating readout interpreted with SAM, total homocysteine and confirmatory testing.

Show evidence (1 reference)

PMID:16435181 SUPPORT DIRECT PRIMARY RESULT 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:15024124 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated."

The index patient had markedly elevated plasma SAH and SAM.

Elevated S-adenosyl-L-methionine (INCREASED)

Context: SAM accumulation accompanies SAH elevation; plasma measurements do not directly establish tissue-specific flux.

Pathograph Readouts

Readout Of AdoMet Accumulation Positive Diagnostic

Elevated AdoMet accompanies AdoHcy accumulation in AHCY deficiency.

Show evidence (1 reference)

PMID:26527160 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT Human Clinical

"In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated."

Quantifies plasma AdoMet elevation in the index patient.

🔬

Diagnosis

4

Biochemical Screening

Measure plasma SAM and SAH alongside amino acids and total homocysteine when clinical or biochemical findings suggest AHCY deficiency. Normal neonatal methionine does not exclude the disorder.

biomarker analysis NCIT:C63333

Focus on methionine, S-adenosylmethionine, and S-adenosylhomocysteine. Total homocysteine is at most mildly elevated, unlike CBS deficiency.

Show evidence (2 references)

PMID:27671891 SUPPORT DIRECT BACKGROUND 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.

PMID:39512434 SUPPORT DIRECT BACKGROUND Human Clinical

"Unfortunately, newborn screening for elevated methionine is not reliable for detecting SAHHD."

The clinical review identifies false-negative methionine screening.

Molecular Genetic Testing

AHCY sequencing or exome sequencing confirms biallelic pathogenic variants.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:26527160 SUPPORT DIRECT PRIMARY RESULT 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

MRI and MRS characterize muscle involvement. In a cross-sectional same-day study of three brothers, proximal lower-limb fat infiltration and elevated extramyocellular lipid predominated, while intramyocellular lipid was normal. Potential use for follow-up was proposed; serial progression and treatment-response validity were not established.

skeletal muscle magnetic resonance spectroscopy NCIT:C16810

Markers: Intramuscular lipid infiltration and elevated muscle lipid fraction

Results: Fat replacement, edema and atrophy with an elevated extramyocellular lipid signal support muscle involvement; findings vary with disease severity and sampled muscle.

Show evidence (1 reference)

PMID:35463910 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MRI and MRS were performed on the same day in three brothers at the age of 13, 11, and 8 years, respectively."

The design was a cross-sectional comparison of three affected brothers, not repeated longitudinal measurements.

AHCY activity measurement

Reduced hydrolase activity in red blood cells, cultured fibroblasts or liver can support the diagnosis alongside SAM/SAH and molecular findings. The index case had tissue-specific residual activity; activity testing is specialized and not available in every reported case.

Biomarker Analysis NCIT:C63333

Show evidence (1 reference)

PMID:15024124 SUPPORT DIRECT PRIMARY RESULT 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.

📈

Progression

2

Severe prenatal or infantile disease

Fetal hydrops, hypotonia, respiratory failure and developmental impairment can begin before or shortly after birth. Early death is reported despite combined dietary treatment; a normal methionine newborn screen does not exclude disease.

Show evidence (1 reference)

PMID:20852937 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days."

One severely affected sibling died despite treatment.

Mild childhood presentation with possible later complications

Some homozygous p.Arg49His children have biochemical liver and muscle abnormalities with little clinical impairment. One confirmed adult developed weakness in her mid-twenties and HCC at 29. These cases establish variability, not a predictable progression or genotype-specific risk rate.

Show evidence (1 reference)

PMID:26527160 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29."

An adult case demonstrates possible later morbidity.

📊

Prevalence

1

Reported cases in the literature

Cases In Literature Ultra Rare

The literature consists of a small, overlapping collection of case reports and families. The 2024 report counted 16 previously reported patients; this is a historical literature count, not a population prevalence estimate. Mild cases may be missed. Population prevalence and reliable phenotype frequencies are unknown.

Show evidence (1 reference)

PMID:39512434 SUPPORT DIRECT BACKGROUND Human Clinical

"Only 16 SAHHD cases have been reported with a broad clinical spectrum"

A historical literature count from the 2024 report; overlapping publications and ascertainment prevent population-rate estimation.

🔀

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 DIRECT BACKGROUND 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.

🧫

Experimental Models

2

Recombinant p.Arg49Cys and p.Asp86Gly AHCY proteins OTHER

Patient-variant proteins expressed in E. coli were studied by enzyme assays, native electrophoresis, gel filtration and cofactor measurements. The experiments distinguish allele-specific activity and stability defects rather than a universal tetramer-assembly failure.

Publication

PMID:19177456

Pathograph links

AHCY Loss of Function measures fidelity: low Recombinant disease alleles reduce hydrolase activity under specified conditions.

Limitations: p.Arg49Cys forms normal-size tetramers by gel filtration at 20 degrees Celsius and pH 7.2 but precipitates after warming. p.Asp86Gly activity increases from 1.5% to about 15.5% of wild type after bacterial chaperone induction. Engineered p.Asp86Glu is a rescue construct, not a clinical allele. DTT and benzyl alcohol were laboratory manipulations, not patient therapies.

Readouts

AHCY Loss of Function

Direction: DECREASED

Interpretation: Recombinant disease alleles reduce hydrolase activity under specified conditions.

Show evidence (1 reference)

PMID:19177456 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The catalytic activity of thioredoxin-tagged p.Arg49Cys, determined in the direction of AdoHcy hydrolysis, was 6.7% that of the wild-type protein"

Reduced catalytic activity was measured in a specific purified recombinant-protein preparation.

Show evidence (1 reference)

PMID:19177456 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The catalytic activity of thioredoxin-tagged p.Arg49Cys, determined in the direction of AdoHcy hydrolysis, was 6.7% that of the wild-type protein"

Reduced catalytic activity was measured in a specific purified recombinant-protein preparation.

Show evidence (1 reference)

PMID:19177456 SUPPORT DIRECT PRIMARY RESULT In Vitro

"for p.Arg49Cys approximately 95.7% of the total bound coenzyme was in the form of NADH."

Bound-cofactor redox state was measured; the active-site explanation was structurally modeled.

Stable AHCY knockdown in SW480 colorectal cancer cells CELL_LINE

Stable AHCY knockdown increased SAH and LEF1 protein abundance. RNA sequencing and pathway analysis predicted signaling-network alterations. SAM did not change significantly. This single cancer-cell background is not a patient-derived neural, hepatic or muscle model.

Cell source

SW480 cancer cell line with lentiviral shRNA knockdown and puromycin selection

Publication

PMID:38003292

Pathograph links

AdoHcy Accumulation measures fidelity: low AHCY knockdown increases cellular SAH in the assayed cell line.

Limitations: RNA sequencing used two cell passages as biological replicates. The paper does not clearly establish independent clone replication or show AHCY re-expression rescue, LEF1 epistasis, Wnt reporter activity, methylome changes or direct invasion assays. Increased total STAT3 does not establish increased phosphorylation.

Readouts

AdoHcy Accumulation

Direction: INCREASED

Interpretation: AHCY knockdown increases cellular SAH in the assayed cell line.

Show evidence (1 reference)

PMID:38003292 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In the AHCY deficient cells, the concentration of SAH was found to be 4.6 ng/mL, whereas in the control cells, it was 2 ng/mL."

Stable shRNA knockdown in SW480 cells increased measured SAH.

Show evidence (1 reference)

PMID:38003292 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In the AHCY deficient cells, the concentration of SAH was found to be 4.6 ng/mL, whereas in the control cells, it was 2 ng/mL."

Stable shRNA knockdown in SW480 cells increased measured SAH.

Show evidence (1 reference)

PMID:38003292 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Quantification of band intensities showed an approximately 50% increase in LEF1 protein expression in the AHCY-deficient cells."

Western blotting measured LEF1 abundance; this was not a beta-catenin localization or Wnt reporter assay.

🐁

Animal Models

3

Ahcy-containing lethal nonagouti deletion mouse

A roughly 100-kb deletion includes Ahcy and causes peri-implantation lethality. Cultured-embryo inhibitor experiments support an AHCY contribution, but the deletion does not genetically isolate Ahcy. This primary abstract supports a restricted embryonic model.

Species

Mouse

Genotype

Homozygous a(x) contiguous deletion encompassing Ahcy

Publication

PMID:8168479

Pathograph links

AHCY Loss of Function partially recapitulates fidelity: low Models loss of Ahcy within a larger deletion, with early embryonic death.

Limitations: Additional deleted sequence and embryonic lethality prevent a specific phenocopy of surviving human disease; the primary full text was not recovered.

Readouts

AHCY Loss of Function

Direction: ALTERED

Interpretation: Models loss of Ahcy within a larger deletion, with early embryonic death.

Show evidence (2 references)

PMID:8168479 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Long range restriction mapping demonstrated a simple deletion of approximately 100 kb"

The primary study mapped a contiguous deletion encompassing Ahcy, rather than a clean single-gene knockout.

+ 1 more reference

Show evidence (2 references)

PMID:8168479 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Long range restriction mapping demonstrated a simple deletion of approximately 100 kb"

The primary study mapped a contiguous deletion encompassing Ahcy, rather than a clean single-gene knockout.

+ 1 more reference

ducttrip Ahcy-deficient zebrafish

Homozygous larvae accumulate SAH and SAM, develop hepatic steatosis and degeneration, and die early. tnfa knockdown improves liver histology and mitochondrial appearance. Wild-type ahcy mRNA rescues the early metabolic abnormality but not the later liver phenotype under the tested injection protocol.

Species

Zebrafish

Genotype

Homozygous dtp missense mutation in the Ahcy NAD-binding domain

Publication

PMID:19201949

Pathograph links

AdoHcy Accumulation partially recapitulates fidelity: low Whole-larval SAH is elevated in homozygous mutants.

Limitations: Adult heterozygotes and pharmacologically inhibited adult fish had unchanged SAH and increased SAM, so results cannot be generalized across stage or genotype.

Readouts

AdoHcy Accumulation

Direction: INCREASED

Interpretation: Whole-larval SAH is elevated in homozygous mutants.

Show evidence (1 reference)

PMID:19201949 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM)."

Whole-larval metabolites increased in homozygous mutants. Adult heterozygotes had a different SAM/SAH pattern.

Show evidence (1 reference)

PMID:19201949 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM)."

Whole-larval metabolites increased in homozygous mutants. Adult heterozygotes had a different SAM/SAH pattern.

Hepatic Injury perturbs fidelity: low Larval liver injury and steatosis are improved by tnfa antisense knockdown.

Limitations: Liver-enriched larval tissue showed reduced global DNA/protein methylation; 5-azacytidine demethylation did not reproduce tnfa induction or steatosis. PC:PE was unchanged. Reduced mitochondrial glutathione was measured in drug-treated adults, not mutant larvae. The route to tnfa induction remains a hypothesis, and human TNF dependence is unproven.

Readouts

Hepatic Injury

Direction: ALTERED

Interpretation: Larval liver injury and steatosis are improved by tnfa antisense knockdown.

Show evidence (1 reference)

PMID:19201949 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae"

A tnfa morpholino rescued larval liver abnormalities in the genetic model; this does not establish anti-TNF treatment efficacy in patients.

Show evidence (1 reference)

PMID:19201949 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae"

A tnfa morpholino rescued larval liver abnormalities in the genetic model; this does not establish anti-TNF treatment efficacy in patients.

AHCY-1 Y145C C. elegans

A partial AHCY-1-deficiency model has moderate SAH elevation, lower SAM and extended lifespan. RNAi of aak-2/AMPK, vrk-1 or daf-16 reduces the longevity phenotype. Normal locomotion and fertility and the distinct metabolic direction limit extrapolation to human disease.

Species

Caenorhabditis elegans

Genotype

Endogenous ahcy-1 Y145C::GFP, equivalent to human p.Tyr143Cys

Publication

PMID:38052822

Pathograph links

AdoHcy Accumulation partially recapitulates fidelity: low Young-adult mutant worms have moderately elevated SAH.

Limitations: SAM is lower, not elevated as in patients. Lifespan assays at 20 degrees Celsius with FUdR address worm aging and do not support human SAH supplementation or treatment.

Readouts

AdoHcy Accumulation

Direction: INCREASED

Interpretation: Young-adult mutant worms have moderately elevated SAH.

Show evidence (1 reference)

PMID:38052822 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Our findings revealed that animals with this endogenous mutation exhibited delayed aging, accompanied by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels."

The endogenous Y145C worm model partly reproduces SAH elevation but has reduced SAM and extended lifespan.

Show evidence (1 reference)

PMID:38052822 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Our findings revealed that animals with this endogenous mutation exhibited delayed aging, accompanied by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels."

The endogenous Y145C worm model partly reproduces SAH elevation but has reduced SAM and extended lifespan.

{ }

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 an autosomal recessive disorder of the methionine
  cycle caused by biallelic AHCY variants. Reduced hydrolase activity produces marked S-adenosylhomocysteine
  (SAH) accumulation, usually accompanied by elevated S-adenosylmethionine (SAM) and methionine. SAH inhibits
  multiple methyltransferases, but the tissue-specific routes to muscle, liver and nervous-system injury
  remain incompletely resolved. Blood DNA hypermethylation in subsets of patients cautions against assuming
  uniform DNA hypomethylation. The spectrum ranges from lethal perinatal disease to childhood biochemical
  abnormalities with little clinical impairment and adult-onset complications.
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.
    quote_role: BACKGROUND
    directness: DIRECT
  - 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.
    quote_role: BACKGROUND
    directness: DIRECT
pathophysiology:
- name: AHCY Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic AHCY variants reduce adenosylhomocysteinase activity. Residual activity is demonstrated
    in tested patient tissues and recombinant alleles, but has not been measured for every genotype. Individual
    substitutions can affect activity, stability or cofactor state in assay-dependent ways.
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:19177456
    reference_title: 'S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Functional analysis of recombinant proteins containing the mutations detected showed that both dramatically
      reduce AHCY activity.
    explanation: >-
      The p.Arg49Cys and p.Asp86Gly proteins had reduced activity in recombinant assays.
  genes:
  - preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  molecular_functions:
  - preferred_term: adenosylhomocysteinase activity
    term:
      id: GO:0004013
      label: adenosylhomocysteinase activity
    modifier: DECREASED
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Biallelic missense or truncating variants impair AHCY function; allele-specific activity and severity
      cannot be inferred from a single universal residual-activity percentage.
  downstream:
  - target: AdoHcy Accumulation
    causal_link_type: DIRECT
    description: Reduced hydrolysis impairs SAH 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: >-
        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.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
    - reference: PMID:15024124
      reference_title: 'S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated.
      explanation: The index patient had markedly elevated plasma SAH and SAM.
  - target: Methionine Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disruption of methionine-cycle metabolism is associated with variable hypermethioninemia through
      unresolved intermediate flux changes.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      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: SAM and methionine accumulate, but neonatal methionine can be normal.
  - target: Variable Blood DNA Hypermethylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical association is reproducible in subsets; the biochemical route and tissue specificity
      are unresolved.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Global DNA methylation was increased in two of three analysed patients.
      explanation: >-
        Peripheral-blood DNA was globally hypermethylated in two of three tested patients; this was not
        a brain or muscle assay.
    - 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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Three patients showed a hypermethylation in up to five imprinted gene DMRs.
      explanation: >-
        Among seven patients, including four siblings, three had variable imprinting-control-region hypermethylation.
        Other patients and loci were unaffected.
  - target: Skeletal Muscle Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular
      events are not established.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle
        groups, and permanently elevated creatine kinase.
      explanation: >-
        Three affected brothers had persistent myopathy and elevated CK; imaging and biopsies characterize
        injury without resolving its molecular mediator.
  - target: Hepatic Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular
      events are not established.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin
        time and low albumin.
      explanation: >-
        The index patient had muscle injury markers, aminotransferase elevation, and impaired hepatic
        synthetic function.
  - target: Hepatic Synthetic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular
      events are not established.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin
        time and low albumin.
      explanation: >-
        The index patient had muscle injury markers, aminotransferase elevation, and impaired hepatic
        synthetic function.
  - target: Impaired Myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular
      events are not established.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination.
      explanation: >-
        Brain MRI showed two distinct abnormalities: loss of white-matter volume and delayed myelination.
  - target: Cerebral White Matter Volume Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular
      events are not established.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination.
      explanation: >-
        Brain MRI showed two distinct abnormalities: loss of white-matter volume and delayed myelination.
  - target: Altered Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical disease associated with biallelic AHCY deficiency; the intervening tissue-specific molecular
      events are not established.
    evidence:
    - reference: PMID:26095522
      reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
        hepatopathy, and factor VII deficiency.
      explanation: >-
        The transplant case had multisystem developmental disease before treatment; evidence is limited
        to the primary abstract.
- name: AdoHcy Accumulation
  biological_scale: MOLECULAR
  description: >-
    SAH accumulates when its AHCY-mediated hydrolysis is impaired. Marked plasma elevation is a characteristic
    diagnostic observation; plasma levels do not directly quantify each tissue compartment.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated.
    explanation: The index patient had markedly elevated plasma SAH and SAM.
  chemical_entities:
  - preferred_term: S-adenosyl-L-homocysteine
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
    modifier: INCREASED
  downstream:
  - target: Methyltransferase Product Inhibition
    causal_link_type: DIRECT
    description: >-
      SAH binds methyltransferase SAM-binding sites and inhibits susceptible enzymes; the degree varies
      with enzyme and substrate conditions.
    evidence:
    - reference: PMID:33869213
      reference_title: Functional and Pathological Roles of AHCY.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: >-
        SAH is structurally similar to SAM and binds with a similar range of affinity to the SAM-binding
        pocket of MTases, thereby inhibiting their activity in a negative feedback loop
      explanation: >-
        The review summarizes product inhibition; sensitivities vary between methyltransferases and cellular
        contexts.
- name: Methyltransferase Product Inhibition
  biological_scale: MOLECULAR
  description: >-
    Accumulated SAH can inhibit SAM-dependent methyltransferases. Susceptibility differs by enzyme and
    cellular context; the SAM:SAH ratio is an index of methylation potential rather than a measurement
    of every methylation reaction.
  evidence:
  - reference: PMID:33869213
    reference_title: Functional and Pathological Roles of AHCY.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      SAH is structurally similar to SAM and binds with a similar range of affinity to the SAM-binding
      pocket of MTases, thereby inhibiting their activity in a negative feedback loop
    explanation: >-
      The review summarizes product inhibition; sensitivities vary between methyltransferases and cellular
      contexts.
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: AdoMet Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced SAM consumption may contribute to the observed SAM accumulation; plasma measurements do
      not resolve intracellular 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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated.
      explanation: The index patient had markedly elevated plasma SAH and SAM.
  - target: Impaired Phosphatidylcholine Synthesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inhibition of the relevant methylation reaction is inferred from metabolite patterns, without a
      direct patient enzyme assay.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine
        and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine.
      explanation: >-
        Plasma metabolites suggest impaired phosphatidylcholine and creatine synthesis, but neither methyltransferase
        was directly assayed in the patient.
  - target: Impaired Creatine Synthesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inhibition of the relevant methylation reaction is inferred from metabolite patterns, without a
      direct patient enzyme assay.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine
        and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine.
      explanation: >-
        Plasma metabolites suggest impaired phosphatidylcholine and creatine synthesis, but neither methyltransferase
        was directly assayed in the patient.
- name: AdoMet Accumulation
  biological_scale: MOLECULAR
  description: >-
    SAM is elevated in plasma in human AHCY deficiency. Reduced consumption through inhibited methylation
    reactions is a proposed contributor; tissue-specific fluxes are not directly established by plasma
    concentrations.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated.
    explanation: The index patient had markedly elevated plasma SAH and SAM.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    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: SAM and methionine accumulate, but neonatal methionine can be normal.
  chemical_entities:
  - preferred_term: S-adenosyl-L-methionine
    term:
      id: CHEBI:15414
      label: S-adenosyl-L-methionine
    modifier: INCREASED
- name: Methionine Accumulation
  biological_scale: MOLECULAR
  description: >-
    Methionine is often elevated, but may be normal in early infancy or during dietary restriction despite
    marked SAM and SAH abnormalities. It is not a sufficient screening or treatment-response marker by
    itself.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    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: SAM and methionine accumulate, but neonatal methionine can be normal.
- name: Impaired Phosphatidylcholine Synthesis
  biological_scale: MOLECULAR
  description: >-
    Low plasma phosphatidylcholine and choline suggest impaired methylation-dependent phosphatidylcholine
    synthesis in the index patient. Direct PEMT activity was not measured, and this does not establish
    the sole cause of myopathy or liver injury.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine
      and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine.
    explanation: >-
      Plasma metabolites suggest impaired phosphatidylcholine and creatine synthesis, but neither methyltransferase
      was directly assayed in the patient.
  mechanism_confidence: HYPOTHETICAL
- name: Impaired Creatine Synthesis
  biological_scale: MOLECULAR
  description: >-
    Elevated guanidinoacetate with variable creatine measurements suggests partial impairment of methylation-dependent
    creatine synthesis. Brain spectroscopy retained a creatine peak; a universal cerebral creatine-depletion
    syndrome is not demonstrated.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine
      and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine.
    explanation: >-
      Plasma metabolites suggest impaired phosphatidylcholine and creatine synthesis, but neither methyltransferase
      was directly assayed in the patient.
  mechanism_confidence: HYPOTHETICAL
- name: Variable Blood DNA Hypermethylation
  biological_scale: MOLECULAR
  description: >-
    Peripheral-blood measurements show global or imprinting-region hypermethylation in subsets of patients.
    In the seven-patient study, four participants were siblings; global methylation was measured in only
    three. No abnormal GTL2, LINE1 or Alu methylation and no consistent relation to plasma SAH were found.
    Differential enzyme inhibition and excess SAM are hypotheses, not directly assayed explanations.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Global DNA methylation was increased in two of three analysed patients.
    explanation: >-
      Peripheral-blood DNA was globally hypermethylated in two of three tested patients; this was not
      a brain or muscle assay.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Three patients showed a hypermethylation in up to five imprinted gene DMRs.
    explanation: >-
      Among seven patients, including four siblings, three had variable imprinting-control-region hypermethylation.
      Other patients and loci were unaffected.
- name: Skeletal Muscle Injury
  biological_scale: TISSUE
  description: >-
    Myopathy includes persistent CK elevation, proximal weakness, variable muscle-fiber degeneration and
    replacement by fat. The molecular route from AHCY deficiency is unresolved. Normal intramyocellular
    lipid in the three-brother imaging study and persistent CK elevation during phosphatidylcholine supplementation
    argue against treating choline deficiency as an established sole mediator.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle
      groups, and permanently elevated creatine kinase.
    explanation: >-
      Three affected brothers had persistent myopathy and elevated CK; imaging and biopsies characterize
      injury without resolving its molecular mediator.
  downstream:
  - target: Myopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle
        groups, and permanently elevated creatine kinase.
      explanation: >-
        Three affected brothers had persistent myopathy and elevated CK; imaging and biopsies characterize
        injury without resolving its molecular mediator.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Proximal muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
    - 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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Elevated circulating creatine kinase activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Areflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Increased muscle fatiguability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      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: Fatigability was documented in the three-brother muscle-imaging study.
  - target: Skeletal muscle atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator
      was not experimentally isolated.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Skeletal muscle MRI showed abnormal fatty infiltration, edema, and atrophy, predominantly in the
        proximal muscles of the lower extremities, in all three patients.
      explanation: >-
        MRI demonstrated muscle atrophy with proximal lower-limb predominance in three brothers.
  - target: Waddling gait
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator
      was not experimentally isolated.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        He complained of fatigability and had muscle weakness, predominantly of the lower limbs, hypotonia
        and hyporeflexia, waddling gait, and positive Gowers sign.
      explanation: Waddling gait was observed in the affected brothers.
  - target: Gowers sign
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator
      was not experimentally isolated.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        He complained of fatigability and had muscle weakness, predominantly of the lower limbs, hypotonia
        and hyporeflexia, waddling gait, and positive Gowers sign.
      explanation: A positive Gowers sign was recorded in the younger two brothers.
  - target: Myalgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Observed clinical manifestation of muscle involvement; the specific tissue-to-function mediator
      was not experimentally isolated.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: He complained of fatigability and occasional lower leg muscle aches.
      explanation: The oldest brother reported occasional lower-leg muscle aches.
- name: Hepatic Injury
  biological_scale: TISSUE
  description: >-
    Hepatic involvement includes aminotransferase elevation and biopsy abnormalities. Transaminases can
    also have a muscle contribution, so they do not alone isolate hepatocyte injury. A confirmed adult
    patient developed hepatocellular carcinoma at age 29, but the incidence and molecular route to malignancy
    are unknown.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin
      time and low albumin.
    explanation: >-
      The index patient had muscle injury markers, aminotransferase elevation, and impaired hepatic synthetic
      function.
  - reference: PMID:26527160
    reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at
      age 29.
    explanation: >-
      One confirmed homozygous p.Arg49His patient developed HCC; her relatives with fatal liver disease
      were not genetically confirmed.
  downstream:
  - target: Elevated circulating hepatic transaminase concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Hepatic Synthetic Dysfunction
  biological_scale: TISSUE
  description: >-
    Low albumin, reduced coagulation factors and hypofibrinogenemia accompany prolonged prothrombin time.
    Biochemical synthetic dysfunction can occur despite few outward symptoms; it is distinct from aminotransferase
    elevation.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin
      time and low albumin.
    explanation: >-
      The index patient had muscle injury markers, aminotransferase elevation, and impaired hepatic synthetic
      function.
  downstream:
  - target: Prolonged prothrombin time
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Hypoalbuminemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin
        time and low albumin.
      explanation: Low albumin was documented in the index patient.
  - target: Hypofibrinogenemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    evidence:
    - reference: PMID:39512434
      reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: low fibrinogen levels of 0.8 g/L (normal 1.7–4.0)
      explanation: Low fibrinogen accompanied coagulation abnormalities in a clinically mild child.
  - target: Reduced factor VII activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    evidence:
    - reference: PMID:26095522
      reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
        hepatopathy, and factor VII deficiency.
      explanation: >-
        Reported in the severely affected child before liver transplantation; the accessible primary report
        is abstract-only.
  - target: Hepatic failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      quote_role: BACKGROUND
      directness: INDIRECT
- name: Impaired Myelination
  biological_scale: TISSUE
  description: >-
    Delayed myelination occurs in affected infants. The responsible methyltransferase, lipid or protein
    abnormalities in patient brain are not established. Improvement during combined dietary treatment
    does not isolate a single causal pathway.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination.
    explanation: >-
      Brain MRI showed two distinct abnormalities: loss of white-matter volume and delayed myelination.
  downstream:
  - target: Delayed myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Cerebral White Matter Volume Loss
  biological_scale: TISSUE
  description: >-
    White-matter atrophy was observed on MRI in the index patient. This structural finding is recorded
    separately from delayed myelination; its specific molecular mediator is unresolved.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination.
    explanation: >-
      Brain MRI showed two distinct abnormalities: loss of white-matter volume and delayed myelination.
  downstream:
  - target: Cerebral white matter atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination.
      explanation: The index MRI showed white-matter atrophy as well as delayed myelination.
- name: Altered Neurodevelopment
  biological_scale: ORGANISM
  description: >-
    Global developmental delay and cognitive or behavioral difficulties vary between patients. Some children
    have little clinical impairment despite substantial biochemical abnormalities. Neither blood DNA methylation
    nor a specific neural methyltransferase defect has been proven to explain the clinical spectrum.
  evidence:
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
      hepatopathy, and factor VII deficiency.
    explanation: >-
      The transplant case had multisystem developmental disease before treatment; evidence is limited
      to the primary abstract.
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
    - reference: PMID:26095522
      reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
        hepatopathy, and factor VII deficiency.
      explanation: >-
        The transplant case had multisystem developmental disease before treatment; evidence is limited
        to the primary abstract.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    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
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Subsequently, stagnation and then regression were noted.
      explanation: >-
        The index infant initially progressed slowly, then stagnated and regressed after approximately
        five months.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation associated with this disease process; specific intervening mechanisms and
      individual penetrance remain unresolved.
    evidence:
    - reference: PMID:26095522
      reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
        hepatopathy, and factor VII deficiency.
      explanation: >-
        Reported in the severely affected child before liver transplantation; the accessible primary report
        is abstract-only.
phenotypes:
- name: Global developmental delay
  description: >-
    Multidomain developmental delay is reported in classical infantile disease, including the child described
    in the transplantation report; it is not universal in mild presentations.
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
      hepatopathy, and factor VII deficiency.
    explanation: >-
      The transplant case had multisystem developmental disease before treatment; evidence is limited
      to the primary abstract.
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Myopathy
  description: Muscle involvement with proximal lower-limb predominance.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      All manifested myopathy, more pronounced in the lower extremities and the proximal skeletal muscle
      groups, and permanently elevated creatine kinase.
    explanation: >-
      Three affected brothers had persistent myopathy and elevated CK; imaging and biopsies characterize
      injury without resolving its molecular mediator.
- name: Proximal 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: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Elevated circulating creatine kinase activity
  description: Serum creatine kinase is often markedly and persistently elevated.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Hepatic failure
  description: >-
    Liver failure is reported at the severe end of the spectrum. Isolated transaminase elevation or mild
    synthetic abnormalities do not by themselves establish clinical 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.
    quote_role: BACKGROUND
    directness: DIRECT
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Leukodystrophy
  description: >-
    Mild diffuse leukodystrophy in a clinically mild child resolved after 12 months of methionine restriction;
    causation by methionine alone remains uncertain.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Hydrops fetalis
  description: >-
    Fetal hydrops was reported in two sisters with severe perinatal disease; the small family does not
    define a universal genotype-phenotype relation.
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Hepatocellular carcinoma
  description: >-
    HCC was diagnosed at age 29 in one genetically confirmed homozygous p.Arg49His woman. Her brother
    who died with HCC at 17 lacked genetic confirmation. Disease-specific risk and surveillance efficacy
    are unquantified.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at
      age 29.
    explanation: >-
      One confirmed homozygous p.Arg49His patient developed HCC; her relatives with fatal liver disease
      were not genetically confirmed.
- name: Microcephaly
  description: >-
    Reported in the severely affected child before liver transplantation; the accessible primary report
    is abstract-only.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
      hepatopathy, and factor VII deficiency.
    explanation: >-
      Reported in the severely affected child before liver transplantation; the accessible primary report
      is abstract-only.
- name: Failure to thrive
  description: >-
    Reported in the severely affected child before liver transplantation; the accessible primary report
    is abstract-only.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
      hepatopathy, and factor VII deficiency.
    explanation: >-
      Reported in the severely affected child before liver transplantation; the accessible primary report
      is abstract-only.
- name: Reduced factor VII activity
  description: >-
    Reported in the severely affected child before liver transplantation; the accessible primary report
    is abstract-only.
  phenotype_term:
    preferred_term: Reduced factor VII activity
    term:
      id: HP:0008169
      label: Reduced factor VII activity
  evidence:
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy,
      hepatopathy, and factor VII deficiency.
    explanation: >-
      Reported in the severely affected child before liver transplantation; the accessible primary report
      is abstract-only.
- name: Esotropia
  description: Convergent strabismus was observed in the index infant.
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Concomitant, convergent strabismus was noted at age 11 months.
    explanation: Convergent strabismus was observed in the index infant.
- name: Developmental regression
  description: >-
    The index infant initially progressed slowly, then stagnated and regressed after approximately five
    months.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Subsequently, stagnation and then regression were noted.
    explanation: >-
      The index infant initially progressed slowly, then stagnated and regressed after approximately five
      months.
- name: Hypoalbuminemia
  description: Low albumin was documented in the index patient.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin
      time and low albumin.
    explanation: Low albumin was documented in the index patient.
- name: Hypofibrinogenemia
  description: Low fibrinogen accompanied coagulation abnormalities in a clinically mild child.
  phenotype_term:
    preferred_term: Hypofibrinogenemia
    term:
      id: HP:0011900
      label: Hypofibrinogenemia
  evidence:
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: coagulation abnormalities, which are frequently seen in SAHH deficiency, were also present, as evidenced by a prolonged PT of 19.8 s (normal 9.6–11.8) and low fibrinogen levels of 0.8 g/L (normal 1.7–4.0)
    explanation: Low fibrinogen accompanied coagulation abnormalities in a clinically mild child.
- name: Cerebral white matter atrophy
  description: The index MRI showed white-matter atrophy as well as delayed myelination.
  phenotype_term:
    preferred_term: Cerebral white matter atrophy
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination.
    explanation: The index MRI showed white-matter atrophy as well as delayed myelination.
- name: Hip dysplasia
  description: Mild bilateral hip dysplasia was observed in one affected infant.
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The boy had mild bilateral hip dysplasia and limited leg abduction.
    explanation: Mild bilateral hip dysplasia was observed in one affected infant.
- name: Increased muscle fatiguability
  description: Fatigability was documented in the three-brother muscle-imaging study.
  phenotype_term:
    preferred_term: Increased muscle fatiguability
    term:
      id: HP:0003750
      label: Increased muscle fatiguability
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    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: Fatigability was documented in the three-brother muscle-imaging study.
- name: Obesity
  description: >-
    Obesity was observed in three brothers and attributed by the authors to low physical activity; this
    family does not establish disease prevalence.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    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: >-
      Obesity was observed in three brothers and attributed by the authors to low physical activity; this
      family does not establish disease prevalence.
- name: Cerebellar hypoplasia
  description: >-
    The consensus review describes these structural brain findings in two sisters with severe perinatal
    disease.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  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
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination
    explanation: >-
      The consensus review describes these structural brain findings in two sisters with severe perinatal
      disease.
- name: Pontine hypoplasia
  description: >-
    The consensus review describes these structural brain findings in two sisters with severe perinatal
    disease.
  phenotype_term:
    preferred_term: Hypoplasia of the pons
    term:
      id: HP:0012110
      label: Hypoplasia of the pons
  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
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination
    explanation: >-
      The consensus review describes these structural brain findings in two sisters with severe perinatal
      disease.
- name: Hypoplasia of the corpus callosum
  description: >-
    The consensus review describes these structural brain findings in two sisters with severe perinatal
    disease.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  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
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination
    explanation: >-
      The consensus review describes these structural brain findings in two sisters with severe perinatal
      disease.
- name: Respiratory failure
  description: Respiratory failure occurred in the severe perinatal sibling presentation.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  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
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      Two sibs presented severely with fetal hydrops, insufficient liver synthetic function and muscular
      hypotonia leading to respiratory failure and death in early infancy.
    explanation: Respiratory failure occurred in the severe perinatal sibling presentation.
- name: Skeletal muscle atrophy
  description: >-
    MRI demonstrated muscle atrophy with proximal lower-limb predominance in three brothers.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Skeletal muscle MRI showed abnormal fatty infiltration, edema, and atrophy, predominantly in the
      proximal muscles of the lower extremities, in all three patients.
    explanation: >-
      MRI demonstrated muscle atrophy with proximal lower-limb predominance in three brothers.
- name: Waddling gait
  description: Waddling gait was observed in the affected brothers.
  phenotype_term:
    preferred_term: Waddling gait
    term:
      id: HP:0002515
      label: Waddling gait
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      He complained of fatigability and had muscle weakness, predominantly of the lower limbs, hypotonia
      and hyporeflexia, waddling gait, and positive Gowers sign.
    explanation: Waddling gait was observed in the affected brothers.
- name: Gowers sign
  description: A positive Gowers sign was recorded in the younger two brothers.
  phenotype_term:
    preferred_term: Gowers sign
    term:
      id: HP:0003391
      label: Gowers sign
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      He complained of fatigability and had muscle weakness, predominantly of the lower limbs, hypotonia
      and hyporeflexia, waddling gait, and positive Gowers sign.
    explanation: A positive Gowers sign was recorded in the younger two brothers.
- name: Myalgia
  description: The oldest brother reported occasional lower-leg muscle aches.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He complained of fatigability and occasional lower leg muscle aches.
    explanation: The oldest brother reported occasional lower-leg muscle aches.
- name: Delayed ability to walk
  description: >-
    The index child acquired independent walking at 19 months after treatment initiation.
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He started to walk unassisted at age 19 months.
    explanation: >-
      The index child acquired independent walking at 19 months after treatment initiation.
- name: Hepatomegaly
  description: >-
    Hepatomegaly occurred in a child with an author-classified likely pathogenic homozygous AHCY variant;
    SAM/SAH and enzyme activity were unavailable, and a second PITX3 variant confounded some features.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      She is 3 years old and has been followed with hepatomegaly, hypotonia, global developmental delay,
      and persistent dysmorphic features.
    explanation: >-
      Hepatomegaly occurred in a child with an author-classified likely pathogenic homozygous AHCY variant;
      SAM/SAH and enzyme activity were unavailable, and a second PITX3 variant confounded some features.
- name: Seizure
  description: >-
    A seizure was reported in one child with a likely pathogenic AHCY genotype, prematurity, neonatal
    sepsis and a second PITX3 variant; attribution to AHCY alone is uncertain.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had her first seizure when she was 6 months old.
    explanation: >-
      A seizure was reported in one child with a likely pathogenic AHCY genotype, prematurity, neonatal
      sepsis and a second PITX3 variant; attribution to AHCY alone is uncertain.
- name: Delayed speech and language development
  description: >-
    The same child had no words at 18 months and severe global developmental delay; the dual genetic diagnosis
    and neonatal complications limit attribution.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had no words. She had no eye contact.
    explanation: >-
      The same child had no words at 18 months and severe global developmental delay; the dual genetic
      diagnosis and neonatal complications limit attribution.
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: Methionine Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated plasma methionine accompanies the metabolic block but can be absent in early infancy or during treatment.
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    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: SAM and methionine accumulate, but neonatal methionine can be normal.
- name: Elevated S-adenosyl-L-homocysteine
  presence: INCREASED
  context: Marked circulating SAH elevation is a characteristic consequence of reduced hydrolase activity.
  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 SAH is a characteristic circulating readout interpreted with SAM, total homocysteine and confirmatory testing.
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated.
    explanation: The index patient had markedly elevated plasma SAH and SAM.
- name: Elevated S-adenosyl-L-methionine
  presence: INCREASED
  context: SAM accumulation accompanies SAH elevation; plasma measurements do not directly establish tissue-specific flux.
  biomarker_term:
    preferred_term: S-adenosyl-L-methionine
    term:
      id: CHEBI:15414
      label: S-adenosyl-L-methionine
  readouts:
  - target: AdoMet Accumulation
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: AHCY
  gene_term:
    preferred_term: AHCY
    term:
      id: hgnc:343
      label: AHCY
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z
    evidence:
    - reference: CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "AHCY | HGNC:343 | hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | MONDO:0013404 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this gene-disease pair as Definitive.
  notes: >-
    Biallelic AHCY missense or truncating variants cause the disease. The index genotype includes p.Trp112Ter
    and p.Tyr143Cys; the review shorthand T112stop is not a p.Thr112Ter allele. Recombinant p.Arg49Cys
    and p.Asp86Gly have condition-dependent functional defects. Homozygous p.Arg49His recurs in Pakistani
    families with mild childhood presentations, but one confirmed adult developed HCC; a uniformly benign
    outcome or measured residual activity for this allele is not established. The 2024 report cites allele
    frequencies of approximately 0.000065 in South Asia and 0.000012 globally, not carrier frequencies
    or disease prevalence. ClinGen classified the gene-disease association as Definitive in December 2024;
    the older Moderate wording remaining in its narrative was superseded by that reevaluation.
  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.
    quote_role: BACKGROUND
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Homozygous c.1043G>T (p.Gly348Val) novel variant in the AHCY gene
    explanation: >-
      A reported likely pathogenic genotype in a child without available SAM/SAH confirmation; a second
      PITX3 variant complicates phenotype attribution.
diagnosis:
- name: Biochemical Screening
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: NCIT:C63333
      label: Biomarker Analysis
  description: >-
    Measure plasma SAM and SAH alongside amino acids and total homocysteine when clinical or biochemical
    findings suggest AHCY deficiency. Normal neonatal methionine does not exclude the disorder.
  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.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      Unfortunately, newborn screening for elevated methionine is not reliable for detecting SAHHD.
    explanation: The clinical review identifies false-negative methionine screening.
- 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Skeletal Muscle Magnetic Resonance Spectroscopy
  diagnosis_term:
    preferred_term: skeletal muscle magnetic resonance spectroscopy
    term:
      id: NCIT:C16810
      label: Magnetic Resonance Spectroscopy
  description: >-
    MRI and MRS characterize muscle involvement. In a cross-sectional same-day study of three brothers,
    proximal lower-limb fat infiltration and elevated extramyocellular lipid predominated, while intramyocellular
    lipid was normal. Potential use for follow-up was proposed; serial progression and treatment-response
    validity were not established.
  markers: Intramuscular lipid infiltration and elevated muscle lipid fraction
  results: Fat replacement, edema and atrophy with an elevated extramyocellular lipid signal support muscle involvement; findings vary with disease severity and sampled muscle.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      MRI and MRS were performed on the same day in three brothers at the age of 13, 11, and 8 years,
      respectively.
    explanation: >-
      The design was a cross-sectional comparison of three affected brothers, not repeated longitudinal
      measurements.
- name: AHCY activity measurement
  description: Reduced hydrolase activity in red blood cells, cultured fibroblasts or liver can support the diagnosis alongside SAM/SAH and molecular findings. The index case had tissue-specific residual activity; activity testing is specialized and not available in every reported case.
  diagnosis_term:
    preferred_term: Biomarker Analysis
    term:
      id: NCIT:C63333
      label: Biomarker Analysis
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
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.
    quote_role: BACKGROUND
    directness: DIRECT
prevalence:
- population: Reported cases in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The literature consists of a small, overlapping collection of case reports and families. The 2024
    report counted 16 previously reported patients; this is a historical literature count, not a population
    prevalence estimate. Mild cases may be missed. Population prevalence and reliable phenotype frequencies
    are unknown.
  evidence:
  - reference: PMID:39512434
    reference_title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Only 16 SAHHD cases have been reported with a broad clinical spectrum
    explanation: >-
      A historical literature count from the 2024 report; overlapping publications and ascertainment prevent
      population-rate estimation.
treatments:
- name: Methionine-restricted diet
  description: >-
    Specialist-supervised methionine restriction with adequate protein, energy and other amino acids is
    the main dietary intervention. Some cases show developmental or MRI improvement, but biochemical and
    clinical responses vary and SAM/SAH, muscle injury and coagulation abnormalities can persist. Evidence
    is uncontrolled; excessive restriction can compromise nutrition.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Methionine Accumulation
    treatment_effect: MODULATES
    description: Restriction can lower plasma methionine while SAM and SAH remain elevated.
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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.
    quote_role: BACKGROUND
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Creatine supplementation
  description: >-
    Creatine has been given with methionine restriction and other supplements to bypass a hypothesized
    biosynthetic deficit. Combined-treatment case reports do not isolate its benefit, and persistent muscle
    disease despite treatment limits efficacy claims.
  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
  target_mechanisms:
  - target: Impaired Creatine Synthesis
    treatment_effect: MODULATES
    description: >-
      Proposed substrate replacement bypasses a methylation-dependent synthetic step; independent clinical
      correction of that step has not been demonstrated.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35789945
    reference_title: The biochemical profile and dietary management in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      We are unable to assess the specific benefit of phosphatidylcholine and creatine supplementation
      as all of these patients were also on methionine-restricted diet
    explanation: >-
      The literature analysis could not isolate either supplement effect from combined therapy.
- name: Phosphatidylcholine supplementation
  description: >-
    Phosphatidylcholine has been given with methionine restriction and other supplements to bypass a hypothesized
    biosynthetic deficit. Combined-treatment case reports do not isolate its benefit, and persistent muscle
    disease despite treatment limits efficacy claims.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phosphatidylcholine
      term:
        id: CHEBI:64482
        label: phosphatidylcholine
  target_mechanisms:
  - target: Impaired Phosphatidylcholine Synthesis
    treatment_effect: MODULATES
    description: >-
      Proposed substrate replacement bypasses a methylation-dependent synthetic step; independent clinical
      correction of that step has not been demonstrated.
    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.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35789945
    reference_title: The biochemical profile and dietary management in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      We are unable to assess the specific benefit of phosphatidylcholine and creatine supplementation
      as all of these patients were also on methionine-restricted diet
    explanation: >-
      The literature analysis could not isolate either supplement effect from combined therapy.
- name: Liver transplantation
  description: >-
    One severely affected child underwent living-donor liver transplantation at 40 months. Over six months
    on an unrestricted diet, methionine and SAM normalized, SAH fell substantially, coagulation improved
    and developmental gains occurred. The SAM:SAH ratio remained below the control mean. This abstract-supported
    single case does not demonstrate complete neurological reversal, extrahepatic cure or established
    indications for mildly affected patients.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: AdoHcy Accumulation
    treatment_effect: MODULATES
    description: >-
      A liver graft substantially reduced circulating SAH in one child; extrahepatic AHCY deficiency is
      not replaced.
    evidence:
    - reference: PMID:26095522
      reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52±0.19 to 1.48±0.79 mol:mol (control 4.10±2.11 mol:mol).
      explanation: A substantial SAH reduction was reported in one transplanted child.
  evidence:
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted
      diet.
    explanation: >-
      Single-case biochemical follow-up after transplantation; SAH fell 96%, but the ratio did not reach
      the control mean.
  - reference: PMID:26095522
    reference_title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains
      in gross motor, language, and social skills.
    explanation: >-
      Promising short-term developmental gains are not evidence of complete reversal of disability.
- name: Multisystem surveillance
  description: >-
    Consensus-based follow-up assesses development, muscle function, nutrition, liver synthetic function
    and coagulation. Serial amino acids, SAM, SAH, CK, liver tests and coagulation studies guide care.
    Liver imaging and alpha-fetoprotein are suggested given the reported adult HCC, without a quantified
    disease-specific cancer risk or proven surveillance benefit.
  therapeutic_modality: OTHER
  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
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: >-
      The following tests are indicated: protein status, amino acids, AdoMet, AdoHcy, liver function tests,
      CK, alpha-fetoprotein, coagulation tests, liver imaging, while others depend on the clinical situation.
    explanation: >-
      Consensus recommendation based on sparse clinical experience; follow-up intervals depend on age
      and course.
- name: Vitamin K for responsive coagulopathy
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  description: >-
    Vitamin K shortened prolonged prothrombin time in one treated child. This is a case-specific supportive
    response, not correction of the underlying AHCY defect.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      However, it was still frequently above the normal limit, but was responsive to vitamin K.
    explanation: >-
      The preceding sentence identifies prothrombin time; responsiveness was reported in one sibling.
- name: Respiratory and feeding support in severe infantile disease
  description: >-
    A severely affected infant required tracheostomy and gastrostomy during prolonged neonatal intensive
    care. These measures supported respiratory and nutritional needs; they did not prevent subsequent
    deterioration.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:35789945
    reference_title: The biochemical profile and dietary management in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Patient was hospitalized for 3.5 months in the neonatal ICU due to respiratory failure and generalized
      hypotonia requiring tracheostomy and gastrostomy tube placement.
    explanation: Actual supportive interventions were reported in the new 2022 case.
animal_models:
- name: Ahcy-containing lethal nonagouti deletion mouse
  species: Mouse
  genotype: Homozygous a(x) contiguous deletion encompassing Ahcy
  publication: PMID:8168479
  description: >-
    A roughly 100-kb deletion includes Ahcy and causes peri-implantation lethality. Cultured-embryo inhibitor
    experiments support an AHCY contribution, but the deletion does not genetically isolate Ahcy. This
    primary abstract supports a restricted embryonic model.
  modeled_mechanisms:
  - target: AHCY Loss of Function
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Models loss of Ahcy within a larger deletion, with early embryonic death.
    limitations: >-
      Additional deleted sequence and embryonic lethality prevent a specific phenocopy of surviving human
      disease; the primary full text was not recovered.
    evidence:
    - reference: PMID:8168479
      reference_title: The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Long range restriction mapping demonstrated a simple deletion of approximately 100 kb
      explanation: >-
        The primary study mapped a contiguous deletion encompassing Ahcy, rather than a clean single-gene
        knockout.
    - reference: PMID:8168479
      reference_title: The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        The Ahcy gene, which codes for the enzyme S-adenosylhomocysteine hydrolase (SAHase), is contained
        within a 20 kb region within the a(x) deletion.
      explanation: Ahcy lies within the larger lethal nonagouti deletion.
    readouts:
    - name: AHCY Loss of Function
      target: AHCY Loss of Function
      direction: ALTERED
      interpretation: Models loss of Ahcy within a larger deletion, with early embryonic death.
      evidence:
      - reference: PMID:8168479
        reference_title: The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Long range restriction mapping demonstrated a simple deletion of approximately 100 kb
        explanation: >-
          The primary study mapped a contiguous deletion encompassing Ahcy, rather than a clean single-gene
          knockout.
      - reference: PMID:8168479
        reference_title: The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          The Ahcy gene, which codes for the enzyme S-adenosylhomocysteine hydrolase (SAHase), is contained
          within a 20 kb region within the a(x) deletion.
        explanation: Ahcy lies within the larger lethal nonagouti deletion.
- name: ducttrip Ahcy-deficient zebrafish
  species: Zebrafish
  genotype: Homozygous dtp missense mutation in the Ahcy NAD-binding domain
  publication: PMID:19201949
  description: >-
    Homozygous larvae accumulate SAH and SAM, develop hepatic steatosis and degeneration, and die early.
    tnfa knockdown improves liver histology and mitochondrial appearance. Wild-type ahcy mRNA rescues
    the early metabolic abnormality but not the later liver phenotype under the tested injection protocol.
  modeled_mechanisms:
  - target: AdoHcy Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Whole-larval SAH is elevated in homozygous mutants.
    limitations: >-
      Adult heterozygotes and pharmacologically inhibited adult fish had unchanged SAH and increased SAM,
      so results cannot be generalized across stage or genotype.
    evidence:
    - reference: PMID:19201949
      reference_title: TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and,
        to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM).
      explanation: >-
        Whole-larval metabolites increased in homozygous mutants. Adult heterozygotes had a different
        SAM/SAH pattern.
    readouts:
    - name: AdoHcy Accumulation
      target: AdoHcy Accumulation
      direction: INCREASED
      interpretation: Whole-larval SAH is elevated in homozygous mutants.
      evidence:
      - reference: PMID:19201949
        reference_title: TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH)
          and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM).
        explanation: >-
          Whole-larval metabolites increased in homozygous mutants. Adult heterozygotes had a different
          SAM/SAH pattern.
  - target: Hepatic Injury
    relationship: PERTURBS
    fidelity: LOW
    description: Larval liver injury and steatosis are improved by tnfa antisense knockdown.
    limitations: >-
      Liver-enriched larval tissue showed reduced global DNA/protein methylation; 5-azacytidine demethylation
      did not reproduce tnfa induction or steatosis. PC:PE was unchanged. Reduced mitochondrial glutathione
      was measured in drug-treated adults, not mutant larvae. The route to tnfa induction remains a hypothesis,
      and human TNF dependence is unproven.
    evidence:
    - reference: PMID:19201949
      reference_title: TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae
      explanation: >-
        A tnfa morpholino rescued larval liver abnormalities in the genetic model; this does not establish
        anti-TNF treatment efficacy in patients.
    readouts:
    - name: Hepatic Injury
      target: Hepatic Injury
      direction: ALTERED
      interpretation: Larval liver injury and steatosis are improved by tnfa antisense knockdown.
      evidence:
      - reference: PMID:19201949
        reference_title: TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae
        explanation: >-
          A tnfa morpholino rescued larval liver abnormalities in the genetic model; this does not establish
          anti-TNF treatment efficacy in patients.
- name: AHCY-1 Y145C C. elegans
  species: Caenorhabditis elegans
  genotype: Endogenous ahcy-1 Y145C::GFP, equivalent to human p.Tyr143Cys
  publication: PMID:38052822
  description: >-
    A partial AHCY-1-deficiency model has moderate SAH elevation, lower SAM and extended lifespan. RNAi
    of aak-2/AMPK, vrk-1 or daf-16 reduces the longevity phenotype. Normal locomotion and fertility and
    the distinct metabolic direction limit extrapolation to human disease.
  modeled_mechanisms:
  - target: AdoHcy Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Young-adult mutant worms have moderately elevated SAH.
    limitations: >-
      SAM is lower, not elevated as in patients. Lifespan assays at 20 degrees Celsius with FUdR address
      worm aging and do not support human SAH supplementation or treatment.
    evidence:
    - reference: PMID:38052822
      reference_title: 'SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Our findings revealed that animals with this endogenous mutation exhibited delayed aging, accompanied
        by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels.
      explanation: >-
        The endogenous Y145C worm model partly reproduces SAH elevation but has reduced SAM and extended
        lifespan.
    readouts:
    - name: AdoHcy Accumulation
      target: AdoHcy Accumulation
      direction: INCREASED
      interpretation: Young-adult mutant worms have moderately elevated SAH.
      evidence:
      - reference: PMID:38052822
        reference_title: 'SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Our findings revealed that animals with this endogenous mutation exhibited delayed aging, accompanied
          by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels.
        explanation: >-
          The endogenous Y145C worm model partly reproduces SAH elevation but has reduced SAM and extended
          lifespan.
experimental_models:
- name: Recombinant p.Arg49Cys and p.Asp86Gly AHCY proteins
  experimental_model_type: OTHER
  description: >-
    Patient-variant proteins expressed in E. coli were studied by enzyme assays, native electrophoresis,
    gel filtration and cofactor measurements. The experiments distinguish allele-specific activity and
    stability defects rather than a universal tetramer-assembly failure.
  publication: PMID:19177456
  modeled_mechanisms:
  - target: AHCY Loss of Function
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Recombinant disease alleles reduce hydrolase activity under specified conditions.
    limitations: >-
      p.Arg49Cys forms normal-size tetramers by gel filtration at 20 degrees Celsius and pH 7.2 but precipitates
      after warming. p.Asp86Gly activity increases from 1.5% to about 15.5% of wild type after bacterial
      chaperone induction. Engineered p.Asp86Glu is a rescue construct, not a clinical allele. DTT and
      benzyl alcohol were laboratory manipulations, not patient therapies.
    evidence:
    - reference: PMID:19177456
      reference_title: 'S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        The catalytic activity of thioredoxin-tagged p.Arg49Cys, determined in the direction of AdoHcy
        hydrolysis, was 6.7% that of the wild-type protein
      explanation: >-
        Reduced catalytic activity was measured in a specific purified recombinant-protein preparation.
    readouts:
    - name: AHCY Loss of Function
      target: AHCY Loss of Function
      direction: DECREASED
      interpretation: >-
        Recombinant disease alleles reduce hydrolase activity under specified conditions.
      evidence:
      - reference: PMID:19177456
        reference_title: 'S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          The catalytic activity of thioredoxin-tagged p.Arg49Cys, determined in the direction of AdoHcy
          hydrolysis, was 6.7% that of the wild-type protein
        explanation: >-
          Reduced catalytic activity was measured in a specific purified recombinant-protein preparation.
  evidence:
  - reference: PMID:19177456
    reference_title: 'S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      for p.Arg49Cys approximately 95.7% of the total bound coenzyme was in the form of NADH.
    explanation: >-
      Bound-cofactor redox state was measured; the active-site explanation was structurally modeled.
- name: Stable AHCY knockdown in SW480 colorectal cancer cells
  experimental_model_type: CELL_LINE
  cell_source: SW480 cancer cell line with lentiviral shRNA knockdown and puromycin selection
  publication: PMID:38003292
  description: >-
    Stable AHCY knockdown increased SAH and LEF1 protein abundance. RNA sequencing and pathway analysis
    predicted signaling-network alterations. SAM did not change significantly. This single cancer-cell
    background is not a patient-derived neural, hepatic or muscle model.
  modeled_mechanisms:
  - target: AdoHcy Accumulation
    relationship: MEASURES
    fidelity: LOW
    description: AHCY knockdown increases cellular SAH in the assayed cell line.
    limitations: >-
      RNA sequencing used two cell passages as biological replicates. The paper does not clearly establish
      independent clone replication or show AHCY re-expression rescue, LEF1 epistasis, Wnt reporter activity,
      methylome changes or direct invasion assays. Increased total STAT3 does not establish increased
      phosphorylation.
    evidence:
    - reference: PMID:38003292
      reference_title: Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        In the AHCY deficient cells, the concentration of SAH was found to be 4.6 ng/mL, whereas in the
        control cells, it was 2 ng/mL.
      explanation: Stable shRNA knockdown in SW480 cells increased measured SAH.
    readouts:
    - name: AdoHcy Accumulation
      target: AdoHcy Accumulation
      direction: INCREASED
      interpretation: AHCY knockdown increases cellular SAH in the assayed cell line.
      evidence:
      - reference: PMID:38003292
        reference_title: Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          In the AHCY deficient cells, the concentration of SAH was found to be 4.6 ng/mL, whereas in
          the control cells, it was 2 ng/mL.
        explanation: Stable shRNA knockdown in SW480 cells increased measured SAH.
  evidence:
  - reference: PMID:38003292
    reference_title: Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Quantification of band intensities showed an approximately 50% increase in LEF1 protein expression
      in the AHCY-deficient cells.
    explanation: >-
      Western blotting measured LEF1 abundance; this was not a beta-catenin localization or Wnt reporter
      assay.
progression:
- phase: Severe prenatal or infantile disease
  notes: >-
    Fetal hydrops, hypotonia, respiratory failure and developmental impairment can begin before or shortly
    after birth. Early death is reported despite combined dietary treatment; a normal methionine newborn
    screen does not exclude disease.
  evidence:
  - reference: PMID:20852937
    reference_title: 'S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine
      and creatine did not prevent her death at age 122 days.
    explanation: One severely affected sibling died despite treatment.
- phase: Mild childhood presentation with possible later complications
  notes: >-
    Some homozygous p.Arg49His children have biochemical liver and muscle abnormalities with little clinical
    impairment. One confirmed adult developed weakness in her mid-twenties and HCC at 29. These cases
    establish variability, not a predictable progression or genotype-specific risk rate.
  evidence:
  - reference: PMID:26527160
    reference_title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at
      age 29.
    explanation: An adult case demonstrates possible later morbidity.
discussions:
- 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This study was performed on DNA extracted from peripheral blood samples.
    explanation: >-
      The tissue restriction prevents direct extrapolation to affected muscle or brain.
  discussion_id: ahcy_tissue_methylation
  prompt: How do tissue-specific methylation changes produce organ disease?
  notes: >-
    Clinical DNA methylation measurements are restricted to blood and vary between patients and loci.
    The 2016 study did not perform the DNMT1 or myelin-protein methyltransferase activity experiments
    quoted in its discussion; those are earlier studies. No direct methylation-to-neurological-phenotype
    mechanism is established. Zebrafish hypomethylation and the worm SAM decrease further demonstrate
    model and tissue differences.
- evidence:
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      S-adenosylhomocysteine (AdoHcy), and S-adenosylmethionine (AdoMet) could not be performed.
    explanation: Biochemical confirmation was unavailable in this dual-diagnosis case.
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We thought that cataract finding in our patient was explained by the genetic variant in the PITX3
      gene.
    explanation: The authors attribute cataract to the second molecular diagnosis.
  - reference: PMID:39634240
    reference_title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      However, prematurity and neonatal problems may have contributed to neurodevelopmental problems.
    explanation: The source itself identifies additional developmental confounding.
  discussion_id: ahcy_dual_diagnosis
  prompt: Which findings in the dual AHCY/PITX3 case are attributable to AHCY?
  notes: >-
    The 2024 dysmorphic case carried homozygous AHCY p.Gly348Val and heterozygous PITX3 p.Tyr144Cys, both
    classified by the authors as likely pathogenic. SAM, SAH and enzyme activity were not available. Cataracts
    were attributed to PITX3; prematurity and neonatal illness also complicate neurodevelopmental attribution.
    The described facial and limb findings are case observations without an established AHCY-specific
    gestalt. The report advises diet and supplements but documents nonadherence, not treatment efficacy.
    Its assertion of HCC risk in heterozygous carriers is not established by the cited single-family primary
    report.
notes: >-
  Reviewed against the matching deep-research report and generated primary full text. Historical case
  counts differ between reviews because ascertainment and overlapping reports differ; no population phenotype
  frequencies are inferred. The later 2024 dysmorphic report counted 19 prior cases, whereas the earlier
  2024 report counted 16. GeneReviews and StatPearls had no disease-specific chapter in the checked repository
  index. Molecular links to tissue disease remain explicitly indirect when the intervening mechanisms
  have not been demonstrated.
references:
- reference: CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z
  title: AHCY / hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (Definitive)
- reference: PMID:15024124
  title: 'S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.'
- reference: PMID:16435181
  title: 'S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy.'
- reference: PMID:19177456
  title: 'S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.'
- reference: PMID:19201949
  title: TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
- reference: PMID:20852937
  title: 'S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes.'
- reference: PMID:26095522
  title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.
- reference: PMID:26527160
  title: Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.
- reference: PMID:26974671
  title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.
- reference: PMID:27671891
  title: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
- reference: PMID:31957987
  title: A Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency.
- reference: PMID:33869213
  title: Functional and Pathological Roles of AHCY.
- reference: PMID:35463910
  title: 'Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology.'
- reference: PMID:35789945
  title: The biochemical profile and dietary management in S-adenosylhomocysteine hydrolase deficiency.
- reference: PMID:38003292
  title: Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells.
- reference: PMID:38052822
  title: 'SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model.'
- reference: PMID:39512434
  title: Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.
- reference: PMID:39634240
  title: Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.
- reference: PMID:8168479
  title: The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.

📚

References & Deep Research

References

19

CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z

AHCY / hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (Definitive)

No top-level findings curated for this source.

PMID:15024124

S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.

No top-level findings curated for this source.

PMID:16435181

S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy.

No top-level findings curated for this source.

PMID:19177456

S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.

No top-level findings curated for this source.

PMID:19201949

TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.

No top-level findings curated for this source.

PMID:20852937

S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes.

No top-level findings curated for this source.

PMID:26095522

Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.

No top-level findings curated for this source.

PMID:26527160

Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency.

No top-level findings curated for this source.

PMID:26974671

Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.

No top-level findings curated for this source.

PMID:27671891

Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.

No top-level findings curated for this source.

PMID:31957987

A Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency.

No top-level findings curated for this source.

PMID:33869213

Functional and Pathological Roles of AHCY.

No top-level findings curated for this source.

PMID:35463910

Case Report: Advanced Skeletal Muscle Imaging in S-Adenosylhomocysteine Hydrolase Deficiency and Further Insight Into Muscle Pathology.

No top-level findings curated for this source.

PMID:35789945

The biochemical profile and dietary management in S-adenosylhomocysteine hydrolase deficiency.

No top-level findings curated for this source.

PMID:38003292

Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells.

No top-level findings curated for this source.

PMID:38052822

SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model.

No top-level findings curated for this source.

PMID:39512434

Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency.

No top-level findings curated for this source.

PMID:39634240

Dysmorphic Findings in SAHH Deficiency with a Novel Variant in the AHCY Gene.

No top-level findings curated for this source.

PMID:8168479

The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Reviewed against the matching deep-research report and generated primary full text. Historical case counts differ between reviews because ascertainment and overlapping reports differ; no population phenotype frequencies are inferred. The later 2024 dysmorphic report counted 19 prior cases, whereas the earlier 2024 report counted 16. GeneReviews and StatPearls had no disease-specific chapter in the checked repository index. Molecular links to tissue disease remain explicitly indirect when the intervening mechanisms have not been demonstrated.

Review AHCY clinical spectrum, methylation evidence and experimental models · 2026-09-21T04:35:20Z · View source

Reviewed the matching deep-research report and citation audit against generated primary references and consensus guidance. Replaced bundled mechanisms with 14 atomic nodes; expanded 15 phenotypes to 38 and added seven care interventions, four diagnostic procedures, three animal and two experimental models. Distinguished variable blood DNA hypermethylation from hypothesized non-DNA methyltransferase inhibition, and identified the DNMT/PRMT percentages as discussion citations rather than primary assays. Corrected cross-sectional muscle imaging, short-term transplant outcomes, allele-versus-carrier frequencies and the age of HCC diagnosis. Qualified the newer AHCY/PITX3 dual-diagnosis case and removed any implication of carrier HCC risk. Primary zebrafish, worm and recombinant studies now constrain model claims by tissue, stage and assay. Independent peer audit confirmed methylation, recombinant and SW480 scope. Schema, live terms and all draft evidence snippets passed; final guards and history validation recorded in the PR. Included the reviewed tracked PMC adapter for reproducible full-text recovery, without ignored environment modifications. All reference changes were generated by just fetch-reference; no reference caches were hand-edited and the frozen dataset accession file was not accessed.

Create: AHCY deficiency (S-adenosylhomocysteine hydrolase) · 2026-08-20T03:18:20Z · View source

De-novo Disease curation of S-adenosylhomocysteine hydrolase (AHCY) deficiency (MONDO:0013404) as kb/disorders/AHCY_Deficiency.yaml. Lump/split: curated as a standalone Disease (single-enzyme methionine-cycle hydrolase block). Not a grouping, not a subtype of Adenosine Kinase Deficiency, and not added to kb/groupings/Intoxication-Type_Inborn_Errors_of_Metabolism.yaml — classic AHCY is developmental/hepatic/myopathic rather than an intoxication-type acute decompensation. Sibling MAT1A/GNMT/ADK/CBS disorders remain separate. Duplicate preflight found AHCY only as a biochemical differential inside Adenosine_Kinase_Deficiency.yaml; ADK was left untouched. Deep research: just research-disorder falcon AHCY_Deficiency (Edison, ~11 min). Report is about AHCY, not ADK/MAT1A/CBS as the primary disease. just preflight-dr research/AHCY_Deficiency-deep-research-falcon.md MONDO:0013404 -> WARN: canonical gene AHCY mentioned 27 times (PASS-level gene signal) but the report cites gene OMIM 180960 while MONDO xrefs disease OMIM 613752. Not NEC. Report reference validation: 12/12 resolved, 0 unresolved, 0 off-topic. GeneReviews: PubMed searches for this disease and for isolated hypermethioninemia returned no GeneReviews chapter. Evidence: PMIDs 15024124, 16435181, 19177456, 20852937, 26527160, 26974671, 27671891, 31957987, 33869213, 35463910, 39512434 fetched via just fetch-reference. ClinGen gene-disease validity rebuilt as CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z (Definitive, AR). Snippets are exact abstract/cache quotes. Curation-loop count-verified-snippets: 54/54 verified against cached references. No enzyme-replacement invented. No conforms_to metabolic_intoxication_decompensation. Orphanet ORPHA:88618 noted in prevalence notes; local Orphadata XML was not present so no ORPHA cache row is cited. Issue 5557 is a metabolic WP-002 package, not a claim on this disease; this work closes claim issue 9019 only.

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

Upstream genetic trigger: biallelic AHCY hypomorphic/loss-of-function variants.
Primary biochemical lesion: reduced hydrolysis of SAH to adenosine and homocysteine.
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).
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.
Tissue injury: myocyte dysfunction and lipid replacement, abnormal myelination/white matter, hepatocellular steatosis and degeneration, synthetic liver failure, fibrosis/cirrhosis, and possibly carcinogenesis.
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

Clinical suspicion: unexplained hypermethioninemia, hypotonia/myopathy, persistent CK elevation, liver dysfunction/coagulopathy, delayed myelination, or fetal hydrops.
First-line chemistry: quantitative plasma amino acids, total homocysteine, liver panel, bilirubin, albumin, coagulation profile, CK, renal profile, glucose, and ammonia as clinically indicated.
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).
Confirmation: biallelic pathogenic/likely pathogenic AHCY variants plus compatible biochemistry; fibroblast, erythrocyte, or liver AHCY activity can provide functional confirmation where available.
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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

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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

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

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S-Adenosylhomocysteine Hydrolase Deficiency: Disease Characteristics Report

Executive summary

1. Disease information

Definition and names

Identifiers

2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

Epigenetics

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

Causal chain

Human mechanistic evidence

Recent molecular profiling

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population

10. Diagnostics

Recommended workflow

Differential diagnosis

11. Outcomes and prognosis

12. Treatment and real-world implementation

Methionine restriction

Supplements

Liver transplantation

Supportive care and surveillance

13. Prevention

14. Other species and natural disease

15. Model organisms

Current expert interpretation and evidence gaps

Key cited publications and URLs

Artifacts

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