hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Summary

hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (MONDO:0013404) is a disease caused by AHCY (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AHCY (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 298
• Phenotypes (HPO): 44

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0002160	Hyperhomocystinemia	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003073	Hypoalbuminemia	Very frequent (80-99%)
HP:0010901	Abnormality of methionine metabolism	Very frequent (80-99%)
HP:0010919	Abnormality of homocysteine metabolism	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001392	Abnormality of the liver	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001789	Hydrops fetalis	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0001976	Reduced antithrombin III activity	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003429	CNS hypomyelination	Frequent (30-79%)
HP:0003560	Muscular dystrophy	Frequent (30-79%)
HP:0008151	Prolonged prothrombin time	Frequent (30-79%)
HP:0008169	Reduced factor VII activity	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011900	Hypofibrinogenemia	Frequent (30-79%)
HP:0011996	Elevated coagulation factor V activity	Frequent (30-79%)
HP:0012110	Hypoplasia of the pons	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001402	Hepatocellular carcinoma	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003235	Hypermethioninemia	Occasional (5-29%)
HP:0007141	Sensorimotor neuropathy	Occasional (5-29%)
HP:0010719	Abnormality of hair texture	Occasional (5-29%)
HP:0012704	Widened subarachnoid space	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
Mondo ID	MONDO:0013404
OMIM	613752
Orphanet	88618
DOID	DOID:0111039
SNOMED CT	724039002
UMLS	C3151058
MedGen	462408
GARD	0013177
Is cancer (heuristic)	no

Also known as: hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Data availability: 298 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › disorder of methionine catabolism › hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Related subtypes (2): glycine N-methyltransferase deficiency, adenosine kinase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

298 retrieved; paginated sample, class counts are floors:

143 likely benign, 100 uncertain significance, 22 conflicting classifications of pathogenicity, 10 benign, 9 likely pathogenic, 6 pathogenic, 4 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12952	NM_000687.4(AHCY):c.336G>A (p.Trp112Ter)	AHCY	Pathogenic	no assertion criteria provided
12953	NM_000687.4(AHCY):c.428A>G (p.Tyr143Cys)	AHCY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2011118	NM_000687.4(AHCY):c.882del (p.Ile295fs)	AHCY	Pathogenic	criteria provided, single submitter
235681	NM_000687.4(AHCY):c.293C>T (p.Pro98Leu)	AHCY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2692384	NM_000687.4(AHCY):c.170C>T (p.Thr57Ile)	AHCY	Pathogenic	no assertion criteria provided
2692385	NM_000687.4(AHCY):c.649G>A (p.Val217Met)	AHCY	Pathogenic	no assertion criteria provided
2893172	NM_000687.4(AHCY):c.145del (p.Arg49fs)	AHCY	Pathogenic	criteria provided, single submitter
631872	NM_000687.4(AHCY):c.257A>G (p.Asp86Gly)	AHCY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
985503	NM_000687.4(AHCY):c.145C>T (p.Arg49Cys)	AHCY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3248297	NC_000020.10:g.(?31571600)(33001705_?)del	SUN5	Pathogenic	criteria provided, single submitter
2584488	NM_000687.4(AHCY):c.106C>T (p.Arg36Trp)	AHCY	Likely pathogenic	criteria provided, single submitter
2912157	NM_000687.4(AHCY):c.558+1_558+2delinsCG	AHCY	Likely pathogenic	criteria provided, single submitter
3587194	NM_000687.4(AHCY):c.972+1G>A	AHCY	Likely pathogenic	criteria provided, single submitter
3587195	NM_000687.4(AHCY):c.763del (p.Glu255fs)	AHCY	Likely pathogenic	criteria provided, single submitter
3587196	NM_000687.4(AHCY):c.373del (p.Leu125fs)	AHCY	Likely pathogenic	criteria provided, single submitter
3587197	NM_000687.4(AHCY):c.322G>A (p.Glu108Lys)	AHCY	Likely pathogenic	criteria provided, single submitter
3587198	NM_000687.4(AHCY):c.28+2T>G	AHCY	Likely pathogenic	criteria provided, single submitter
3587199	NM_000687.4(AHCY):c.6del (p.Asp3fs)	AHCY	Likely pathogenic	criteria provided, single submitter
4746907	NM_000687.4(AHCY):c.266C>G (p.Ala89Gly)	AHCY	Likely pathogenic	criteria provided, single submitter
1037891	NM_000687.4(AHCY):c.1228A>T (p.Thr410Ser)	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1045453	NM_000687.4(AHCY):c.1001G>A (p.Arg334His)	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303246	NM_000687.4(AHCY):c.982T>G (p.Tyr328Asp)	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218468	NM_000687.4(AHCY):c.-34C>T	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2231293	NM_000687.4(AHCY):c.1168-5C>T	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2243828	NM_000687.4(AHCY):c.142G>A (p.Ala48Thr)	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235584	NM_000687.4(AHCY):c.274A>G (p.Ile92Val)	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338271	NM_000687.4(AHCY):c.918C>T (p.Ile306=)	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338272	NM_000687.4(AHCY):c.855-8C>T	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338277	NM_000687.4(AHCY):c.445+11C>T	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338278	NM_000687.4(AHCY):c.219+8C>T	AHCY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AHCY	Strong	Autosomal recessive	hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AHCY	Orphanet:88618	S-adenosylhomocysteine hydrolase deficiency
SUN5	Orphanet:529970	Male infertility due to acephalic spermatozoa

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AHCY	HGNC:343	ENSG00000101444	P23526	Adenosylhomocysteinase	gencc,clinvar
SUN5	HGNC:16252	ENSG00000167098	Q8TC36	SUN domain-containing protein 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AHCY	Adenosylhomocysteinase	Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine.
SUN5	SUN domain-containing protein 5	Plays an essential role in anchoring sperm head to the tail.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AHCY	Enzyme (other)	yes	3.3.1.1	Adenosylhomocysteinase-like, Ado_hCys_hydrolase_NAD-bd, S-Ado-L-homoCys_hydrolase_CS
SUN5	Other/Unknown	no		SUN_dom, SUN1-5

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
lower esophagus mucosa	1
right lobe of liver	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AHCY	145	ubiquitous	marker	lower esophagus mucosa, body of pancreas, right lobe of liver
SUN5	28	tissue_specific	yes	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AHCY	4,138
SUN5	1,108

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AHCY	P23526	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SUN5	Q8TC36	75.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective AHCY causes HMAHCHD	1	11420.0×	0.001	AHCY
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	1427.5×	0.004	AHCY
Metabolic disorders of biological oxidation enzymes	1	878.5×	0.004	AHCY
Methylation	1	815.7×	0.004	AHCY
Sulfur amino acid metabolism	1	571.0×	0.004	AHCY
Phase II - Conjugation of compounds	1	278.5×	0.007	AHCY
Selenoamino acid metabolism	1	196.9×	0.009	AHCY
Biological oxidations	1	129.8×	0.012	AHCY
Diseases of metabolism	1	80.4×	0.017	AHCY
Metabolism of amino acids and derivatives	1	67.6×	0.018	AHCY
Disease	1	13.1×	0.083	AHCY
Metabolism	1	11.6×	0.086	AHCY

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-methionine cycle	1	2106.5×	0.002	AHCY
one-carbon metabolic process	1	561.7×	0.004	AHCY
spermatid development	1	72.6×	0.018	SUN5
spermatogenesis	1	17.6×	0.056	SUN5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AHCY	1	2
SUN5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	AHCY

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AHCY	211	Binding:197, Functional:14

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AHCY	3.3.1.1	adenosylhomocysteinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
AHCY	211

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	AHCY

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	AHCY
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SUN5

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SUN5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.