Homocystinuria

Summary

Homocystinuria (MONDO:0004737) is a disease (an umbrella term covering 5 Mondo subtypes) with 3 cohort genes and 16 clinical trials. Top therapeutic interventions include betaine, pegtibatinase, and creatine.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 76
• Clinical trials: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	homocystinuria
Mondo ID	MONDO:0004737
MeSH	D006712
DOID	DOID:9263
ICD-10-CM	E72.11
NCIT	C84765
SNOMED CT	11282001
UMLS	C0019880
MedGen	42485
GARD	0010770
Is cancer (heuristic)	no

Also known as: CBS deficiency · cystathionine beta synthase deficiency · cystathionine synthase deficiency · homocystinuria · homocystinuria (disease)

Data availability: 76 ClinVar variants · 1 HPO phenotype · 27 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

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 › homocystinuria

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Subtypes (5): hyperhomocysteinemia, classic homocystinuria, homocystinuria due to methylene tetrahydrofolate reductase deficiency, methylmalonic aciduria and homocystinuria, homocystinuria without methylmalonic aciduria

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

76 retrieved; paginated sample, class counts are floors:

40 pathogenic/likely pathogenic, 23 pathogenic, 7 likely pathogenic, 6 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066972	NM_000071.3(CBS):c.869C>T (p.Pro290Leu)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
117	NM_000071.3(CBS):c.919G>A (p.Gly307Ser)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
118	NM_000071.3(CBS):c.434C>T (p.Pro145Leu)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
119	NM_000071.3(CBS):c.341C>T (p.Ala114Val)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120	NM_000071.3(CBS):c.833T>C (p.Ile278Thr)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
122	NM_000071.3(CBS):c.430G>A (p.Glu144Lys)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
125	NM_000071.3(CBS):c.797G>A (p.Arg266Lys)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126	NM_000071.3(CBS):c.1330G>A (p.Asp444Asn)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
128	NM_000071.3(CBS):c.1224-2A>C	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
131	NM_000071.3(CBS):c.1058C>T (p.Thr353Met)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
132	NM_000071.3(CBS):c.572C>T (p.Thr191Met)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1339663	NM_000071.3(CBS):c.1039+1G>T	CBS	Pathogenic	criteria provided, single submitter
1481680	NM_000071.3(CBS):c.473C>T (p.Ala158Val)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188784	NM_000071.3(CBS):c.1566del (p.Lys523fs)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188787	NM_000071.3(CBS):c.346G>A (p.Gly116Arg)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188801	NM_000071.3(CBS):c.1039G>A (p.Gly347Ser)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188825	NM_000071.3(CBS):c.1136G>A (p.Arg379Gln)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188829	NM_000071.3(CBS):c.689del (p.Leu230fs)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188911	NM_000071.3(CBS):c.667-14_667-7del	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188927	NM_000071.3(CBS):c.770C>T (p.Thr257Met)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188948	NM_000071.3(CBS):c.362G>A (p.Arg121His)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189185	NM_000071.3(CBS):c.302T>C (p.Leu101Pro)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197625	NM_000071.3(CBS):c.374G>A (p.Arg125Gln)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
198988	NM_000071.3(CBS):c.785C>T (p.Thr262Met)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212842	NM_000071.3(CBS):c.361C>T (p.Arg121Cys)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212852	NM_000071.3(CBS):c.700G>A (p.Asp234Asn)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212857	NM_000071.3(CBS):c.992C>A (p.Ala331Glu)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212862	NM_000071.3(CBS):c.1111G>A (p.Val371Met)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212873	NM_000071.3(CBS):c.162G>A (p.Trp54Ter)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212878	NM_000071.3(CBS):c.325T>C (p.Cys109Arg)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CBS	Orphanet:394	Homocystinuria due to cystathionine beta-synthase deficiency
MMACHC	Orphanet:79282	Methylmalonic acidemia with homocystinuria, type cblC
MTR	Orphanet:2170	Methylcobalamin deficiency type cblG

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CBS	HGNC:1550	ENSG00000160200	P35520	Cystathionine beta-synthase	clinvar
MMACHC	HGNC:24525	ENSG00000132763	Q9Y4U1	Cyanocobalamin reductase / alkylcobalamin dealkylase	clinvar
MTR	HGNC:7468	ENSG00000116984	Q99707	Methionine synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CBS	Cystathionine beta-synthase	Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine.
MMACHC	Cyanocobalamin reductase / alkylcobalamin dealkylase	Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate.
MTR	Methionine synthase	Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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)	3	12.0×	6e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CBS	Enzyme (other)	yes	4.2.1.22	CBS_dom, P-phosphate_BS, TrpB-like_PALP
MMACHC	Enzyme (other)	yes	2.5.1.151	MMACHC
MTR	Enzyme (other)	yes	2.1.1.13	Pterin-binding_dom, HCY_dom, Cbl-bd_cap

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
body of pancreas	1
hindlimb stylopod muscle	1
caput epididymis	1
corpus epididymis	1
decidua	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CBS	134	tissue_specific	marker	right lobe of liver, body of pancreas, liver
MMACHC	177	ubiquitous	marker	right lobe of liver, liver, hindlimb stylopod muscle
MTR	294	ubiquitous	marker	caput epididymis, corpus epididymis, decidua

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTR	2,607
MMACHC	1,383
CBS	346

Intra-cohort edges

A	B	Sources
MMACHC	MTR	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBS	P35520	19
MTR	Q99707	9
MMACHC	Q9Y4U1	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cobalamin (Cbl) metabolism	2	845.9×	4e-05	MMACHC, MTR
Defects in cobalamin (B12) metabolism	2	543.8×	5e-05	MMACHC, MTR
Cobalamin (Cbl, vitamin B12) transport and metabolism	2	423.0×	5e-05	MMACHC, MTR
Defects in vitamin and cofactor metabolism	2	400.7×	5e-05	MMACHC, MTR
Sulfur amino acid metabolism	2	380.7×	5e-05	CBS, MTR
Metabolism of water-soluble vitamins and cofactors	2	120.8×	4e-04	MMACHC, MTR
Metabolism of vitamins and cofactors	2	77.7×	8e-04	MMACHC, MTR
Cysteine formation from homocysteine	1	1903.3×	0.001	CBS
Defective MTRR causes HMAE	1	1903.3×	0.001	MTR
Defective MTR causes HMAG	1	1903.3×	0.001	MTR
Defective MMACHC causes MAHCC	1	1903.3×	0.001	MMACHC
Diseases of metabolism	2	53.6×	0.001	MMACHC, MTR
Metabolism of amino acids and derivatives	2	45.0×	0.001	CBS, MTR
Metabolism	3	11.6×	0.001	CBS, MMACHC, MTR
Defective MMADHC causes MMAHCD	1	1268.9×	0.001	MMACHC
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	475.8×	0.003	CBS
Methylation	1	271.9×	0.006	MTR
RHOH GTPase cycle	1	102.9×	0.014	MTR
Phase II - Conjugation of compounds	1	92.8×	0.015	MTR
Selenoamino acid metabolism	1	65.6×	0.020	CBS
Disease	2	8.7×	0.021	MMACHC, MTR
Biological oxidations	1	43.3×	0.027	MTR
RHO GTPase cycle	1	20.0×	0.055	MTR
Signaling by Rho GTPases	1	11.4×	0.090	MTR
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.090	MTR
Signal Transduction	1	3.4×	0.267	MTR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
homocysteine metabolic process	2	1248.3×	2e-05	CBS, MTR
cobalamin metabolic process	2	1021.3×	2e-05	MMACHC, MTR
sulfur amino acid metabolic process	1	5617.3×	0.002	MTR
obsolete L-cysteine biosynthetic process from L-serine	1	5617.3×	0.002	CBS
obsolete regulation of nitric oxide mediated signal transduction	1	2808.7×	0.002	CBS
obsolete L-cysteine biosynthetic process via L-cystathionine	1	2808.7×	0.002	CBS
L-cysteine biosynthetic process	1	1872.4×	0.002	CBS
cerebellum morphogenesis	1	1872.4×	0.002	CBS
L-homocysteine catabolic process	1	1872.4×	0.002	CBS
hydrogen sulfide biosynthetic process	1	1872.4×	0.002	CBS
L-serine catabolic process	1	1404.3×	0.002	CBS
transsulfuration	1	1404.3×	0.002	CBS
L-cysteine catabolic process	1	1404.3×	0.002	CBS
demethylation	1	1404.3×	0.002	MMACHC
obsolete methionine biosynthetic process	1	1123.5×	0.002	MTR
DNA protection	1	936.2×	0.002	CBS
tetrahydrofolate metabolic process	1	802.5×	0.002	MTR
response to folic acid	1	802.5×	0.002	CBS
cartilage development involved in endochondral bone morphogenesis	1	802.5×	0.002	CBS
L-serine metabolic process	1	561.7×	0.003	CBS
axon regeneration	1	374.5×	0.004	MTR
superoxide metabolic process	1	330.4×	0.005	CBS
maternal process involved in female pregnancy	1	312.1×	0.005	CBS
cellular response to nitric oxide	1	312.1×	0.005	MTR
regulation of JNK cascade	1	295.6×	0.005	CBS
blood vessel diameter maintenance	1	208.1×	0.006	CBS
endochondral ossification	1	181.2×	0.007	CBS
response to axon injury	1	170.2×	0.007	MTR
blood vessel remodeling	1	127.7×	0.009	CBS
glutathione metabolic process	1	117.0×	0.010	MMACHC

Therapeutics

Drugs indicated for this disease

1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Betaine	Approved (phase 4)
Pegtibatinase	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcysteine.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MTR	LOMITAPIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CBS	1	3
MTR	1	4
MMACHC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOMITAPIDE	4	MTR
HYPERICIN	3	CBS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
CBS	22	Binding:22
MTR	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CBS	4.2.1.22	cystathionine beta-synthase
MMACHC	2.5.1.151	alkylcobalamin dealkylase
MTR	2.1.1.13	methionine synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
LOMITAPIDE	4	MTR
HYPERICIN	3	CBS

Druggability pyramid

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

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

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)
MMACHC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 16.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE1/PHASE2	3
PHASE3	2
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06247085	PHASE3	RECRUITING	A Study to Investigate Efficacy and Safety of Pegtibatinase Compared With Placebo in Participants ≥12 to ≤65 Years of Age With Classical Homocystinuria (HCU) Due to Cystathionine Beta Synthase Deficiency Receiving Standard of Care Treatment
NCT06431893	PHASE3	ENROLLING_BY_INVITATION	A Long-term Extension Study to Assess the Long-term Safety and Efficacy of Pegtibatinase Treatment in Participants ≥5 to ≤65 Years of Age With Classical Homocystinuria (HCU) (ENSEMBLE)
NCT03406611	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Pegtibatinase As an Enzyme Therapy for Patients with Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency (COMPOSE)
NCT00483314	PHASE2	COMPLETED	Homocystinuria: Treatment With N-Acetylcysteine
NCT01192828	PHASE1/PHASE2	COMPLETED	Oxidative Stress Markers In Inherited Homocystinuria And The Impact Of Taurine
NCT02404337	PHASE2	COMPLETED	Betaine METABOLISM OF PATIENTS With Homocystinuria
NCT04015557	PHASE1/PHASE2	SUSPENDED	Effect of Acetaminophen and N-Acetylcysteine on Liver Metabolism on Homocystinuria
NCT05462132	PHASE1	COMPLETED	Safety, Tolerability and Pharmacodynamics of SYNB1353 in Healthy Adult Volunteers
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06495567	Not specified	ACTIVE_NOT_RECRUITING	Proof of Concept Creatine Supplementation for Homocystinuria Study
NCT06556615	Not specified	RECRUITING	Health Related Quality of Life (HrQoL) in Classical Homocystinuria (CBS Deficiency)
NCT00004356	Not specified	COMPLETED	Study of Homocysteine Metabolism in Homocystinuria
NCT04021732	Not specified	COMPLETED	Effects of Exercise on Metabolic Parameters in Classical Homocystinuria
NCT05051657	Not specified	COMPLETED	Evaluation of the Express Plus Range
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BETAINE	4	1
PEGTIBATINASE	3	3
CREATINE	3	1
TAURINE	3	1
CHEMBL5435500	0	2
GLYCINEBETAINE	0	1