Homocystinuria without methylmalonic aciduria

Summary

Homocystinuria without methylmalonic aciduria (MONDO:0018964) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		73	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001980	Megaloblastic bone marrow	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000709	Psychosis	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	homocystinuria without methylmalonic aciduria
Mondo ID	MONDO:0018964
OMIM	236270
Orphanet	622
ICD-11	726186034
SNOMED CT	721225009
UMLS	C4303479
MedGen	929148
GARD	0016537
Is cancer (heuristic)	no

Also known as: functional methionine synthase deficiency · homocystinuria without methylmalonic aciduria · methylcobalamin deficiency

Data availability: 1 ClinVar variant.

Disease family

An umbrella term covering 4 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 › homocystinuria without methylmalonic aciduria

Related subtypes (4): hyperhomocysteinemia, classic homocystinuria, homocystinuria due to methylene tetrahydrofolate reductase deficiency, methylmalonic aciduria and homocystinuria

Subtypes (4): methylcobalamin deficiency type cblE, methylcobalamin deficiency type cblG, methylcobalamin deficiency type cblDv1, homocystinuria-megaloblastic anemia cblD type

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
666994	NM_002454.3(MTRR):c.340C>T (p.Arg114Ter)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTRR	Orphanet:2169	Methylcobalamin deficiency type cblE

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTRR	HGNC:7473	ENSG00000124275	Q9UBK8	Methionine synthase reductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTRR	Methionine synthase reductase	Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTRR	Enzyme (other)	yes	1.16.1.8	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
choroid plexus epithelium	1
endothelial cell	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTRR	291	ubiquitous	marker	endothelial cell, pancreatic ductal cell, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTRR	1,455

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTRR	Q9UBK8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 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 MTRR causes HMAE	1	5710.0×	0.001	MTRR
Defective MTR causes HMAG	1	5710.0×	0.001	MTRR
Cobalamin (Cbl) metabolism	1	1268.9×	0.004	MTRR
Methylation	1	815.7×	0.004	MTRR
Defects in cobalamin (B12) metabolism	1	815.7×	0.004	MTRR
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.004	MTRR
Defects in vitamin and cofactor metabolism	1	601.0×	0.004	MTRR
Sulfur amino acid metabolism	1	571.0×	0.004	MTRR
Phase II - Conjugation of compounds	1	278.5×	0.006	MTRR
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	MTRR
Biological oxidations	1	129.8×	0.011	MTRR
Metabolism of vitamins and cofactors	1	116.5×	0.011	MTRR
Diseases of metabolism	1	80.4×	0.015	MTRR
Metabolism of amino acids and derivatives	1	67.6×	0.017	MTRR
Disease	1	13.1×	0.082	MTRR
Metabolism	1	11.6×	0.086	MTRR

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-homocysteine catabolic process	1	5617.3×	6e-04	MTRR
L-methionine cycle	1	4213.0×	6e-04	MTRR
obsolete methionine biosynthetic process	1	3370.4×	6e-04	MTRR
homocysteine metabolic process	1	1872.4×	8e-04	MTRR
cobalamin metabolic process	1	1532.0×	8e-04	MTRR
folic acid metabolic process	1	1123.5×	9e-04	MTRR

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTRR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTRR	1.16.1.8	[methionine synthase] reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	1	MTRR
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)
MTRR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.