Methylmalonic aciduria and homocystinuria

Summary

Methylmalonic aciduria and homocystinuria (MONDO:0016826) is a disease (an umbrella term covering 6 Mondo subtypes) with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000488	Retinopathy	Very frequent (80-99%)
HP:0000646	Amblyopia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001980	Megaloblastic bone marrow	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0000988	Skin rash	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria and homocystinuria
Mondo ID	MONDO:0016826
MeSH	C537359
OMIM	277400
Orphanet	26
UMLS	C5848324
MedGen	1864102
GARD	0003579
Is cancer (heuristic)	no

Also known as: combined defect in adenosylcobalamin and methylcobalamin synthesis · methylmalonic acidemia and homocystinemia · methylmalonic aciduria with homocystinuria

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 6 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 › inborn organic aciduria › methylmalonic acidemia › methylmalonic aciduria and homocystinuria

Related subtypes (6): methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency, methylmalonic acidemia due to transcobalamin receptor defect, combined malonic and methylmalonic acidemia, vitamin B12-responsive methylmalonic acidemia, isolated methylmalonic aciduria cblD type

Subtypes (6): methylmalonic aciduria and homocystinuria type cblF, methylmalonic aciduria and homocystinuria type cblC, methylmalonic aciduria and homocystinuria type cblD, methylmalonic acidemia with homocystinuria, type cblX, methylmalonic acidemia with homocystinuria, type cblJ, methylmalonic aciduria and homocystinuria, cb1L 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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1421	NM_015506.3(MMACHC):c.271dup (p.Arg91fs)	MMACHC	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
THAP11	Limited	Autosomal recessive	methylmalonic aciduria and homocystinuria	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMACHC	Orphanet:79282	Methylmalonic acidemia with homocystinuria, type cblC

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
THAP11	HGNC:23194	ENSG00000168286	Q96EK4	THAP domain-containing protein 11	gencc
MMACHC	HGNC:24525	ENSG00000132763	Q9Y4U1	Cyanocobalamin reductase / alkylcobalamin dealkylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THAP11	THAP domain-containing protein 11	Transcription factor, which has both transcriptional activation and repression activities.
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.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THAP11	Transcription factor	no		THAP_Znf
MMACHC	Enzyme (other)	yes	2.5.1.151	MMACHC

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amniotic fluid	1
primordial germ cell in gonad	1
skeletal muscle tissue of rectus abdominis	1
hindlimb stylopod muscle	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THAP11	289	ubiquitous	marker	amniotic fluid, skeletal muscle tissue of rectus abdominis, primordial germ cell in gonad
MMACHC	177	ubiquitous	marker	right lobe of liver, liver, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMACHC	1,383
THAP11	789

Intra-cohort edges

A	B	Sources
MMACHC	THAP11	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMACHC	Q9Y4U1	7
THAP11	Q96EK4	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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 MMACHC causes MAHCC	1	5710.0×	0.001	MMACHC
Defective MMADHC causes MMAHCD	1	3806.7×	0.001	MMACHC
Cobalamin (Cbl) metabolism	1	1268.9×	0.003	MMACHC
Defects in cobalamin (B12) metabolism	1	815.7×	0.003	MMACHC
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.003	MMACHC
Defects in vitamin and cofactor metabolism	1	601.0×	0.003	MMACHC
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	MMACHC
Metabolism of vitamins and cofactors	1	116.5×	0.012	MMACHC
Diseases of metabolism	1	80.4×	0.015	MMACHC
Disease	1	13.1×	0.084	MMACHC
Metabolism	1	11.6×	0.086	MMACHC

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
demethylation	1	2106.5×	0.003	MMACHC
regulation of mitochondrial transcription	1	936.2×	0.003	THAP11
cobalamin metabolic process	1	766.0×	0.003	MMACHC
electron transport chain	1	766.0×	0.003	THAP11
glutathione metabolic process	1	175.5×	0.011	MMACHC
negative regulation of neuron apoptotic process	1	55.4×	0.025	THAP11
cell population proliferation	1	51.4×	0.025	THAP11
neuron differentiation	1	50.1×	0.025	THAP11
negative regulation of transcription by RNA polymerase II	1	8.9×	0.122	THAP11
regulation of transcription by RNA polymerase II	1	5.8×	0.164	THAP11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
THAP11	0	0
MMACHC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMACHC	2.5.1.151	alkylcobalamin dealkylase

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

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	MMACHC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	THAP11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
THAP11	0	—
MMACHC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.