methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Summary

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (MONDO:0009612) is a disease caused by MMUT (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: MMUT (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 405
• Phenotypes (HPO): 25
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001259	Coma	Very frequent (80-99%)
HP:0001944	Dehydration	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001882	Leukopenia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001733	Pancreatitis	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001972	Macrocytic anemia	Occasional (5-29%)
HP:0001987	Hyperammonemia	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002273	Tetraparesis	Occasional (5-29%)
HP:0002385	Paraparesis	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Mondo ID	MONDO:0009612
MeSH	C565390
OMIM	251000
Orphanet	27
DOID	DOID:0060740
NCIT	C148366
UMLS	C1855114
MedGen	344424
GARD	0003586
Is cancer (heuristic)	no

Also known as: MCM deficiency · methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency · methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency · methylmalonyl-CoA mutase deficiency · methylmalonyl-Coenzyme A mutase deficiency · vitamin B12-unresponsive methylmalonic aciduria

Data availability: 405 ClinVar variants · 4 GenCC gene-disease records · 212 cell lines.

Disease family

An umbrella term covering 2 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 due to methylmalonyl-CoA mutase deficiency

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

Subtypes (2): vitamin B12-unresponsive methylmalonic acidemia type mut0, vitamin B12-unresponsive methylmalonic acidemia type mut-

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

405 retrieved; paginated sample, class counts are floors:

115 pathogenic, 93 uncertain significance, 65 likely pathogenic, 56 pathogenic/likely pathogenic, 36 conflicting classifications of pathogenicity, 15 likely benign, 12 benign, 8 benign/likely benign, 5 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
424788	NM_000255.3(MMUT):c.[1891delG];[322C>T]		Pathogenic	criteria provided, single submitter
590807	NM_000528.4(MAN2B1):c.729_730insTT (p.Ser244fs)	MAN2B1	Pathogenic	no assertion criteria provided
1423	NM_015506.3(MMACHC):c.394C>T (p.Arg132Ter)	MMACHC	Pathogenic	criteria provided, multiple submitters, no conflicts
1425	NM_015506.3(MMACHC):c.482G>A (p.Arg161Gln)	MMACHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100707	NM_000255.4(MMUT):c.323G>A (p.Arg108His)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1027373	NM_000255.4(MMUT):c.438T>A (p.Tyr146Ter)	MMUT	Pathogenic	criteria provided, single submitter
1072649	NM_000255.4(MMUT):c.29del (p.Leu10fs)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073632	NM_000255.4(MMUT):c.581C>T (p.Pro194Leu)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323284	NM_000255.4(MMUT):c.1240G>T (p.Glu414Ter)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1358455	NM_000255.4(MMUT):c.839dup (p.Leu281fs)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1422287	NM_000255.4(MMUT):c.1159A>C (p.Thr387Pro)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453225	NM_000255.4(MMUT):c.751A>T (p.Lys251Ter)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459267	NM_000255.4(MMUT):c.1871A>G (p.Gln624Arg)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459268	NM_000255.4(MMUT):c.1844C>T (p.Pro615Leu)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1499715	NM_000255.4(MMUT):c.785G>A (p.Ser262Asn)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1522733	NM_000255.4(MMUT):c.545T>G (p.Met182Arg)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167310	NM_000255.4(MMUT):c.1207C>T (p.Arg403Ter)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
167312	NM_000255.4(MMUT):c.280G>A (p.Gly94Arg)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685951	NM_000255.4(MMUT):c.1843C>A (p.Pro615Thr)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1705196	NM_000255.4(MMUT):c.544dup (p.Met182fs)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1804011	NM_000255.4(MMUT):c.1162A>C (p.Asn388His)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810220	NM_000255.4(MMUT):c.1675A>G (p.Arg559Gly)	MMUT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1877	NM_000255.4(MMUT):c.52C>T (p.Gln18Ter)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1878	NM_000255.4(MMUT):c.313T>C (p.Trp105Arg)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1880	NM_000255.4(MMUT):c.278G>A (p.Arg93His)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1881	NM_000255.4(MMUT):c.2150G>T (p.Gly717Val)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1882	NM_000255.4(MMUT):c.349G>T (p.Glu117Ter)	MMUT	Pathogenic	criteria provided, single submitter
1884	NM_000255.4(MMUT):c.1867G>A (p.Gly623Arg)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1886	NM_000255.4(MMUT):c.655A>T (p.Asn219Tyr)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts
1887	NM_000255.4(MMUT):c.322C>T (p.Arg108Cys)	MMUT	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 9 · 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
MMUT	Definitive	Autosomal recessive	methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMUT	Orphanet:289916	Vitamin B12-unresponsive methylmalonic acidemia type mut0
MMUT	Orphanet:79312	Vitamin B12-unresponsive methylmalonic acidemia type mut-
MMACHC	Orphanet:79282	Methylmalonic acidemia with homocystinuria, type cblC
MAN2B1	Orphanet:309282	Alpha-mannosidosis, infantile form
MAN2B1	Orphanet:309288	Alpha-mannosidosis, adult form
PEX16	Orphanet:44	Neonatal adrenoleukodystrophy
PEX16	Orphanet:642954	Autosomal recessive ataxia due to PEX16 deficiency
PEX16	Orphanet:772	Infantile Refsum disease
PEX16	Orphanet:912	Zellweger syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MMUT	HGNC:7526	ENSG00000146085	P22033	Methylmalonyl-CoA mutase, mitochondrial	gencc,clinvar
MMACHC	HGNC:24525	ENSG00000132763	Q9Y4U1	Cyanocobalamin reductase / alkylcobalamin dealkylase	clinvar
MAN2B1	HGNC:6826	ENSG00000104774	O00754	Lysosomal alpha-mannosidase	clinvar
PEX16	HGNC:8857	ENSG00000121680	Q9Y5Y5	Peroxisomal membrane protein PEX16	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMUT	Methylmalonyl-CoA mutase, mitochondrial	Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key inte…
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.
MAN2B1	Lysosomal alpha-mannosidase	Can hydrolyze a variety of glycan substrates containing terminal alpha-mannosidic linkages.
PEX16	Peroxisomal membrane protein PEX16	Required for peroxisome membrane biogenesis.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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	9.0×	0.004
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMUT	Enzyme (other)	yes	5.4.99.2	MMCoA_mutase_a_cat, MeMalonylCoA_mutase_a/b_cat, Cobalamin-bd
MMACHC	Enzyme (other)	yes	2.5.1.151	MMACHC
MAN2B1	Enzyme (other)	yes	3.2.1.24	Glyco_hydro_38_N, Gal_mutarotase_sf_dom, Glyco_hydro/deAcase_b/a-brl
PEX16	Other/Unknown	no		Pex16

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
granulocyte	2
choroid plexus epithelium	1
nephron tubule	1
oocyte	1
hindlimb stylopod muscle	1
liver	1
bone marrow cell	1
monocyte	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMUT	296	ubiquitous	marker	choroid plexus epithelium, oocyte, nephron tubule
MMACHC	177	ubiquitous	marker	right lobe of liver, liver, hindlimb stylopod muscle
MAN2B1	138	ubiquitous	marker	bone marrow cell, granulocyte, monocyte
PEX16	281	ubiquitous	marker	prefrontal cortex, granulocyte, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMUT	3,709
MMACHC	1,383
PEX16	1,231
MAN2B1	1,077

Intra-cohort edges

A	B	Sources
MMACHC	MMUT	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMACHC	Q9Y4U1	7
MMUT	P22033	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAN2B1	O00754	91.78
PEX16	Q9Y5Y5	83.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 4 evidence-associated genes (4 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 4 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	634.4×	8e-05	MMUT, MMACHC
Defects in cobalamin (B12) metabolism	2	407.9×	1e-04	MMUT, MMACHC
Cobalamin (Cbl, vitamin B12) transport and metabolism	2	317.2×	1e-04	MMUT, MMACHC
Defects in vitamin and cofactor metabolism	2	300.5×	1e-04	MMUT, MMACHC
Metabolism of water-soluble vitamins and cofactors	2	90.6×	9e-04	MMUT, MMACHC
Defective MMACHC causes MAHCC	1	1427.5×	0.002	MMACHC
Defective MMAA causes MMA, cblA type	1	1427.5×	0.002	MMUT
Defective MUT causes MMAM	1	1427.5×	0.002	MMUT
Diseases of mitochondrial beta oxidation	1	1427.5×	0.002	MMUT
Diseases of propionyl-CoA catabolism	1	1427.5×	0.002	MMUT
Metabolism of vitamins and cofactors	2	58.3×	0.002	MMUT, MMACHC
Diseases of metabolism	2	40.2×	0.002	MMUT, MMACHC
Defective MMADHC causes MMAHCD	1	951.7×	0.002	MMACHC
Lysosomal oligosaccharide catabolism	1	713.8×	0.003	MAN2B1
Propionyl-CoA catabolism	1	571.0×	0.003	MMUT
Metabolism	3	8.7×	0.004	MMUT, MMACHC, MAN2B1
Class I peroxisomal membrane protein import	1	129.8×	0.011	PEX16
Mitochondrial Fatty Acid Beta-Oxidation	1	95.2×	0.015	MMUT
Fatty acid metabolism	1	32.8×	0.039	MMUT
Metabolism of carbohydrates and carbohydrate derivatives	1	30.1×	0.039	MAN2B1
Disease	2	6.5×	0.039	MMUT, MMACHC
Metabolism of lipids	1	7.9×	0.137	MMUT
Innate Immune System	1	6.4×	0.161	MAN2B1
Neutrophil degranulation	1	5.8×	0.169	MAN2B1
Immune System	1	3.2×	0.275	MAN2B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete propionate metabolic process, methylmalonyl pathway	1	4213.0×	0.002	MMUT
ER-dependent peroxisome organization	1	4213.0×	0.002	PEX16
ER-dependent peroxisome localization	1	4213.0×	0.002	PEX16
succinyl-CoA biosynthetic process	1	2106.5×	0.002	MMUT
peroxisome membrane biogenesis	1	1404.3×	0.003	PEX16
demethylation	1	1053.2×	0.003	MMACHC
protein to membrane docking	1	842.6×	0.003	PEX16
protein import into peroxisome membrane	1	702.2×	0.003	PEX16
mannose metabolic process	1	526.6×	0.004	MAN2B1
homocysteine metabolic process	1	468.1×	0.004	MMUT
protein targeting to peroxisome	1	421.3×	0.004	PEX16
cobalamin metabolic process	1	383.0×	0.004	MMACHC
protein import into peroxisome matrix	1	351.1×	0.004	PEX16
glycoprotein catabolic process	1	263.3×	0.005	MAN2B1
peroxisome organization	1	200.6×	0.006	PEX16
glutathione metabolic process	1	87.8×	0.013	MMACHC
positive regulation of GTPase activity	1	69.1×	0.016	MMUT
learning or memory	1	60.2×	0.017	MAN2B1
post-embryonic development	1	51.4×	0.019	MMUT

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
MAN2B1	1	2
MMUT	0	0
MMACHC	0	0
PEX16	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIDOLGOSIR	2	MAN2B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MAN2B1	53	Binding:52, ADMET:1
PEX16	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMUT	5.4.99.2	methylmalonyl-CoA mutase
MMACHC	2.5.1.151	alkylcobalamin dealkylase
MAN2B1	3.2.1.24	alpha-mannosidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
TRIDOLGOSIR	2	MAN2B1

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	MAN2B1
C	Druggable family + PDB, no drug	2	MMUT, MMACHC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PEX16

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MMUT	0	—
MMACHC	0	—
PEX16	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns