methylmalonic aciduria and homocystinuria type cblD

Summary

methylmalonic aciduria and homocystinuria type cblD (MONDO:0010185) is a disease caused by MMADHC (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MMADHC (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 358
• Phenotypes (HPO): 12
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001980	Megaloblastic bone marrow	Very frequent (80-99%)
HP:0002039	Anorexia	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria and homocystinuria type cblD
Mondo ID	MONDO:0010185
MeSH	C564743
OMIM	277410
Orphanet	79283
DOID	DOID:0050716
SNOMED CT	31220004
UMLS	C1848552
MedGen	341253
GARD	0003582
Is cancer (heuristic)	no

Also known as: cblD defect · cobalamin D defect · cobalamin d disease · combined defect in adenosylcobalamin and methylcobalamin synthesis, type cblD · homocystinuria, cblD type, variant 1, included · MAHCD · mehtylmalonic acidemia with homocystinuria cbI d · methylmalonic acidemia with homocystinuria type cblD · methylmalonic acidemia, Cblh type · methylmalonic aciduria and homocystinuria type cblD · methylmalonic aciduria with homocystinuria, type cblD · methylmalonic aciduria, cblD type, variant 2, included · methylmalonic aciduria, Cblh type

Data availability: 358 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: 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 › methylmalonic aciduria and homocystinuria type cblD

Related subtypes (5): methylmalonic aciduria and homocystinuria type cblF, methylmalonic aciduria and homocystinuria type cblC, 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

358 retrieved; paginated sample, class counts are floors:

175 likely benign, 75 uncertain significance, 38 pathogenic, 27 likely pathogenic, 13 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 9 benign, 9 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3256599	NM_015702.3(MMADHC):c.9+5G>A	LOC126806368	Pathogenic	criteria provided, single submitter
1423	NM_015506.3(MMACHC):c.394C>T (p.Arg132Ter)	MMACHC	Pathogenic	criteria provided, multiple submitters, no conflicts
1072551	NC_000002.11:g.(?150443583)(150443631_?)del	MMADHC	Pathogenic	criteria provided, single submitter
1388511	NM_015702.3(MMADHC):c.663G>A (p.Trp221Ter)	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1432468	NM_015702.3(MMADHC):c.692T>A (p.Leu231Ter)	MMADHC	Pathogenic	criteria provided, single submitter
1436154	NM_015702.3(MMADHC):c.433A>T (p.Arg145Ter)	MMADHC	Pathogenic	criteria provided, multiple submitters, no conflicts
1455539	NM_015702.3(MMADHC):c.585_588del (p.Arg197fs)	MMADHC	Pathogenic	criteria provided, single submitter
1456251	NM_015702.3(MMADHC):c.352C>T (p.Gln118Ter)	MMADHC	Pathogenic	criteria provided, single submitter
1457271	NM_015702.3(MMADHC):c.128_129del (p.His43fs)	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458974	NC_000002.11:g.(?150438631)(150438795_?)del	MMADHC	Pathogenic	criteria provided, single submitter
1459027	NM_015702.3(MMADHC):c.638_642del (p.Tyr213fs)	MMADHC	Pathogenic	criteria provided, single submitter
1958245	NM_015702.3(MMADHC):c.653_654dup (p.Gly219fs)	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1963718	NM_015702.3(MMADHC):c.202C>T (p.Gln68Ter)	MMADHC	Pathogenic	criteria provided, multiple submitters, no conflicts
2012128	NM_015702.3(MMADHC):c.151dup (p.Ile51fs)	MMADHC	Pathogenic	criteria provided, single submitter
2030444	NM_015702.3(MMADHC):c.240_241insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGGAACATAGGTTTT (p.Asp81delinsPhePhePhePhePhePheXaaXaaXaaXaaLeuThrSerTer)	MMADHC	Pathogenic	criteria provided, single submitter
2096130	NM_015702.3(MMADHC):c.546_547del (p.Lys183fs)	MMADHC	Pathogenic	criteria provided, single submitter
219000	NM_015702.3(MMADHC):c.228dup (p.Asn77fs)	MMADHC	Pathogenic	criteria provided, single submitter
219001	NM_015702.3(MMADHC):c.60_61insAT (p.Leu21fs)	MMADHC	Pathogenic	criteria provided, single submitter
219002	NM_015702.3(MMADHC):c.455dup (p.Cys153fs)	MMADHC	Pathogenic	criteria provided, single submitter
2426213	NC_000002.11:g.(?150443583)(150443611_?)del	MMADHC	Pathogenic	criteria provided, single submitter
2507317	NM_015702.3(MMADHC):c.683C>G (p.Ser228Ter)	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265247	NM_015702.3(MMADHC):c.472C>T (p.Arg158Ter)	MMADHC	Pathogenic	criteria provided, multiple submitters, no conflicts
2694795	NM_015702.3(MMADHC):c.233_248dup (p.His83_Leu84insArgPheTer)	MMADHC	Pathogenic	criteria provided, single submitter
2701308	NM_015702.3(MMADHC):c.22dup (p.Arg8fs)	MMADHC	Pathogenic	criteria provided, single submitter
2734282	NM_015702.3(MMADHC):c.538C>T (p.Gln180Ter)	MMADHC	Pathogenic	criteria provided, single submitter
2779693	NM_015702.3(MMADHC):c.171G>A (p.Trp57Ter)	MMADHC	Pathogenic	criteria provided, single submitter
2832478	NM_015702.3(MMADHC):c.634dup (p.Cys212fs)	MMADHC	Pathogenic	criteria provided, single submitter
2849488	NM_015702.3(MMADHC):c.10-1G>A	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2850205	NM_015702.3(MMADHC):c.391dup (p.Glu131fs)	MMADHC	Pathogenic	criteria provided, single submitter
2989373	NM_015702.3(MMADHC):c.566G>A (p.Trp189Ter)	MMADHC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
MMADHC	Definitive	Autosomal recessive	methylmalonic aciduria and homocystinuria type cblD	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMADHC	Orphanet:308380	Methylcobalamin deficiency type cblDv1
MMADHC	Orphanet:308442	Vitamin B12-responsive methylmalonic acidemia, type cblDv2
MMADHC	Orphanet:79283	Methylmalonic acidemia with homocystinuria, type cblD
MMACHC	Orphanet:79282	Methylmalonic acidemia with homocystinuria, type cblC
TSEN54	Orphanet:166063	Pontocerebellar hypoplasia type 4
TSEN54	Orphanet:2524	Pontocerebellar hypoplasia type 2

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
MMADHC	HGNC:25221	ENSG00000168288	Q9H3L0	Cobalamin trafficking protein CblD	gencc,clinvar
MMACHC	HGNC:24525	ENSG00000132763	Q9Y4U1	Cyanocobalamin reductase / alkylcobalamin dealkylase	clinvar
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMADHC	Cobalamin trafficking protein CblD	Involved in cobalamin metabolism and trafficking.
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.
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMADHC	Other/Unknown	no		MMADHC
MMACHC	Enzyme (other)	yes	2.5.1.151	MMACHC
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54

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
epithelium of nasopharynx	1
nasopharynx	1
palpebral conjunctiva	1
hindlimb stylopod muscle	1
liver	1
right lobe of liver	1
cerebellar hemisphere	1
granulocyte	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMADHC	294	ubiquitous	marker	palpebral conjunctiva, epithelium of nasopharynx, nasopharynx
MMACHC	177	ubiquitous	marker	right lobe of liver, liver, hindlimb stylopod muscle
TSEN54	232	ubiquitous	marker	granulocyte, right uterine tube, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMACHC	1,383
MMADHC	1,201
TSEN54	1,085

Intra-cohort edges

A	B	Sources
MMACHC	MMADHC	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMACHC	Q9Y4U1	7
TSEN54	Q7Z6J9	5
MMADHC	Q9H3L0	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Defective MMADHC causes MMAHCD	2	2537.8×	2e-06	MMADHC, MMACHC
Cobalamin (Cbl) metabolism	2	845.9×	1e-05	MMADHC, MMACHC
Defects in cobalamin (B12) metabolism	2	543.8×	2e-05	MMADHC, MMACHC
Cobalamin (Cbl, vitamin B12) transport and metabolism	2	423.0×	2e-05	MMADHC, MMACHC
Defects in vitamin and cofactor metabolism	2	400.7×	2e-05	MMADHC, MMACHC
Metabolism of water-soluble vitamins and cofactors	2	120.8×	2e-04	MMADHC, MMACHC
Metabolism of vitamins and cofactors	2	77.7×	4e-04	MMADHC, MMACHC
Diseases of metabolism	2	53.6×	8e-04	MMADHC, MMACHC
Defective MMACHC causes MAHCC	1	1903.3×	8e-04	MMACHC
tRNA processing	1	119.0×	0.012	TSEN54
tRNA processing in the nucleus	1	65.6×	0.019	TSEN54
Disease	2	8.7×	0.019	MMADHC, MMACHC
Metabolism	2	7.7×	0.023	MMADHC, MMACHC
Metabolism of RNA	1	13.9×	0.070	TSEN54

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
cobalamin metabolic process	2	1021.3×	7e-06	MMADHC, MMACHC
tRNA-type intron splice site recognition and cleavage	1	1872.4×	0.001	TSEN54
demethylation	1	1404.3×	0.001	MMACHC
tRNA splicing, via endonucleolytic cleavage and ligation	1	468.1×	0.003	TSEN54
glutathione metabolic process	1	117.0×	0.010	MMACHC
mRNA processing	1	26.2×	0.038	TSEN54

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMADHC	0	0
MMACHC	0	0
TSEN54	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MMADHC	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMACHC	2.5.1.151	alkylcobalamin dealkylase
TSEN54	4.6.1.16	tRNA-intron lyase

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

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	2	MMACHC, TSEN54
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MMADHC

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)
MMADHC	4	—
MMACHC	0	—
TSEN54	0	—

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