Intermediate maple syrup urine disease

Summary

Intermediate maple syrup urine disease (MONDO:0017052) is a disease with 4 cohort genes. The dominant Reactome pathway is H139Hfs13 PPM1K causes a mild variant of MSUD* (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intermediate maple syrup urine disease
Mondo ID	MONDO:0017052
Orphanet	268162
SNOMED CT	405287008
UMLS	C1621920
MedGen	301223
GARD	0017264
Is cancer (heuristic)	no

Also known as: Intermediate BCKD deficiency · Intermediate branched-chain 2-ketoacid dehydrogenase deficiency · Intermediate branched-chain alpha-ketoacid dehydrogenase deficiency · intermediate maple syrup urine disease · Intermediate MSUD

Data availability: 4 GenCC gene-disease records.

Disease family

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 › maple syrup urine disease › intermediate maple syrup urine disease

Related subtypes (8): pyruvate dehydrogenase E3 deficiency, maple syrup urine disease, mild variant, classic maple syrup urine disease, intermittent maple syrup urine disease, thiamine-responsive maple syrup urine disease, maple syrup urine disease type 1A, maple syrup urine disease type 1B, maple syrup urine disease type 2

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 11 · 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
BCKDHA	Definitive	Autosomal recessive	maple syrup urine disease	9
BCKDHB	Definitive	Autosomal recessive	maple syrup urine disease type 1B	8
DBT	Definitive	Autosomal recessive	maple syrup urine disease type 2	8
PPM1K	Moderate	Autosomal recessive	maple syrup urine disease, mild variant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPM1K	Orphanet:268162	Intermediate maple syrup urine disease
DBT	Orphanet:268145	Classic maple syrup urine disease
DBT	Orphanet:268162	Intermediate maple syrup urine disease
DBT	Orphanet:268173	Intermittent maple syrup urine disease
DBT	Orphanet:268184	Thiamine-responsive maple syrup urine disease
BCKDHA	Orphanet:268145	Classic maple syrup urine disease
BCKDHA	Orphanet:268162	Intermediate maple syrup urine disease
BCKDHA	Orphanet:268173	Intermittent maple syrup urine disease
BCKDHB	Orphanet:268145	Classic maple syrup urine disease
BCKDHB	Orphanet:268162	Intermediate maple syrup urine disease
BCKDHB	Orphanet:268173	Intermittent maple syrup urine disease

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
PPM1K	HGNC:25415	ENSG00000163644	Q8N3J5	Protein phosphatase Mn(2+)-dependent 1K	gencc
DBT	HGNC:2698	ENSG00000137992	P11182	Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial	gencc
BCKDHA	HGNC:986	ENSG00000248098	P12694	2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial	gencc
BCKDHB	HGNC:987	ENSG00000083123	P21953	2-oxoisovalerate dehydrogenase subunit beta, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPM1K	Protein phosphatase Mn(2+)-dependent 1K	Serine/threonine-protein phosphatase component of macronutrients metabolism.
DBT	Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial	The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2).
BCKDHA	2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial	Together with BCKDHB forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex.
BCKDHB	2-oxoisovalerate dehydrogenase subunit beta, mitochondrial	Together with BCKDHA forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Phosphatase	1	21.0×	0.141
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPM1K	Phosphatase	yes	3.1.3.16	PP2C_BS, PPM-type_phosphatase-like_dom, PP2C
DBT	Enzyme (other)	yes	2.3.1.168	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
BCKDHA	Other/Unknown	no		DH_E1, THDP-binding, Alpha-ketoacid_DH_E1_comp
BCKDHB	Other/Unknown	no		Transketolase-like_Pyr-bd, Transketo_C/PFOR_II, THDP-binding

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
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
buccal mucosa cell	1
endothelial cell	1
renal medulla	1
apex of heart	1
lower esophagus mucosa	1
right adrenal gland	1
liver	1
rectum	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPM1K	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
DBT	290	ubiquitous	marker	buccal mucosa cell, renal medulla, endothelial cell
BCKDHA	143	ubiquitous	marker	lower esophagus mucosa, right adrenal gland, apex of heart
BCKDHB	247	ubiquitous	marker	right lobe of liver, rectum, liver

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DBT	3,393
BCKDHB	2,616
BCKDHA	2,321
PPM1K	1,991

Intra-cohort edges

A	B	Sources
BCKDHA	BCKDHB	biogrid_interaction, intact, string_interaction
BCKDHA	DBT	string_interaction
BCKDHA	PPM1K	biogrid_interaction, intact, string_interaction
BCKDHB	DBT	biogrid_interaction, intact, string_interaction
BCKDHB	PPM1K	biogrid_interaction, intact, string_interaction
DBT	PPM1K	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCKDHA	P12694	24
BCKDHB	P21953	24
DBT	P11182	5
PPM1K	Q8N3J5	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
H139Hfs13* PPM1K causes a mild variant of MSUD	4	2284.0×	7e-14	PPM1K, DBT, BCKDHA, BCKDHB
Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD	3	2855.0×	5e-11	DBT, BCKDHA, BCKDHB
Branched-chain amino acid catabolism	4	475.8×	5e-11	PPM1K, DBT, BCKDHA, BCKDHB
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	3	2141.2×	1e-10	DBT, BCKDHA, BCKDHB
Loss-of-function mutations in DBT cause MSUD2	3	2141.2×	1e-10	DBT, BCKDHA, BCKDHB
Loss-of-function mutations in DLD cause MSUD3/DLDD	3	2141.2×	1e-10	DBT, BCKDHA, BCKDHB
Branched-chain ketoacid dehydrogenase kinase deficiency	3	1713.0×	2e-10	DBT, BCKDHA, BCKDHB
Protein lipoylation	1	259.6×	0.005	DBT
RHOH GTPase cycle	1	77.2×	0.014	DBT
Mitochondrial protein degradation	1	28.6×	0.035	DBT

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
branched-chain amino acid catabolic process	4	1053.2×	3e-12	PPM1K, DBT, BCKDHA, BCKDHB
branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	3	3159.8×	5e-11	DBT, BCKDHA, BCKDHB
regulation of mitochondrial membrane permeability involved in apoptotic process	1	702.2×	0.002	PPM1K
regulation of intracellular signal transduction	1	221.7×	0.006	PPM1K
response to nutrient	1	73.9×	0.013	BCKDHB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPM1K	0	0
DBT	0	0
BCKDHA	0	0
BCKDHB	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
BCKDHB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPM1K	3.1.3.16, 3.1.3.52	protein-serine/threonine phosphatase, [3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase
DBT	2.3.1.168	dihydrolipoyllysine-residue (2-methylpropanoyl)transferase

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

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	PPM1K, DBT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BCKDHA, BCKDHB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PPM1K	0	—
DBT	0	—
BCKDHA	0	—
BCKDHB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.