maple syrup urine disease type 1A

Summary

maple syrup urine disease type 1A (MONDO:0023691) is a disease caused by variants in BCKDHA, BCKDHB, and DBT, with 4 cohort genes. The dominant Reactome pathway is Branched-chain ketoacid dehydrogenase kinase deficiency (4 cohort genes).

At a glance

• Causal genes: BCKDHA (GenCC Definitive), BCKDHB (GenCC Strong), DBT (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 380

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maple syrup urine disease type 1A
Mondo ID	MONDO:0023691
OMIM	248600
DOID	DOID:0061203
UMLS	C1855369
MedGen	383668
GARD	0008594
Is cancer (heuristic)	no

Also known as: maple syrup urine disease type 1A · maple syrup urine disease, type IA · MSUD type 1A

Data availability: 380 ClinVar variants · 5 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 › maple syrup urine disease type 1A

Related subtypes (8): pyruvate dehydrogenase E3 deficiency, maple syrup urine disease, mild variant, classic maple syrup urine disease, intermediate maple syrup urine disease, intermittent maple syrup urine disease, thiamine-responsive maple syrup urine disease, 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

ClinVar germline variants

380 retrieved; paginated sample, class counts are floors:

90 pathogenic/likely pathogenic, 71 likely pathogenic, 69 uncertain significance, 58 pathogenic, 42 conflicting classifications of pathogenicity, 25 likely benign, 13 benign/likely benign, 12 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100009	NM_000709.4(BCKDHA):c.1312T>A (p.Tyr438Asn)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065902	NM_000709.4(BCKDHA):c.794G>A (p.Arg265Gln)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323975	NM_000709.4(BCKDHA):c.647C>T (p.Ala216Val)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324386	NM_000709.4(BCKDHA):c.78del (p.Gln27fs)	BCKDHA	Pathogenic	criteria provided, single submitter
1325805	NM_000709.4(BCKDHA):c.773_774delinsAA (p.Cys258Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344509	NM_000709.4(BCKDHA):c.1312T>C (p.Tyr438His)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166741	NM_000709.4(BCKDHA):c.117dup (p.Arg40fs)	BCKDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1685566	NM_000709.4(BCKDHA):c.454G>A (p.Asp152Asn)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1929553	NM_000709.4(BCKDHA):c.995+1G>A	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1973712	NM_000709.4(BCKDHA):c.507C>G (p.Tyr169Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198433	NM_000709.4(BCKDHA):c.861_868del (p.Gly288fs)	BCKDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
203638	NM_000709.4(BCKDHA):c.661_664del (p.Tyr221fs)	BCKDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
204378	NM_000709.4(BCKDHA):c.476G>A (p.Arg159Gln)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204379	NM_000709.4(BCKDHA):c.1198A>T (p.Lys400Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2157299	NM_000709.4(BCKDHA):c.835del (p.Tyr279fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2172648	NM_000709.4(BCKDHA):c.67del (p.Leu23fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224072	NM_000709.4(BCKDHA):c.940C>T (p.Arg314Ter)	BCKDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
2377	NM_000709.4(BCKDHA):c.868G>A (p.Gly290Arg)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2381	NM_000709.4(BCKDHA):c.929C>G (p.Thr310Arg)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680117	NM_000709.4(BCKDHA):c.308T>C (p.Leu103Pro)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680123	NM_000709.4(BCKDHA):c.164del (p.Pro55fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680124	NM_000709.4(BCKDHA):c.410_426dup (p.Gly143fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680126	NM_000709.4(BCKDHA):c.529C>T (p.Gln177Ter)	BCKDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
2758939	NM_000709.4(BCKDHA):c.1237dup (p.Tyr413fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2814673	NM_000709.4(BCKDHA):c.1121G>A (p.Trp374Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2896558	NM_000709.4(BCKDHA):c.402del (p.Tyr135fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370729	NM_000709.4(BCKDHA):c.137C>A (p.Ser46Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431985	NM_000709.4(BCKDHA):c.647-1G>C	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431986	NM_000709.4(BCKDHA):c.1168-2A>G	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4814468	NM_000709.4(BCKDHA):c.288+1G>T	BCKDHA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare 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
BCKDK	Orphanet:308410	Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency

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
DBT	HGNC:2698	ENSG00000137992	P11182	Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial	gencc,clinvar
BCKDHA	HGNC:986	ENSG00000248098	P12694	2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial	gencc,clinvar
BCKDHB	HGNC:987	ENSG00000083123	P21953	2-oxoisovalerate dehydrogenase subunit beta, mitochondrial	gencc,clinvar
BCKDK	HGNC:16902	ENSG00000103507	O14874	Branched-chain alpha-ketoacid dehydrogenase kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
BCKDK	Branched-chain alpha-ketoacid dehydrogenase kinase	Serine/threonine-protein kinase component of macronutrients metabolism.

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
Kinase	1	6.9×	0.410
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
BCKDK	Kinase	yes		HATPase_dom, Sig_transdc_His_kin-like_C, His_kinase_dom

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
apex of heart	2
right adrenal gland	2
buccal mucosa cell	1
endothelial cell	1
renal medulla	1
lower esophagus mucosa	1
liver	1
rectum	1
right lobe of liver	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
BCKDK	257	ubiquitous	marker	apex of heart, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCKDK	3,756
DBT	3,393
BCKDHB	2,616
BCKDHA	2,321

Intra-cohort edges

A	B	Sources
BCKDHA	BCKDHB	biogrid_interaction, intact, string_interaction
BCKDHA	BCKDK	biogrid_interaction, string_interaction
BCKDHA	DBT	string_interaction
BCKDHB	BCKDK	string_interaction
BCKDHB	DBT	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
BCKDK	O14874	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Branched-chain ketoacid dehydrogenase kinase deficiency	4	2284.0×	1e-13	DBT, BCKDHA, BCKDHB, BCKDK
Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD	3	2855.0×	8e-11	DBT, BCKDHA, BCKDHB
Branched-chain amino acid catabolism	4	475.8×	8e-11	DBT, BCKDHA, BCKDHB, BCKDK
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	3	2141.2×	2e-10	DBT, BCKDHA, BCKDHB
Loss-of-function mutations in DBT cause MSUD2	3	2141.2×	2e-10	DBT, BCKDHA, BCKDHB
Loss-of-function mutations in DLD cause MSUD3/DLDD	3	2141.2×	2e-10	DBT, BCKDHA, BCKDHB
H139Hfs13* PPM1K causes a mild variant of MSUD	3	1713.0×	3e-10	DBT, BCKDHA, BCKDHB
Diseases of branched-chain amino acid catabolism	1	475.8×	0.004	BCKDK
Protein lipoylation	1	259.6×	0.006	DBT
RHOH GTPase cycle	1	77.2×	0.019	DBT
Mitochondrial protein degradation	1	28.6×	0.047	DBT
Diseases of metabolism	1	20.1×	0.061	BCKDK
Metabolism of amino acids and derivatives	1	16.9×	0.067	BCKDK
Disease	1	3.3×	0.292	BCKDK
Metabolism	1	2.9×	0.302	BCKDK

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×	6e-12	DBT, BCKDHA, BCKDHB, BCKDK
branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	3	3159.8×	1e-10	DBT, BCKDHA, BCKDHB
L-valine catabolic process	1	842.6×	0.003	BCKDK
L-isoleucine catabolic process	1	702.2×	0.003	BCKDK
amino acid catabolic process	1	702.2×	0.003	BCKDK
regulation of pyruvate decarboxylation to acetyl-CoA	1	702.2×	0.003	BCKDK
L-leucine catabolic process	1	601.9×	0.003	BCKDK
lipid biosynthetic process	1	247.8×	0.006	BCKDK
regulation of glucose metabolic process	1	140.4×	0.009	BCKDK
response to nutrient	1	73.9×	0.015	BCKDHB
spermatogenesis	1	8.8×	0.109	BCKDK

Therapeutics

Drug target analysis

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

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
DBT	0	0
BCKDHA	0	0
BCKDHB	0	0
BCKDK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BCKDK	18	Binding:18
BCKDHB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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	DBT, BCKDK
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)
DBT	0	—
BCKDHA	0	—
BCKDHB	1	—
BCKDK	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.