Maple syrup urine disease

Summary

Maple syrup urine disease (MONDO:0009563) is a disease (an umbrella term covering 9 Mondo subtypes) caused by variants in BCKDHA, BCKDHB, and DBT, with 7 cohort genes and 11 clinical trials. The dominant Reactome pathway is Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD (3 cohort genes). Top therapeutic interventions include phenylbutanoic acid and valine.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: BCKDHA (GenCC Definitive), BCKDHB (GenCC Strong), DBT (GenCC Strong)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 2,070
• Phenotypes (HPO): 11
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.67	Worldwide	Validated
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 1 000 000	0.396	China	Validated
Prevalence at birth	1-9 / 1 000 000	0.78	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.79	Italy	Validated
Prevalence at birth	1-9 / 100 000	7.3	Tunisia	Validated
Prevalence at birth	1-9 / 1 000 000	0.19	Japan	Validated
Prevalence at birth	1-9 / 100 000	1.15	Portugal	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.86	Taiwan, Province of China	Validated
Prevalence at birth	1-9 / 100 000	4.8	Israel	Validated
Prevalence at birth	1-5 / 10 000	10.2	Specific population	Validated
Prevalence at birth	1-9 / 1 000 000	0.34	Czech Republic	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0000600	Abnormality of the pharynx	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:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0001608	Abnormality of the voice	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0008344	Elevated plasma branched chain amino acids	Very frequent (80-99%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0004374	Hemiplegia/hemiparesis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	maple syrup urine disease
Mondo ID	MONDO:0009563
MeSH	D008375
OMIM	248600
Orphanet	511
DOID	DOID:9269
ICD-10-CM	E71.0
ICD-11	1623706568
NCIT	C34806
SNOMED CT	27718001
UMLS	C0024776
MedGen	6217
GARD	0003228
MedDRA	10026817
NORD	1400
Is cancer (heuristic)	no

Also known as: BCKD deficiency · BCKDH deficiency · branched chain ketoaciduria · branched-chain 2-ketoacid dehydrogenase deficiency · branched-chain ketoaciduria · Ketoacidaemia · maple syrup urine disease · maple syrup urine disease, type 1A · maple syrup urine disease, type 1B · maple syrup urine disease, type 2 · MSUD

Data availability: 2,070 ClinVar variants · 4 GenCC gene-disease records · 25 cell lines.

Disease family

An umbrella term covering 9 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 › maple syrup urine disease

Related subtypes (6): methylmalonic acidemia, glutaryl-CoA dehydrogenase deficiency, glutaric acidemia type 3, malonic aciduria, methylmalonate semialdehyde dehydrogenase deficiency, classic organic aciduria

Subtypes (9): 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 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

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

379 likely benign, 66 uncertain significance, 51 likely pathogenic, 44 pathogenic, 27 pathogenic/likely pathogenic, 19 conflicting classifications of pathogenicity, 12 benign, 2 benign/likely 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
1067117	NM_000709.4(BCKDHA):c.109-1G>A	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069052	NM_000709.4(BCKDHA):c.130C>T (p.Gln44Ter)	BCKDHA	Pathogenic	criteria provided, single submitter
1072888	NM_000709.4(BCKDHA):c.1306G>T (p.Glu436Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073900	NM_000709.4(BCKDHA):c.884C>A (p.Ser295Ter)	BCKDHA	Pathogenic	criteria provided, single submitter
1075126	NM_000709.4(BCKDHA):c.701_702del (p.Cys234fs)	BCKDHA	Pathogenic	criteria provided, single submitter
1075614	NC_000019.9:g.(?41903723)(41930736_?)del	BCKDHA	Pathogenic	criteria provided, single submitter
1075615	NC_000019.9:g.(?41903723)(41903850_?)del	BCKDHA	Pathogenic	criteria provided, single submitter
1075969	NM_000709.4(BCKDHA):c.116_117dup (p.Arg40fs)	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
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
1395580	NM_000709.4(BCKDHA):c.1028C>G (p.Ser343Ter)	BCKDHA	Pathogenic	criteria provided, single submitter
1406283	NC_000019.9:g.(?41903723)(41916924_?)del	BCKDHA	Pathogenic	criteria provided, single submitter
1423652	NM_000709.4(BCKDHA):c.663del (p.Ala220_Tyr221insTer)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455786	NM_000709.4(BCKDHA):c.357_358del (p.Leu119_Tyr120insTer)	BCKDHA	Pathogenic	criteria provided, single submitter
1456714	NM_000709.4(BCKDHA):c.33G>A (p.Trp11Ter)	BCKDHA	Pathogenic	criteria provided, single submitter
1459942	NC_000019.9:g.(?41925030)(41930736_?)del	BCKDHA	Pathogenic	criteria provided, single submitter
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
1724025	NM_000709.4(BCKDHA):c.655del (p.Ala219fs)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1726679	NM_000709.4(BCKDHA):c.253C>T (p.Gln85Ter)	BCKDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069097	NM_183050.4(BCKDHB):c.196G>A (p.Gly66Arg)	BCKDHB	Pathogenic	criteria provided, single submitter
1070281	NC_000006.11:g.(?80816391)(81053541_?)del	BCKDHB	Pathogenic	criteria provided, single submitter
1072285	NM_183050.4(BCKDHB):c.234_249del (p.Ser79fs)	BCKDHB	Pathogenic	criteria provided, single submitter
1072640	NM_183050.4(BCKDHB):c.396del (p.Phe132fs)	BCKDHB	Pathogenic	criteria provided, single submitter
1076705	NM_183050.4(BCKDHB):c.322dup (p.Val108fs)	BCKDHB	Pathogenic	criteria provided, single submitter
11937	NM_183050.4(BCKDHB):c.548G>C (p.Arg183Pro)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319976	NM_183050.4(BCKDHB):c.329_330delinsAA (p.Leu110Ter)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

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
AGL	Orphanet:366	Glycogen storage disease due to glycogen debranching enzyme deficiency

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

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
QTGAL	HGNC:21727	ENSG00000175711	Q67FW5	Queuosine-tRNA galactosyltransferase	clinvar
B3GNT8	HGNC:24139	ENSG00000177191	Q7Z7M8	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 8	clinvar
ACTMAP	HGNC:24758	ENSG00000188493	Q5BKX5	Actin maturation protease	clinvar
AGL	HGNC:321	ENSG00000162688	P35573	Glycogen debranching enzyme	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.
QTGAL	Queuosine-tRNA galactosyltransferase	Glycosyltransferase that specifically catalyzes galactosylation of cytoplasmic tRNA(Tyr) modified with queuosine at position 34 (queuosine(34)).
B3GNT8	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 8	Beta-1,3-N-acetylglucosaminyltransferase that functions in the elongation of specific branch structures of multiantennary N-glycans.
ACTMAP	Actin maturation protease	Actin maturation protease that specifically mediates the cleavage of immature acetylated N-terminal actin, thereby contributing to actin maturation.
AGL	Glycogen debranching enzyme	Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.29

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	3.4×	0.220
Other/Unknown	5	1.3×	0.332

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
QTGAL	Other/Unknown	no		Glyco_trans_2-like, Nucleotide-diphossugar_trans
B3GNT8	Other/Unknown	no		Glyco_trans_31
ACTMAP	Other/Unknown	no		ACTMAP
AGL	Enzyme (other)	yes	3.2.1.33	Glycogen_debranch_met, 6-hairpin_glycosidase_sf, AGL/Gdb1

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	2
buccal mucosa cell	1
endothelial cell	1
renal medulla	1
apex of heart	1
right adrenal gland	1
liver	1
rectum	1
right lobe of liver	1
blood	1
granulocyte	1
right uterine tube	1
esophagus mucosa	1
mucosa of transverse colon	1
hindlimb stylopod muscle	1
pancreatic ductal cell	1
primordial germ cell in gonad	1
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
vastus lateralis	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
QTGAL	135	ubiquitous	marker	blood, granulocyte, right uterine tube
B3GNT8	170	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, esophagus mucosa
ACTMAP	266	ubiquitous	marker	pancreatic ductal cell, primordial germ cell in gonad, hindlimb stylopod muscle
AGL	294	ubiquitous	marker	vastus lateralis, biceps brachii, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DBT	3,393
BCKDHB	2,616
BCKDHA	2,321
AGL	1,726
ACTMAP	1,011
B3GNT8	410
QTGAL	337

Intra-cohort edges

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

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCKDHA	P12694	24
BCKDHB	P21953	24
DBT	P11182	5
AGL	P35573	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
QTGAL	Q67FW5	96.05
B3GNT8	Q7Z7M8	88.18
ACTMAP	Q5BKX5	83.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD	3	1903.3×	1e-09	DBT, BCKDHA, BCKDHB
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	3	1427.5×	1e-09	DBT, BCKDHA, BCKDHB
Loss-of-function mutations in DBT cause MSUD2	3	1427.5×	1e-09	DBT, BCKDHA, BCKDHB
Loss-of-function mutations in DLD cause MSUD3/DLDD	3	1427.5×	1e-09	DBT, BCKDHA, BCKDHB
Branched-chain ketoacid dehydrogenase kinase deficiency	3	1142.0×	2e-09	DBT, BCKDHA, BCKDHB
H139Hfs13* PPM1K causes a mild variant of MSUD	3	1142.0×	2e-09	DBT, BCKDHA, BCKDHB
Branched-chain amino acid catabolism	3	237.9×	4e-07	DBT, BCKDHA, BCKDHB
O-linked glycosylation of mucins	2	61.4×	9e-04	QTGAL, B3GNT8
Protein lipoylation	1	173.0×	0.010	DBT
Glycogen breakdown (glycogenolysis)	1	126.9×	0.013	AGL
RHOH GTPase cycle	1	51.4×	0.028	DBT
O-linked glycosylation	1	24.1×	0.054	B3GNT8
Mitochondrial protein degradation	1	19.0×	0.063	DBT
Neutrophil degranulation	1	3.9×	0.267	AGL
Post-translational protein modification	1	3.2×	0.293	B3GNT8
Metabolism of proteins	1	2.1×	0.397	B3GNT8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 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 alpha-keto acid decarboxylation to branched-chain acyl-CoA	3	1805.6×	2e-09	DBT, BCKDHA, BCKDHB
branched-chain amino acid catabolic process	3	451.4×	1e-07	DBT, BCKDHA, BCKDHB
response to nutrient	2	84.5×	9e-04	BCKDHB, AGL
tRNA wobble guanine modification	1	481.5×	0.006	QTGAL
poly-N-acetyllactosamine biosynthetic process	1	300.9×	0.008	B3GNT8
glycogen catabolic process	1	172.0×	0.012	AGL
glycogen biosynthetic process	1	133.8×	0.013	AGL
tRNA modification	1	86.0×	0.017	QTGAL
response to glucocorticoid	1	46.3×	0.029	AGL
protein O-linked glycosylation	1	32.1×	0.034	B3GNT8
regulation of translation	1	31.3×	0.034	QTGAL
protein processing	1	24.3×	0.040	ACTMAP

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

1 drug in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Phenylbutanoic Acid	Phase 2

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AGL	MIGLUSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGL	4	4
DBT	0	0
BCKDHA	0	0
BCKDHB	0	0
QTGAL	0	0
B3GNT8	0	0
ACTMAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	AGL
MIGALASTAT	4	AGL
LUCERASTAT	3	AGL
DUVOGLUSTAT	2	AGL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
AGL	4	Binding:4
BCKDHB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DBT	2.3.1.168	dihydrolipoyllysine-residue (2-methylpropanoyl)transferase
AGL	3.2.1.33	amylo-alpha-1,6-glucosidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 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)
MIGLUSTAT	4	AGL
MIGALASTAT	4	AGL
LUCERASTAT	3	AGL
DUVOGLUSTAT	2	AGL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AGL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DBT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	BCKDHA, BCKDHB, QTGAL, B3GNT8, ACTMAP

Undrugged target profiles

6 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	—
QTGAL	0	—
B3GNT8	0	—
ACTMAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01529060	PHASE2/PHASE3	COMPLETED	Phenylbutyrate Therapy for Maple Syrup Urine Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04602325	Not specified	RECRUITING	Systemic Biomarkers of Brain Injury From Hyperammonemia
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies
NCT06581991	Not specified	NOT_YET_RECRUITING	Liquid Valine and Isoleucine in Maple Syrup Urine Disease
NCT06664840	Not specified	NOT_YET_RECRUITING	MyRareDiet A Novel Diet Tracking Tool
NCT04248062	Not specified	COMPLETED	Patient and Observer Reported Outcome Measurements in Inborn Errors of Metabolism
NCT04828863	Not specified	COMPLETED	Neurocognitive Outcomes and Quality of Life in Adults With Maple Syrup Urine Disease (MSUD)
NCT05051657	Not specified	COMPLETED	Evaluation of the Express Plus Range
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYLBUTANOIC ACID	4	1
VALINE	2	1