Glycogen storage disease due to glycogen branching enzyme deficiency

Summary

Glycogen storage disease due to glycogen branching enzyme deficiency (MONDO:0009292) is a disease (an umbrella term covering 8 Mondo subtypes) caused by GBE1 (GenCC Definitive), with 3 cohort genes and 4 clinical trials. Top therapeutic interventions include triheptanoin.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GBE1 (GenCC Definitive)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 1,008
• Phenotypes (HPO): 30
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.1	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0001410	Decreased liver function	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0011354	Generalized abnormality of skin	Very frequent (80-99%)
HP:0012269	Abnormal muscle glycogen content	Very frequent (80-99%)
HP:0031331	Abnormal cardiomyocyte morphology	Very frequent (80-99%)
HP:0500032	Abnormal neuron branching	Very frequent (80-99%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001644	Dilated cardiomyopathy	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003073	Hypoalbuminemia	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0001409	Portal hypertension	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001790	Nonimmune hydrops fetalis	Occasional (5-29%)
HP:0001989	Fetal akinesia sequence	Occasional (5-29%)
HP:0002040	Esophageal varix	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003645	Prolonged partial thromboplastin time	Occasional (5-29%)
HP:0006829	Severe muscular hypotonia	Occasional (5-29%)
HP:0008151	Prolonged prothrombin time	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease due to glycogen branching enzyme deficiency
Mondo ID	MONDO:0009292
OMIM	232500
Orphanet	367
DOID	DOID:2750
NCIT	C84737
SNOMED CT	124267007
UMLS	C0017923
MedGen	6642
GARD	0002520
MedDRA	10053249
NORD	770
Is cancer (heuristic)	no

Also known as: amylopectinosis · Andersen disease · Andersen Disease (GSD IV) · Andersen’s disease · GBE1 glycogen storage disease · glycogen storage disease caused by mutation in GBE1 · glycogen storage disease due to glycogen branching enzyme deficiency · glycogen storage disease IV · glycogen storage disease type 4 · glycogen storage disease type IV · glycogenosis due to glycogen branching enzyme deficiency · glycogenosis type 4 · glycogenosis type IV · GSD due to glycogen branching enzyme deficiency · GSD IV · GSD type 4 · GSD type IV · GSD4

Data availability: 1,008 ClinVar variants · 6 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › glycogen storage disease due to glycogen branching enzyme deficiency

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease IXd, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

Subtypes (8): adult polyglucosan body disease, glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form, glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form, glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form, glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form, glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form, glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form, glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form

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:

313 likely benign, 122 uncertain significance, 47 likely pathogenic, 42 pathogenic, 35 pathogenic/likely pathogenic, 25 conflicting classifications of pathogenicity, 10 benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1053439	NM_000158.4(GBE1):c.2081T>A (p.Ile694Asn)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066767	NM_000158.4(GBE1):c.143+2T>C	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068507	NM_000158.4(GBE1):c.909_912del (p.Phe303fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069462	NM_000158.4(GBE1):c.1675_1676dup (p.Ser559fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069503	NM_000158.4(GBE1):c.1336-1G>A	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069726	NM_000158.4(GBE1):c.808C>T (p.Gln270Ter)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069996	NM_000158.4(GBE1):c.1479G>A (p.Trp493Ter)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071657	NM_000158.4(GBE1):c.216del (p.Tyr73fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075597	NM_000158.4(GBE1):c.43G>T (p.Glu15Ter)	GBE1	Pathogenic	criteria provided, single submitter
1076126	NC_000003.11:g.(?81810516)(81810678_?)del	GBE1	Pathogenic	criteria provided, single submitter
1076127	NC_000003.11:g.(?81584336)(81584486_?)del	GBE1	Pathogenic	criteria provided, single submitter
1076128	NC_000003.11:g.(?81627056)(81810688_?)del	GBE1	Pathogenic	criteria provided, single submitter
1076129	NC_000003.11:g.(?81584336)(81810678_?)del	GBE1	Pathogenic	criteria provided, single submitter
1076130	NC_000003.11:g.(?81539548)(81754774_?)del	GBE1	Pathogenic	criteria provided, single submitter
1076542	NM_000158.4(GBE1):c.1561A>T (p.Lys521Ter)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076919	NM_000158.4(GBE1):c.505del (p.Asp169fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322988	NM_000158.4(GBE1):c.1403del (p.Arg468fs)	GBE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1341385	NM_000158.4(GBE1):c.1825G>T (p.Glu609Ter)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341394	NM_000158.4(GBE1):c.895G>T (p.Gly299Ter)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1354603	NM_000158.4(GBE1):c.1343_1344del (p.Lys448fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1376912	NM_000158.4(GBE1):c.480G>A (p.Trp160Ter)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426965	NM_000158.4(GBE1):c.466_470del (p.Arg156fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430861	NM_000158.4(GBE1):c.149del (p.Lys50fs)	GBE1	Pathogenic	criteria provided, single submitter
1440801	NM_000158.4(GBE1):c.42C>G (p.Tyr14Ter)	GBE1	Pathogenic	criteria provided, single submitter
1440888	NM_000158.4(GBE1):c.1333C>T (p.Gln445Ter)	GBE1	Pathogenic	criteria provided, single submitter
1443192	NM_000158.4(GBE1):c.810_811delinsTT (p.Gln270_Glu271delinsHisTer)	GBE1	Pathogenic	criteria provided, single submitter
1452840	NM_000158.4(GBE1):c.1861_1875CTT[2]TTCATTTTCTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCTTCTTTTCATTTTC[1] (p.Asn626delinsPhePhePhePhePhePheXaaXaaXaaXaaCysTer)	GBE1	Pathogenic	criteria provided, single submitter
1453400	NM_000158.4(GBE1):c.47del (p.Ala16fs)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453753	NM_000158.4(GBE1):c.317del (p.Gly106fs)	GBE1	Pathogenic	criteria provided, single submitter
1453763	NC_000003.11:g.(?81584336)(81754774_?)del	GBE1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 12 · 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
GBE1	Definitive	Autosomal recessive	glycogen storage disease due to glycogen branching enzyme deficiency	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GBE1	Orphanet:206583	Adult polyglucosan body disease
GBE1	Orphanet:308621	Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form
GBE1	Orphanet:308638	Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form
GBE1	Orphanet:308655	Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form
GBE1	Orphanet:308670	Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form
GBE1	Orphanet:308684	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form
GBE1	Orphanet:308698	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form
GBE1	Orphanet:308712	Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form
RBCK1	Orphanet:329173	Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis
RBCK1	Orphanet:397937	Polyglucosan body myopathy type 1
GAA	Orphanet:308552	Glycogen storage disease due to acid maltase deficiency, infantile onset
GAA	Orphanet:420429	Glycogen storage disease due to acid maltase deficiency, late-onset

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
GBE1	HGNC:4180	ENSG00000114480	Q04446	1,4-alpha-glucan-branching enzyme	gencc,clinvar
RBCK1	HGNC:15864	ENSG00000125826	Q9BYM8	RanBP-type and C3HC4-type zinc finger-containing protein 1	clinvar
GAA	HGNC:4065	ENSG00000171298	P10253	Lysosomal alpha-glucosidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBE1	1,4-alpha-glucan-branching enzyme	Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.
RBCK1	RanBP-type and C3HC4-type zinc finger-containing protein 1	E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates.
GAA	Lysosomal alpha-glucosidase	Essential for the degradation of glycogen in lysosomes.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · 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
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBE1	Antibody/Immunoglobulin	yes		Glyco_hydro_13_N, GH13_cat_dom, A-amylase/branching_C
RBCK1	Transcription factor	no		Ubiquitin-like_dom, Znf_RING, Znf_RanBP2
GAA	Enzyme (other)	yes	3.2.1.20	Glyco_hydro_31_TIM, P_trefoil_dom, Gal_mutarotase_sf_dom

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
biceps brachii	1
gluteal muscle	1
tibialis anterior	1
adenohypophysis	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
granulocyte	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBE1	293	ubiquitous	marker	gluteal muscle, tibialis anterior, biceps brachii
RBCK1	279	ubiquitous	marker	right hemisphere of cerebellum, adenohypophysis, cerebellar hemisphere
GAA	261	ubiquitous	marker	granulocyte, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBE1	3,402
RBCK1	2,468
GAA	2,116

Intra-cohort edges

A	B	Sources
GAA	GBE1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GAA	P10253	19
RBCK1	Q9BYM8	11
GBE1	Q04446	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Glycogen storage diseases	1	1903.3×	0.005	GAA
Glycogen storage disease type II (GAA)	1	1903.3×	0.005	GAA
Glycogen storage disease type IV (GBE1)	1	1268.9×	0.005	GBE1
Glycogen metabolism	1	634.4×	0.007	GAA
Glycogen synthesis	1	271.9×	0.010	GBE1
Diseases of carbohydrate metabolism	1	271.9×	0.010	GAA
Glycogen breakdown (glycogenolysis)	1	253.8×	0.010	GAA
TNFR1-induced proapoptotic signaling	1	146.4×	0.015	RBCK1
TNFR1-induced NF-kappa-B signaling pathway	1	112.0×	0.018	RBCK1
Regulation of TNFR1 signaling	1	74.6×	0.024	RBCK1
Metabolism of carbohydrates and carbohydrate derivatives	1	40.1×	0.041	GAA
Diseases of metabolism	1	26.8×	0.055	GAA
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.109	RBCK1
Innate Immune System	1	8.5×	0.145	GAA
Neutrophil degranulation	1	7.7×	0.149	GAA
Disease	1	4.4×	0.227	GAA
Immune System	1	4.3×	0.227	GAA
Metabolism	1	3.9×	0.237	GAA

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
maltose metabolic process	1	5617.3×	0.002	GAA
sucrose metabolic process	1	5617.3×	0.002	GAA
obsolete vacuolar sequestering	1	5617.3×	0.002	GAA
protein linear polyubiquitination	1	1872.4×	0.005	RBCK1
diaphragm contraction	1	1404.3×	0.005	GAA
tissue development	1	624.1×	0.009	GAA
glycophagy	1	468.1×	0.009	GAA
glycogen catabolic process	1	401.2×	0.009	GAA
neuromuscular process controlling posture	1	351.1×	0.009	GAA
regulation of the force of heart contraction	1	330.4×	0.009	GAA
negative regulation of necroptotic process	1	330.4×	0.009	RBCK1
glycogen biosynthetic process	1	312.1×	0.009	GBE1
muscle cell cellular homeostasis	1	216.1×	0.012	GAA
aorta development	1	187.2×	0.013	GAA
glycogen metabolic process	1	175.5×	0.013	GBE1
positive regulation of extrinsic apoptotic signaling pathway	1	151.8×	0.014	RBCK1
cardiac muscle contraction	1	133.8×	0.014	GAA
heart morphogenesis	1	124.8×	0.014	GAA
canonical NF-kappaB signal transduction	1	122.1×	0.014	RBCK1
obsolete negative regulation of NF-kappaB transcription factor activity	1	119.5×	0.014	RBCK1
generation of precursor metabolites and energy	1	114.6×	0.014	GBE1
neuromuscular process controlling balance	1	110.1×	0.014	GAA
lysosome organization	1	102.1×	0.014	GAA
glucose metabolic process	1	85.1×	0.016	GAA
positive regulation of non-canonical NF-kappaB signal transduction	1	85.1×	0.016	RBCK1
obsolete positive regulation of NF-kappaB transcription factor activity	1	68.5×	0.019	RBCK1
locomotory behavior	1	59.8×	0.021	GAA
negative regulation of canonical NF-kappaB signal transduction	1	57.3×	0.021	RBCK1
T cell receptor signaling pathway	1	50.6×	0.023	RBCK1
protein polyubiquitination	1	38.5×	0.029	RBCK1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
GAA	DIENESTROL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GAA	112	4
GBE1	0	0
RBCK1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIENESTROL	4	GAA
MIGLUSTAT	4	GAA
DICLOFENAC SODIUM	4	GAA
DIBUCAINE	4	GAA
AMLEXANOX	4	GAA
MIGALASTAT	4	GAA
ARIPIPRAZOLE	4	GAA
DULOXETINE	4	GAA
LABETALOL HYDROCHLORIDE	4	GAA
MORICIZINE HYDROCHLORIDE	4	GAA
PHENYLEPHRINE HYDROCHLORIDE	4	GAA
DEMECLOCYCLINE HYDROCHLORIDE	4	GAA
DOXAZOSIN MESYLATE	4	GAA
PRILOCAINE HYDROCHLORIDE	4	GAA
FLUOROMETHOLONE	4	GAA
PHENELZINE SULFATE	4	GAA
RABEPRAZOLE SODIUM	4	GAA
METHYSERGIDE MALEATE	4	GAA
ACRISORCIN	4	GAA
ECONAZOLE NITRATE	4	GAA
ISOETHARINE MESYLATE	4	GAA
QUINESTROL	4	GAA
DEFEROXAMINE MESYLATE	4	GAA
MAPROTILINE HYDROCHLORIDE	4	GAA
EPINEPHRINE BITARTRATE	4	GAA
PROCHLORPERAZINE MALEATE	4	GAA
IRBESARTAN	4	GAA
OXYTETRACYCLINE	4	GAA
DOPAMINE HYDROCHLORIDE	4	GAA
PRAZOSIN HYDROCHLORIDE	4	GAA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GAA	280	Binding:267, Functional:13
RBCK1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GAA	3.2.1.20	alpha-glucosidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GAA	280

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

30 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)
DIENESTROL	4	GAA
MIGLUSTAT	4	GAA
DICLOFENAC SODIUM	4	GAA
DIBUCAINE	4	GAA
AMLEXANOX	4	GAA
MIGALASTAT	4	GAA
ARIPIPRAZOLE	4	GAA
DULOXETINE	4	GAA
LABETALOL HYDROCHLORIDE	4	GAA
MORICIZINE HYDROCHLORIDE	4	GAA
PHENYLEPHRINE HYDROCHLORIDE	4	GAA
DEMECLOCYCLINE HYDROCHLORIDE	4	GAA
DOXAZOSIN MESYLATE	4	GAA
PRILOCAINE HYDROCHLORIDE	4	GAA
FLUOROMETHOLONE	4	GAA
PHENELZINE SULFATE	4	GAA
RABEPRAZOLE SODIUM	4	GAA
METHYSERGIDE MALEATE	4	GAA
ACRISORCIN	4	GAA
ECONAZOLE NITRATE	4	GAA
ISOETHARINE MESYLATE	4	GAA
QUINESTROL	4	GAA
DEFEROXAMINE MESYLATE	4	GAA
MAPROTILINE HYDROCHLORIDE	4	GAA
EPINEPHRINE BITARTRATE	4	GAA
PROCHLORPERAZINE MALEATE	4	GAA
IRBESARTAN	4	GAA
OXYTETRACYCLINE	4	GAA
DOPAMINE HYDROCHLORIDE	4	GAA
PRAZOSIN HYDROCHLORIDE	4	GAA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GAA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GBE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RBCK1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GBE1	0	—
RBCK1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00947960	PHASE2	COMPLETED	Triheptanoin Treatment Trial for Patients With Adult Polyglucosan Body Disease
NCT02683512	Not specified	RECRUITING	GBE Deficiency (GSD IV and APBD) Natural History Study
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEPTANOIN	4	1