glycogen storage disease III

Summary

glycogen storage disease III (MONDO:0009291) is a disease caused by AGL (GenCC Definitive), with 2 cohort genes and 8 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: AGL (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 2,820
• Phenotypes (HPO): 7
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1	United States	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000293	Full cheeks	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0003198	Myopathy	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease III
Mondo ID	MONDO:0009291
MeSH	D006010
OMIM	232400
Orphanet	366
DOID	DOID:2748
ICD-10-CM	E74.03
NCIT	C84736
SNOMED CT	66937008
UMLS	C0017922
MedGen	6641
GARD	0009442
MedDRA	10053250
Is cancer (heuristic)	no

Also known as: AGL glycogen storage disease · amylo-1,6-glucosidase deficiency · Cori disease · Cori-Forbes disease · Forbes disease · GDE deficiency · glycogen storage disease caused by mutation in AGL · glycogen storage disease III · glycogen storage disease type 3 · glycogen storage disease type III · glycogenosis due to glycogen debranching enzyme deficiency · glycogenosis type 3 · glycogenosis type III · GSD due to glycogen debranching enzyme deficiency · GSD type 3 · GSD3 · GSDIII · limit dextrinosis

Data availability: 2,820 ClinVar variants · 8 GenCC gene-disease records · 13 cell lines.

Disease family

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 III

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease due to glycogen branching enzyme deficiency, 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

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:

256 likely benign, 250 uncertain significance, 49 pathogenic, 23 pathogenic/likely pathogenic, 12 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027598	NM_000642.3(AGL):c.1020del (p.Glu340fs)	AGL	Pathogenic	criteria provided, multiple submitters, no conflicts
1068942	NM_000642.3(AGL):c.1537_1538del (p.Tyr512_Thr513insTer)	AGL	Pathogenic	criteria provided, single submitter
1069089	NM_000642.3(AGL):c.716dup (p.Asn240fs)	AGL	Pathogenic	criteria provided, single submitter
1069430	NM_000642.3(AGL):c.685C>T (p.Gln229Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069636	NM_000642.3(AGL):c.4220_4221del (p.Lys1407fs)	AGL	Pathogenic	criteria provided, single submitter
1069998	NM_000642.3(AGL):c.1505_1514del (p.Cys502fs)	AGL	Pathogenic	criteria provided, single submitter
1070173	NM_000642.3(AGL):c.328del (p.Asp110fs)	AGL	Pathogenic	criteria provided, single submitter
1070363	NM_000642.3(AGL):c.2963del (p.Leu988fs)	AGL	Pathogenic	criteria provided, single submitter
1070429	NM_000642.3(AGL):c.4027G>T (p.Glu1343Ter)	AGL	Pathogenic	criteria provided, single submitter
1070447	NM_000642.3(AGL):c.3928G>T (p.Glu1310Ter)	AGL	Pathogenic	criteria provided, single submitter
1070570	NM_000642.3(AGL):c.2793del (p.Lys932fs)	AGL	Pathogenic	criteria provided, single submitter
1070714	NM_000642.3(AGL):c.4352G>A (p.Trp1451Ter)	AGL	Pathogenic	criteria provided, single submitter
1071501	NM_000642.3(AGL):c.955C>T (p.Gln319Ter)	AGL	Pathogenic	criteria provided, single submitter
1071635	NM_000642.3(AGL):c.1639C>T (p.Gln547Ter)	AGL	Pathogenic	criteria provided, single submitter
1071920	NM_000642.3(AGL):c.966dup (p.Arg323fs)	AGL	Pathogenic	criteria provided, single submitter
1072510	NM_000642.3(AGL):c.4258_4259insGGAGATTCCTTAAAGAACTAAAAGTAGGCTCNNNNNAAAAAGAAAACTTTAGATCCAG (p.Asp1420fs)	AGL	Pathogenic	criteria provided, single submitter
1072797	NM_000642.3(AGL):c.582del (p.Thr193_Trp194insTer)	AGL	Pathogenic	criteria provided, single submitter
1073425	NM_000642.3(AGL):c.2346del (p.Ile782fs)	AGL	Pathogenic	criteria provided, single submitter
1075113	NM_000642.3(AGL):c.4115G>A (p.Trp1372Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075182	NM_000642.3(AGL):c.3756dup (p.Arg1253fs)	AGL	Pathogenic	criteria provided, single submitter
1075303	NM_000642.3(AGL):c.1041dup (p.Val348fs)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075419	NM_000642.3(AGL):c.4100del (p.Gly1367fs)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075561	NM_000642.3(AGL):c.1942dup (p.Ser648fs)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075611	NC_000001.10:g.(?100340233)(100343394_?)del	AGL	Pathogenic	criteria provided, single submitter
1076525	NM_000642.3(AGL):c.671del (p.Asn224fs)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1094	NM_000642.3(AGL):c.4529dup (p.Tyr1510Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1095	NM_000642.3(AGL):c.16C>T (p.Gln6Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1096	NM_000642.3(AGL):c.2039G>A (p.Trp680Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098	NM_000642.3(AGL):c.4456del (p.Ser1486fs)	AGL	Pathogenic	criteria provided, multiple submitters, no conflicts
1099	NM_000642.3(AGL):c.4260-12A>G	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
AGL	Definitive	Autosomal recessive	glycogen storage disease III	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGL	Orphanet:366	Glycogen storage disease due to glycogen debranching enzyme deficiency
AFG3L2	Orphanet:101109	Spinocerebellar ataxia type 28
AFG3L2	Orphanet:313772	Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AGL	HGNC:321	ENSG00000162688	P35573	Glycogen debranching enzyme	gencc,clinvar
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
AFG3L2	Mitochondrial inner membrane m-AAA protease component AFG3L2	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	18.3×	0.108
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGL	Enzyme (other)	yes	3.2.1.33	Glycogen_debranch_met, 6-hairpin_glycosidase_sf, AGL/Gdb1
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
vastus lateralis	1
Brodmann (1909) area 23	1
endothelial cell	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGL	294	ubiquitous	marker	vastus lateralis, biceps brachii, skeletal muscle tissue of rectus abdominis
AFG3L2	288	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AFG3L2	4,260
AGL	1,726

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AFG3L2	Q9Y4W6	2
AGL	P35573	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen breakdown (glycogenolysis)	1	380.7×	0.009	AGL
Processing of SMDT1	1	317.2×	0.009	AFG3L2
Mitochondrial calcium ion transport	1	271.9×	0.009	AFG3L2
Mitochondrial protein degradation	1	57.1×	0.031	AFG3L2
Transport of small molecules	1	12.6×	0.099	AFG3L2
Neutrophil degranulation	1	11.5×	0.099	AGL
Metabolism of proteins	1	6.2×	0.155	AFG3L2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to glutathione	1	8426.0×	0.003	AFG3L2
regulation of calcium import into the mitochondrion	1	2808.7×	0.004	AFG3L2
mitochondrial protein quality control	1	2106.5×	0.004	AFG3L2
mitochondrial protein processing	1	1404.3×	0.004	AFG3L2
righting reflex	1	936.2×	0.004	AFG3L2
glycogen catabolic process	1	601.9×	0.004	AGL
calcium import into the mitochondrion	1	601.9×	0.004	AFG3L2
membrane protein proteolysis	1	526.6×	0.004	AFG3L2
cristae formation	1	526.6×	0.004	AFG3L2
mitochondrial calcium ion homeostasis	1	495.6×	0.004	AFG3L2
glycogen biosynthetic process	1	468.1×	0.004	AGL
nerve development	1	468.1×	0.004	AFG3L2
muscle cell development	1	468.1×	0.004	AFG3L2
mitochondrial fusion	1	421.3×	0.004	AFG3L2
protein autoprocessing	1	324.1×	0.005	AFG3L2
regulation of multicellular organism growth	1	324.1×	0.005	AFG3L2
neuromuscular junction development	1	263.3×	0.006	AFG3L2
response to glucocorticoid	1	162.0×	0.009	AGL
response to nutrient	1	147.8×	0.009	AGL
myelination	1	125.8×	0.010	AFG3L2
protein catabolic process	1	118.7×	0.010	AFG3L2
protein processing	1	85.1×	0.013	AFG3L2
protein maturation	1	81.8×	0.013	AFG3L2
axonogenesis	1	80.2×	0.013	AFG3L2
proteolysis	1	17.1×	0.058	AFG3L2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
AFG3L2	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
AFG3L2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGL	3.2.1.33	amylo-alpha-1,6-glucosidase
AFG3L2	3.4.24.B18

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	AFG3L2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AFG3L2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04990388	PHASE1/PHASE2	TERMINATED	Safety, Tolerability, and Pharmacokinetics of UX053 in Patients With Glycogen Storage Disease Type III (GSD III)
NCT06616545	Not specified	RECRUITING	French Observatory for Patients with Type 3 Glycogenosis
NCT02054832	Not specified	COMPLETED	Sleep and Quality of Life in Patients With Glycogen Storage Disease on Standard Versus Modified Uncooked Cornstarch
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT02448667	Not specified	COMPLETED	Energy Supplements to Improve Exercise Tolerance in Metabolic Myopathies
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT04574830	Not specified	COMPLETED	Study to Evaluate Biomarkers and Clinical Manifestations in Individuals With Glycogen Storage Disease Type III (GSD III)
NCT05196165	Not specified	TERMINATED	Clinical Survey Study to Assess Physical Function and the Incidence of Hypoglycemia in Participants With Glycogen Storage Disease Type III