glycogen storage disease I

Summary

glycogen storage disease I (MONDO:0002413) is a disease with 2 cohort genes and 10 clinical trials. Top therapeutic interventions include empagliflozin, lactic acid, and triheptanoin.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 54
• Phenotypes (HPO): 11
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000293	Full cheeks	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0002149	Hyperuricemia	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0003077	Hyperlipidemia	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000991	Xanthomatosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease I
Mondo ID	MONDO:0002413
MeSH	D005953
Orphanet	364
DOID	DOID:0081329
ICD-10-CM	E74.01
NCIT	C84733
SNOMED CT	7265005
UMLS	C0017920
MedGen	6640
GARD	0016523
MedDRA	10018464
NORD	1193
Is cancer (heuristic)	no

Also known as: G6P deficiency · glycogen storage disease due to G6P deficiency · glycogen storage disease due to glucose-6-phosphatase deficiency · glycogen storage disease I · glycogen storage disease type 1 · Glycogen Storage Disease Type I · glycogen storage disease type I · glycogen storage disease, type I · glycogenosis type 1 · glycogenosis type I · GSD due to G6P deficiency · GSD type 1 · GSD type I · GSD1 · hepatorenal glycogenosis · von Gierke disease · von Gierke’s disease

Data availability: 54 ClinVar variants · 18 cell lines.

Disease family

An umbrella term covering 3 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 I

Related subtypes (23): glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, 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

Subtypes (3): glycogen storage disease due to glucose-6-phosphatase deficiency type IA, glycogen storage disease type 1 due to SLC37A4 mutation, glycogen storage disease Id

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

54 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 10 conflicting classifications of pathogenicity, 8 pathogenic, 6 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11997	NM_000151.4(G6PC1):c.379_380dup (p.Tyr128fs)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
11998	NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
12008	NM_000151.4(G6PC1):c.562G>C (p.Gly188Arg)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
21062	NM_000151.4(G6PC1):c.79del (p.Gln27fs)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2851502	NM_001164277.2(SLC37A4):c.180T>G (p.Tyr60Ter)	SLC37A4	Pathogenic	criteria provided, multiple submitters, no conflicts
4081800	NM_001164277.2(SLC37A4):c.678del (p.Trp227fs)	SLC37A4	Pathogenic	criteria provided, single submitter
4081801	NM_001164277.2(SLC37A4):c.1225del (p.Ala409fs)	SLC37A4	Pathogenic	criteria provided, single submitter
6926	NM_001164277.2(SLC37A4):c.1042_1043del (p.Leu348fs)	SLC37A4	Pathogenic	criteria provided, multiple submitters, no conflicts
285532	NM_000151.4(G6PC1):c.340+10C>A	G6PC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724190	NM_000151.4(G6PC1):c.992C>T (p.Ala331Val)	G6PC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215177	NM_001164277.2(SLC37A4):c.467C>T (p.Ala156Val)	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302706	NM_001164277.2(SLC37A4):c.492C>T (p.Ser164=)	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302707	NM_001164277.2(SLC37A4):c.465G>C (p.Leu155=)	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302721	NM_001164277.2(SLC37A4):c.-700+9C>T	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392126	NM_001164277.2(SLC37A4):c.-183C>T	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68290	NM_001164277.2(SLC37A4):c.81T>A (p.Asn27Lys)	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877115	NM_001164277.2(SLC37A4):c.339C>T (p.Ala113=)	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878151	NM_001164277.2(SLC37A4):c.45A>G (p.Ser15=)	SLC37A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302717	NM_001164277.2(SLC37A4):c.-384G>A	LOC130006883	Uncertain significance	criteria provided, single submitter
879970	NM_001164277.2(SLC37A4):c.-439T>C	LOC130006883	Uncertain significance	criteria provided, single submitter
302696	NM_001164277.2(SLC37A4):c.*360C>G	SLC37A4	Uncertain significance	criteria provided, single submitter
302697	NM_001164277.2(SLC37A4):c.*298C>T	SLC37A4	Uncertain significance	criteria provided, single submitter
302698	NM_001164277.2(SLC37A4):c.*283T>C	SLC37A4	Uncertain significance	criteria provided, single submitter
302699	NM_001164277.2(SLC37A4):c.*139G>T	SLC37A4	Uncertain significance	criteria provided, single submitter
302700	NM_001164277.2(SLC37A4):c.*138C>T	SLC37A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
302702	NM_001164277.2(SLC37A4):c.*31C>T	SLC37A4	Uncertain significance	criteria provided, single submitter
302703	NM_001164277.2(SLC37A4):c.*5A>C	SLC37A4	Uncertain significance	criteria provided, single submitter
302708	NM_001164277.2(SLC37A4):c.382-6C>A	SLC37A4	Uncertain significance	criteria provided, single submitter
302710	NM_001164277.2(SLC37A4):c.-50T>G	SLC37A4	Uncertain significance	criteria provided, single submitter
302711	NM_001164277.2(SLC37A4):c.-64C>T	SLC37A4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
G6PC1	Orphanet:79258	Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
SLC37A4	Orphanet:79259	Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib

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
G6PC1	HGNC:4056	ENSG00000131482	P35575	Glucose-6-phosphatase catalytic subunit 1	clinvar
SLC37A4	HGNC:4061	ENSG00000137700	O43826	Glucose-6-phosphate exchanger SLC37A4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
G6PC1	Glucose-6-phosphatase catalytic subunit 1	Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum.
SLC37A4	Glucose-6-phosphate exchanger SLC37A4	Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum.

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
Phosphatase	1	42.0×	0.026
Transporter	1	38.9×	0.026

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
G6PC1	Phosphatase	yes	3.1.3.9	PAP2/HPO, Glucose-6-phosphatase, PAP2/HPO_sf
SLC37A4	Transporter	yes		Sugar_P_transporter, MFS, MFS_dom

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
liver	2
right lobe of liver	2
nephron tubule	1
duodenum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
G6PC1	66	tissue_specific	marker	right lobe of liver, liver, nephron tubule
SLC37A4	134	ubiquitous	marker	right lobe of liver, liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
G6PC1	2,193
SLC37A4	1,242

Intra-cohort edges

A	B	Sources
G6PC1	SLC37A4	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC37A4	O43826	25
G6PC1	P35575	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen storage disease type Ia (G6PC)	1	11420.0×	4e-04	G6PC1
Gluconeogenesis	1	439.2×	0.004	G6PC1
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.004	G6PC1
Interaction of NuRD complexes with transcription factors	1	126.9×	0.008	G6PC1

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
glucose-6-phosphate transport	2	2808.7×	2e-06	G6PC1, SLC37A4
gluconeogenesis	2	324.1×	9e-05	G6PC1, SLC37A4
glucose homeostasis	2	130.6×	4e-04	G6PC1, SLC37A4
response to resveratrol	1	1685.2×	0.003	G6PC1
response to carbohydrate	1	842.6×	0.003	G6PC1
urate metabolic process	1	766.0×	0.003	G6PC1
response to caloric restriction	1	766.0×	0.003	G6PC1
glucose 6-phosphate metabolic process	1	648.1×	0.003	G6PC1
glycogen catabolic process	1	601.9×	0.003	G6PC1
phosphate ion transmembrane transport	1	601.9×	0.003	SLC37A4
glycogen metabolic process	1	263.3×	0.006	G6PC1
response to food	1	247.8×	0.006	G6PC1
triglyceride metabolic process	1	221.7×	0.007	G6PC1
steroid metabolic process	1	168.5×	0.008	G6PC1
glucose metabolic process	1	127.7×	0.010	SLC37A4
cellular response to insulin stimulus	1	85.1×	0.014	G6PC1
cholesterol homeostasis	1	78.0×	0.014	G6PC1
multicellular organism growth	1	68.5×	0.015	G6PC1
regulation of gene expression	1	41.7×	0.024	G6PC1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Empagliflozin.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 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
G6PC1	0	0
SLC37A4	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
G6PC1	8	Binding:8
SLC37A4	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
G6PC1	3.1.3.9	glucose-6-phosphatase

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

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	G6PC1, SLC37A4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
G6PC1	8	—
SLC37A4	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE1/PHASE2	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03517085	PHASE1/PHASE2	COMPLETED	Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in Adults With Glycogen Storage Disease Type Ia (GSDIa)
NCT04138251	PHASE2	UNKNOWN	Safety, Efficacy Evaluation of Empagliflozin Administration for Neutropenia in Glycogenosis Type 1b and G6PC3 Deficiency
NCT03665636	EARLY_PHASE1	COMPLETED	Anaplerotic Therapy Using Triheptanoin for Patients With Glycogen Storage Disease Type I
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06852612	Not specified	RECRUITING	Dietary Treatment Strategies and Metabolic Control in Glycogen Storage Disease Type I
NCT07459582	Not specified	RECRUITING	Accuracy of Home Lactate Meter and Accu-chek Glucometer in Patients With Glycogen Storage Disease
NCT01961076	Not specified	COMPLETED	Overnight Feeding Study in Glycogen Storage Disease Type 1
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT03871673	Not specified	COMPLETED	The Use of Uncooked Sweet Manioc Starch to Treat Hepatic Glycogen Storage Diseases
NCT03970278	Not specified	COMPLETED	Study of Long-Term Safety and Efficacy on Gene Therapy in Glycogen Storage Disease Type Ia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMPAGLIFLOZIN	4	1
LACTIC ACID	4	1
TRIHEPTANOIN	4	1
D-LACTIC ACID	3	1
GALACTOSE	3	1
STARCH, CORN	3	1
FRUCTOSE	2	1
PARIGLASGENE BRECAPARVOVEC	1	1
CHEMBL604608	0	1