glycogen storage disease V

Summary

glycogen storage disease V (MONDO:0009293) is a disease caused by PYGM (GenCC Strong), with 2 cohort genes and 15 clinical trials. Top therapeutic interventions include triheptanoin, valproate sodium, and mavodelpar.

At a glance

• Prevalence: 1-9 / 1 000 000 (Spain) [Orphanet-validated]
• Causal gene: PYGM (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,487
• Phenotypes (HPO): 24
• Clinical trials: 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.035	Spain	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003546	Exercise intolerance	Very frequent (80-99%)
HP:0009051	Increased muscle glycogen content	Very frequent (80-99%)
HP:0030231	Glycogen accumulation in muscle fiber lysosomes	Very frequent (80-99%)
HP:0030234	Highly elevated creatine kinase	Very frequent (80-99%)
HP:0003201	Rhabdomyolysis	Frequent (30-79%)
HP:0003652	Recurrent myoglobinuria	Frequent (30-79%)
HP:0003710	Exercise-induced muscle cramps	Frequent (30-79%)
HP:0008305	Exercise-induced myoglobinuria	Frequent (30-79%)
HP:0040319	Dark urine	Frequent (30-79%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0001649	Tachycardia	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003738	Exercise-induced myalgia	Occasional (5-29%)
HP:0008967	Exercise-induced muscle stiffness	Occasional (5-29%)
HP:0009073	Progressive proximal muscle weakness	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0030973	Postexertional malaise	Occasional (5-29%)
HP:0002015	Dysphagia	Very rare (<1-4%)
HP:0005216	Impaired mastication	Very rare (<1-4%)
HP:0012622	Chronic kidney disease	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease V
Mondo ID	MONDO:0009293
MeSH	D006012
OMIM	232600
Orphanet	368
DOID	DOID:2746
ICD-10-CM	E74.04
NCIT	C84738
SNOMED CT	55912009
UMLS	C0017924
MedGen	5341
GARD	0006528
MedDRA	10018462
Is cancer (heuristic)	no

Also known as: glycogen storage disease caused by mutation in PYGM · glycogen storage disease type 5 · glycogen storage disease type V · glycogen storage disease V · glycogenosis due to muscle glycogen phosphorylase deficiency · glycogenosis type 5 · glycogenosis type V · GSD due to muscle glycogen phosphorylase deficiency · GSD type 5 · GSD type V · GSD5 · McArdle disease · Mcardle disease · McArdle type glycogen storage disease · myophosphorylase deficiency · PYGM glycogen storage disease

Data availability: 1,487 ClinVar variants · 5 GenCC gene-disease records · 14 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 V

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 due to glycogen branching enzyme deficiency, 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:

344 likely benign, 126 uncertain significance, 53 pathogenic, 26 pathogenic/likely pathogenic, 26 conflicting classifications of pathogenicity, 14 likely pathogenic, 7 benign, 2 not provided, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1449359	NC_000011.9:g.(?64522783)(66283694_?)del	AP5B1	Pathogenic	criteria provided, single submitter
1066872	NM_005609.4(PYGM):c.2385_2386del (p.Glu797fs)	PYGM	Pathogenic	criteria provided, multiple submitters, no conflicts
1069239	NM_005609.4(PYGM):c.1119T>A (p.Cys373Ter)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069632	NM_005609.4(PYGM):c.1353dup (p.Ala452fs)	PYGM	Pathogenic	criteria provided, multiple submitters, no conflicts
1069821	NM_005609.4(PYGM):c.493_514del (p.Gly165fs)	PYGM	Pathogenic	criteria provided, single submitter
1069823	NM_005609.4(PYGM):c.1159del (p.Arg387fs)	PYGM	Pathogenic	criteria provided, single submitter
1070312	NM_005609.4(PYGM):c.1403+1G>A	PYGM	Pathogenic	criteria provided, multiple submitters, no conflicts
1070313	NM_005609.4(PYGM):c.225C>A (p.Tyr75Ter)	PYGM	Pathogenic	criteria provided, multiple submitters, no conflicts
1070372	NM_005609.4(PYGM):c.1523del (p.Ile508fs)	PYGM	Pathogenic	criteria provided, single submitter
1071212	NM_005609.4(PYGM):c.1507del (p.Val503fs)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073391	NM_005609.4(PYGM):c.681C>A (p.Tyr227Ter)	PYGM	Pathogenic	criteria provided, single submitter
1074725	NM_005609.4(PYGM):c.2363_2366del (p.Val788fs)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076041	NC_000011.9:g.(?64525241)(64527380_?)del	PYGM	Pathogenic	criteria provided, single submitter
1076857	NM_005609.4(PYGM):c.521del (p.Gly174fs)	PYGM	Pathogenic	criteria provided, single submitter
1193689	NM_005609.4(PYGM):c.658_659del (p.Gln220fs)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299506	NM_005609.4(PYGM):c.2113_2114del (p.Gly705fs)	PYGM	Pathogenic	criteria provided, single submitter
1323509	NM_005609.4(PYGM):c.2379+2_2379+3delinsAT	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323510	NM_005609.4(PYGM):c.1774A>T (p.Lys592Ter)	PYGM	Pathogenic	criteria provided, single submitter
1332748	NM_005609.4(PYGM):c.2448dup (p.Thr817fs)	PYGM	Pathogenic	criteria provided, single submitter
1351367	NM_005609.4(PYGM):c.2154del (p.Asp718fs)	PYGM	Pathogenic	criteria provided, single submitter
1355803	NM_005609.4(PYGM):c.1138_1144del (p.Val380fs)	PYGM	Pathogenic	criteria provided, single submitter
1373318	NM_005609.4(PYGM):c.260_261del (p.Ser87fs)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1377601	NM_005609.4(PYGM):c.157del (p.Tyr53fs)	PYGM	Pathogenic	criteria provided, single submitter
139608	NM_005609.4(PYGM):c.255C>A (p.Tyr85Ter)	PYGM	Pathogenic	criteria provided, multiple submitters, no conflicts
139609	NM_005609.4(PYGM):c.2125TTC[1] (p.Phe710del)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407712	NM_005609.4(PYGM):c.549G>A (p.Trp183Ter)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410779	NM_005609.4(PYGM):c.1853dup (p.Met619fs)	PYGM	Pathogenic	criteria provided, single submitter
1440473	NM_005609.4(PYGM):c.506AGA[1] (p.Lys170del)	PYGM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449350	NC_000011.9:g.(?64517838)(64522318_?)del	PYGM	Pathogenic	criteria provided, single submitter
1451644	NM_005609.4(PYGM):c.1358_1364del (p.Val453fs)	PYGM	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
PYGM	Strong	Autosomal recessive	glycogen storage disease V	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PYGM	Orphanet:368	Glycogen storage disease due to muscle glycogen phosphorylase deficiency

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
PYGM	HGNC:9726	ENSG00000068976	P11217	Glycogen phosphorylase, muscle form	gencc,clinvar
AP5B1	HGNC:25104	ENSG00000254470	Q2VPB7	AP-5 complex subunit beta-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PYGM	Glycogen phosphorylase, muscle form	Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.
AP5B1	AP-5 complex subunit beta-1	As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PYGM	Other/Unknown	no		Glyco_trans_35, Glycg_phsphrylas, Pyridoxal_P_attach_site
AP5B1	Other/Unknown	no		AP5B1, AP5B1_N, AP5B1_middle

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1
bone marrow cell	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PYGM	227	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, gastrocnemius
AP5B1	178	ubiquitous	yes	monocyte, leukocyte, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PYGM	2,565
AP5B1	1,170

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP5B1	Q2VPB7	2
PYGM	P11217	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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 breakdown (glycogenolysis)	1	761.3×	0.001	PYGM

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
glycogen catabolic process	1	601.9×	0.008	PYGM
glycogen metabolic process	1	263.3×	0.009	PYGM
endosomal transport	1	122.1×	0.014	AP5B1
vesicle-mediated transport	1	48.1×	0.026	AP5B1
protein transport	1	21.9×	0.045	AP5B1

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): Triheptanoin.

Drug target analysis

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

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
PYGM	1	3
AP5B1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALVOCIDIB	3	PYGM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PYGM	18	Binding:18

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

1 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)
ALVOCIDIB	3	PYGM

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	1	PYGM
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AP5B1

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)
AP5B1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE2	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02432768	PHASE2	COMPLETED	The Effect of Triheptanoin in Adults With McArdle Disease (Glycogen Storage Disease Type V)
NCT02919631	PHASE2	COMPLETED	Triheptanoin in Mc Ardle
NCT03112889	PHASE2	COMPLETED	Sodium Valproate for GSDV
NCT04226274	PHASE1	COMPLETED	A Study of the Safety of REN001 in Patients With McArdle Disease
NCT04929002	Not specified	ACTIVE_NOT_RECRUITING	Carbon-13 Magnetic Resonance Spectroscopy in Glycogen Storage Diseases
NCT05943678	Not specified	ACTIVE_NOT_RECRUITING	Novel Metabolic Muscular Biomarkers in Pompe Disease - a Non-invasive Magnetic Resonance Exploratory Pilot 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
NCT03211923	Not specified	UNKNOWN	Muscle Relaxation in Myopathies With Positive Muscle Phenomena
NCT03843606	Not specified	COMPLETED	Modified Ketogenic Diet in Patients With McArdle Disease Part A
NCT03844022	Not specified	COMPLETED	MRI in McArdle Disease (GSDV)
NCT03945370	Not specified	COMPLETED	Oral Ketone Body Supplementation in Patients With McArdle Disease
NCT04044508	Not specified	COMPLETED	Modified Ketogenic Diet in Patients With McArdle Disease Part B
NCT04349566	Not specified	COMPLETED	Fast Troponin as a Biomarker to Assess Exercise-induced Muscle Damage in Muscle Diseases
NCT04694547	Not specified	COMPLETED	Ketogenic Diet Survey in Patients With McArdle Disease (GSDV)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEPTANOIN	4	2
VALPROATE SODIUM	4	1
MAVODELPAR	2	1