glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

Summary

glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (MONDO:0013047) is a disease caused by LDHA (GenCC Strong), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include lactic acid and d-lactic acid.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: LDHA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 193
• Phenotypes (HPO): 23
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001787	Abnormal delivery	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0008305	Exercise-induced myoglobinuria	Frequent (30-79%)
HP:0008331	Elevated creatine kinase after exercise	Frequent (30-79%)
HP:0009045	Exercise-induced rhabdomyolysis	Frequent (30-79%)
HP:0011356	Regional abnormality of skin	Frequent (30-79%)
HP:0025474	Erythematous plaque	Frequent (30-79%)
HP:0025526	Psoriasiform lesion	Frequent (30-79%)
HP:0025528	Annular cutaneous lesion	Frequent (30-79%)
HP:0040189	Scaling skin	Frequent (30-79%)
HP:0200039	Pustule	Frequent (30-79%)
HP:0001036	Parakeratosis	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0002046	Heat intolerance	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003072	Hypercalcemia	Occasional (5-29%)
HP:0007432	Intermittent generalized erythematous papular rash	Occasional (5-29%)
HP:0012622	Chronic kidney disease	Occasional (5-29%)
HP:0031190	Superficial dermal perivascular inflammatory infiltrate	Occasional (5-29%)
HP:0031236	Predominantly dermal neutrophilic infiltrate	Occasional (5-29%)
HP:0045040	Abnormal lactate dehydrogenase activity	Occasional (5-29%)
HP:0000989	Pruritus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease due to lactate dehydrogenase M-subunit deficiency
Mondo ID	MONDO:0013047
MeSH	C538133
OMIM	612933
Orphanet	284426
SNOMED CT	237982007
UMLS	C2931743
MedGen	419152
GARD	0003160
Is cancer (heuristic)	no

Also known as: glycogen storage disease caused by mutation in LDHA · glycogen storage disease type 11 · glycogen storage disease XI · glycogenosis due to lactate dehydrogenase M-subunit deficiency · glycogenosis type 11 · GSD 11 · GSD due to lactate dehydrogenase M-subunit deficiency · GSD type 11 · GSD XI · GSD11 · lactate dehydrogenase A deficiency · lactate dehydrogenase deficiency type A · LDH-M subunit deficiency · LDHA glycogen storage disease

Data availability: 193 ClinVar variants · 4 GenCC gene-disease records.

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 due to lactate dehydrogenase M-subunit 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 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, 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

193 retrieved; paginated sample, class counts are floors:

97 uncertain significance, 60 likely benign, 10 conflicting classifications of pathogenicity, 9 benign, 8 pathogenic, 5 likely pathogenic, 3 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14566	NM_005566.4(LDHA):c.759_778del (p.Leu254fs)	LDHA	Pathogenic	no assertion criteria provided
2137028	NM_005566.4(LDHA):c.505C>T (p.Arg169Ter)	LDHA	Pathogenic	criteria provided, single submitter
2848332	NM_005566.4(LDHA):c.631_632dup (p.Leu211_Lys212insTer)	LDHA	Pathogenic	criteria provided, single submitter
2903039	NM_005566.4(LDHA):c.410C>A (p.Ser137Ter)	LDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
3599467	NM_005566.4(LDHA):c.686_687del (p.Glu229fs)	LDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4709813	NM_005566.4(LDHA):c.640_641del (p.Leu214fs)	LDHA	Pathogenic	criteria provided, single submitter
4715484	NM_005566.4(LDHA):c.298C>T (p.Gln100Ter)	LDHA	Pathogenic	criteria provided, single submitter
4807073	NM_005566.4(LDHA):c.467dup (p.Asn156fs)	LDHA	Pathogenic	criteria provided, single submitter
976711	GRCh37/hg19 11p15.1(chr11:18418095-18422557)	LDHA	Pathogenic	criteria provided, single submitter
1925742	NM_005566.4(LDHA):c.126+2T>C	LDHA	Likely pathogenic	criteria provided, single submitter
2137026	NM_005566.4(LDHA):c.244G>A (p.Asp82Asn)	LDHA	Likely pathogenic	criteria provided, single submitter
3599453	NM_005566.4(LDHA):c.710+1del	LDHA	Likely pathogenic	criteria provided, single submitter
4712109	NM_005566.4(LDHA):c.419-1G>C	LDHA	Likely pathogenic	criteria provided, single submitter
4773910	NM_005566.4(LDHA):c.593-1del	LDHA	Likely pathogenic	criteria provided, single submitter
2173614	NM_005566.4(LDHA):c.843C>T (p.Tyr281=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2195924	NM_005566.4(LDHA):c.810G>A (p.Val270=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303909	NM_005566.4(LDHA):c.57C>T (p.Pro19=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303911	NM_005566.4(LDHA):c.222A>G (p.Thr74=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
386298	NM_005566.4(LDHA):c.183G>A (p.Glu61=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392797	NM_005566.4(LDHA):c.285G>A (p.Thr95=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471325	NM_005566.4(LDHA):c.696G>C (p.Lys232Asn)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
558834	NM_005566.4(LDHA):c.439G>T (p.Ala147Ser)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879830	NM_005566.4(LDHA):c.249T>C (p.Tyr83=)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879831	NM_005566.4(LDHA):c.406G>A (p.Val136Ile)	LDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2425376	NC_000011.9:g.(?18301429)(18428828_?)dup	GTF2H1	Uncertain significance	criteria provided, single submitter
1006351	NM_005566.4(LDHA):c.944G>A (p.Arg315His)	LDHA	Uncertain significance	criteria provided, single submitter
1028398	NM_005566.4(LDHA):c.476T>A (p.Ile159Asn)	LDHA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1046949	NM_005566.4(LDHA):c.8C>T (p.Thr3Ile)	LDHA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047167	NM_005566.4(LDHA):c.163G>A (p.Glu55Lys)	LDHA	Uncertain significance	criteria provided, single submitter
1394691	NM_005566.4(LDHA):c.833A>C (p.Lys278Thr)	LDHA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
LDHA	Strong	Autosomal recessive	glycogen storage disease due to lactate dehydrogenase M-subunit deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LDHA	Orphanet:284426	Glycogen storage disease due to lactate dehydrogenase M-subunit 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
LDHA	HGNC:6535	ENSG00000134333	P00338	L-lactate dehydrogenase A chain	gencc,clinvar
GTF2H1	HGNC:4655	ENSG00000110768	P32780	General transcription factor IIH subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LDHA	L-lactate dehydrogenase A chain	Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+).
GTF2H1	General transcription factor IIH subunit 1	Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LDHA	Enzyme (other)	yes	1.1.1.27	Lactate/malate_DH_N, L-lactate/malate_DH, L-lactate_DH
GTF2H1	Other/Unknown	no		BSD_dom, PH-like_dom_sf, TFIIH_BTF_p62_N

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
skin of leg	1
ventricular zone	1
zone of skin	1
adrenal tissue	1
calcaneal tendon	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LDHA	157	ubiquitous	marker	ventricular zone, zone of skin, skin of leg
GTF2H1	146	ubiquitous	marker	calcaneal tendon, adrenal tissue, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LDHA	6,660
GTF2H1	1,899

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GTF2H1	P32780	52
LDHA	P00338	46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. 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
Regulation of pyruvate metabolism	1	285.5×	0.017	LDHA
Global Genome Nucleotide Excision Repair (GG-NER)	1	228.4×	0.017	GTF2H1
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	203.9×	0.017	GTF2H1
Pyruvate metabolism	1	203.9×	0.017	LDHA
RNA Pol II CTD phosphorylation and interaction with CE	1	203.9×	0.017	GTF2H1
mRNA Capping	1	190.3×	0.017	GTF2H1
Formation of the Early Elongation Complex	1	167.9×	0.017	GTF2H1
Formation of the HIV-1 Early Elongation Complex	1	167.9×	0.017	GTF2H1
HIV Transcription Elongation	1	167.9×	0.017	GTF2H1
RNA Polymerase I Transcription Termination	1	163.1×	0.017	GTF2H1
RNA Polymerase I Promoter Clearance	1	146.4×	0.017	GTF2H1
Nucleotide Excision Repair	1	142.8×	0.017	GTF2H1
RNA Polymerase I Transcription	1	142.8×	0.017	GTF2H1
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	132.8×	0.017	GTF2H1
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	129.8×	0.017	GTF2H1
Tat-mediated elongation of the HIV-1 transcript	1	129.8×	0.017	GTF2H1
Negative epigenetic regulation of rRNA expression	1	129.8×	0.017	GTF2H1
Dual Incision in GG-NER	1	129.8×	0.017	GTF2H1
Formation of Incision Complex in GG-NER	1	126.9×	0.017	GTF2H1
Formation of HIV elongation complex in the absence of HIV Tat	1	124.1×	0.017	GTF2H1
HIV Transcription Initiation	1	116.5×	0.017	GTF2H1
RNA Polymerase II HIV Promoter Escape	1	116.5×	0.017	GTF2H1
RNA Polymerase II Promoter Escape	1	116.5×	0.017	GTF2H1
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	1	116.5×	0.017	GTF2H1
RNA Polymerase II Transcription Initiation	1	116.5×	0.017	GTF2H1
RNA Polymerase II Transcription Initiation And Promoter Clearance	1	116.5×	0.017	GTF2H1
RNA Polymerase I Transcription Initiation	1	112.0×	0.017	GTF2H1
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.018	GTF2H1
Formation of RNA Pol II elongation complex	1	96.8×	0.018	GTF2H1
RNA Polymerase II Transcription Elongation	1	96.8×	0.018	GTF2H1

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
obsolete homolactic fermentation	1	2808.7×	0.005	LDHA
pyruvate catabolic process	1	1053.2×	0.005	LDHA
lactate metabolic process	1	936.2×	0.005	LDHA
transcription by RNA polymerase I	1	702.2×	0.005	GTF2H1
regulation of cyclin-dependent protein serine/threonine kinase activity	1	366.4×	0.007	GTF2H1
hormone-mediated signaling pathway	1	200.6×	0.007	GTF2H1
glycolytic process	1	191.5×	0.007	LDHA
nucleotide-excision repair	1	191.5×	0.007	GTF2H1
transcription initiation at RNA polymerase II promoter	1	187.2×	0.007	GTF2H1
substantia nigra development	1	183.2×	0.007	LDHA
transcription by RNA polymerase II	1	35.3×	0.033	GTF2H1
DNA repair	1	31.9×	0.034	GTF2H1
positive regulation of DNA-templated transcription	1	14.0×	0.070	GTF2H1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

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
LDHA	CANNABIDIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LDHA	4	4
GTF2H1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABIDIOL	4	LDHA
DRONABINOL	4	LDHA
ADENOSINE PHOSPHATE	4	LDHA
GOSSYPOL	3	LDHA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LDHA	199	Binding:197, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LDHA	1.1.1.27	L-lactate dehydrogenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
LDHA	199

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)
CANNABIDIOL	4	LDHA
DRONABINOL	4	LDHA
ADENOSINE PHOSPHATE	4	LDHA
GOSSYPOL	3	LDHA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LDHA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GTF2H1

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)
GTF2H1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07459582	Not specified	RECRUITING	Accuracy of Home Lactate Meter and Accu-chek Glucometer in Patients With Glycogen Storage Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LACTIC ACID	4	1
D-LACTIC ACID	3	1