glycogen storage disease due to aldolase A deficiency

Summary

glycogen storage disease due to aldolase A deficiency (MONDO:0012747) is a disease caused by ALDOA (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ALDOA (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 269
• Phenotypes (HPO): 21

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001945	Fever	Very frequent (80-99%)
HP:0012545	Reduced aldolase level	Very frequent (80-99%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001878	Hemolytic anemia	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003558	Viral infection-induced rhabdomyolysis	Frequent (30-79%)
HP:0003756	Skeletal myopathy	Frequent (30-79%)
HP:0008331	Elevated creatine kinase after exercise	Frequent (30-79%)
HP:0009045	Exercise-induced rhabdomyolysis	Frequent (30-79%)
HP:0100295	Muscle fiber atrophy	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0002153	Hyperkalemia	Occasional (5-29%)
HP:0002913	Myoglobinuria	Occasional (5-29%)
HP:0003199	Decreased muscle mass	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease due to aldolase A deficiency
Mondo ID	MONDO:0012747
MeSH	C562718
OMIM	611881
Orphanet	57
ICD-11	1020924235
SNOMED CT	111578003
UMLS	C0272066
MedGen	82895
GARD	0000600
Is cancer (heuristic)	no

Also known as: aldolase deficiency red cell · glycogen storage disease 12 · glycogen storage disease due to aldolase A deficiency · glycogen storage disease type 12 · glycogen storage disease type XII · glycogen storage disease XII · glycogenosis due to aldolase A deficiency · glycogenosis type 12 · glycogenosis type XII · GSD due to aldolase A deficiency · GSD type 12 · GSD type XII · GSD12

Data availability: 269 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › familial hemolytic anemia › glycogen storage disease due to aldolase A deficiency

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, cryohydrocytosis, dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, abetalipoproteinemia, hemolytic anemia due to diphosphoglycerate mutase deficiency, glycogen storage disease VII, cutaneous porphyria, hereditary cryohydrocytosis with reduced stomatin, familial pseudohyperkalemia, renal tubular acidosis, distal, 4, with hemolytic anemia, elliptocytosis 1, primary CD59 deficiency, triosephosphate isomerase deficiency, dehydrated hereditary stomatocytosis 2, Rh deficiency syndrome, hereditary spherocytosis, congenital dyserythropoietic anemia, X-linked congenital hemolytic anemia, hemolytic disease of fetus and newborn, RH-induced

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

269 retrieved; paginated sample, class counts are floors:

135 likely benign, 105 uncertain significance, 7 pathogenic, 6 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 likely pathogenic, 4 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2803048	NM_001243177.4(ALDOA):c.349_361del (p.Leu117fs)	ALDOA	Pathogenic	criteria provided, single submitter
4710258	NM_001243177.4(ALDOA):c.1072C>T (p.Arg358Ter)	ALDOA	Pathogenic	criteria provided, single submitter
1299556	NM_001243177.4(ALDOA):c.1001C>T (p.Ala334Val)	LOC112694756	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18177	NM_001243177.4(ALDOA):c.548A>G (p.Asp183Gly)	LOC112694756	Pathogenic	no assertion criteria provided
18178	NM_001243177.4(ALDOA):c.781G>A (p.Glu261Lys)	LOC112694756	Pathogenic	no assertion criteria provided
2077160	NM_001243177.4(ALDOA):c.951del (p.Ala318fs)	LOC112694756	Pathogenic	criteria provided, single submitter
3657301	NM_001243177.4(ALDOA):c.404dup (p.His135fs)	LOC112694756	Pathogenic	criteria provided, single submitter
1054446	NC_000016.9:g.(?29802081)(30199917_?)del	MAZ	Pathogenic	criteria provided, single submitter
2956786	NM_001243177.4(ALDOA):c.786+2T>C	ALDOA	Likely pathogenic	criteria provided, single submitter
3338430	GRCh37/hg19 16p11.2(chr16:29624260-29874118)x3	ALDOA	Likely pathogenic	no assertion criteria provided
3697760	NM_001243177.4(ALDOA):c.702+1G>A	ALDOA	Likely pathogenic	criteria provided, single submitter
1299547	NM_001243177.4(ALDOA):c.1178G>A (p.Cys393Tyr)	LOC112694756	Likely pathogenic	criteria provided, single submitter
3013293	NM_001243177.4(ALDOA):c.787-2A>G	LOC112694756	Likely pathogenic	criteria provided, single submitter
1147947	NM_001243177.4(ALDOA):c.1233C>T (p.Leu411=)	ALDOA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1577398	NM_001243177.4(ALDOA):c.668A>G (p.Asn223Ser)	ALDOA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318840	NM_001243177.4(ALDOA):c.1201G>A (p.Gly401Ser)	ALDOA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
450306	NM_001243177.4(ALDOA):c.922G>A (p.Val308Ile)	ALDOA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
503727	NM_001243177.4(ALDOA):c.274+4C>T	ALDOA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
559007	NM_001243177.4(ALDOA):c.996G>C (p.Glu332Asp)	LOC112694756	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015557	NM_001243177.4(ALDOA):c.563G>A (p.Arg188His)	ALDOA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022859	NM_001243177.4(ALDOA):c.375C>G (p.Asn125Lys)	ALDOA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1043680	NM_001243177.4(ALDOA):c.274+5G>A	ALDOA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163978	NM_001243177.4(ALDOA):c.679C>T (p.Arg227Cys)	ALDOA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1378736	NM_001243177.4(ALDOA):c.400T>C (p.Phe134Leu)	ALDOA	Uncertain significance	criteria provided, single submitter
1406126	NM_001243177.4(ALDOA):c.520A>G (p.Asn174Asp)	ALDOA	Uncertain significance	criteria provided, single submitter
1416209	NM_001243177.4(ALDOA):c.937C>T (p.Arg313Cys)	ALDOA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1424187	NM_001243177.4(ALDOA):c.382A>C (p.Ile128Leu)	ALDOA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1432377	NM_001243177.4(ALDOA):c.821A>G (p.His274Arg)	ALDOA	Uncertain significance	criteria provided, single submitter
1465716	NM_001243177.4(ALDOA):c.807G>T (p.Lys269Asn)	ALDOA	Uncertain significance	criteria provided, single submitter
1508859	NM_001243177.4(ALDOA):c.1069G>A (p.Gly357Ser)	ALDOA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ALDOA	Definitive	Autosomal recessive	glycogen storage disease due to aldolase A deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDOA	Orphanet:57	Glycogen storage disease due to aldolase A deficiency

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
ALDOA	HGNC:414	ENSG00000149925	P04075	Fructose-bisphosphate aldolase A	gencc,clinvar
FIMP1	HGNC:26346	ENSG00000167194	Q96LL3	Fertilization-influencing membrane protein	clinvar
MAZ	HGNC:6914	ENSG00000103495	P56270	Myc-associated zinc finger protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDOA	Fructose-bisphosphate aldolase A	Catalyzes the reversible conversion of beta-D-fructose 1,6-bisphosphate (FBP) into two triose phosphate and plays a key role in glycolysis and gluconeogenesis.
FIMP1	Fertilization-influencing membrane protein	May play a role in sperm-oocyte fusion during fertilization.
MAZ	Myc-associated zinc finger protein	Transcriptional regulator, potentially with dual roles in transcription initiation and termination.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDOA	Enzyme (other)	yes	4.1.2.13	FBA_I, Aldolase_TIM, Aldolase_I_AS
FIMP1	Other/Unknown	no		FIMP
MAZ	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDOA	134	ubiquitous	marker	skeletal muscle tissue, gastrocnemius, hindlimb stylopod muscle
FIMP1	114		yes	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis
MAZ	288	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDOA	3,591
MAZ	1,839
FIMP1	317

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDOA	P04075	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FIMP1	Q96LL3	65.84
MAZ	P56270	60.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 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
Glucose metabolism	1	878.5×	0.014	ALDOA
Gluconeogenesis	1	439.2×	0.014	ALDOA
Glycolysis	1	285.5×	0.014	ALDOA
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.018	ALDOA
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.019	ALDOA
Platelet activation, signaling and aggregation	1	105.7×	0.019	ALDOA
Platelet degranulation	1	87.8×	0.020	ALDOA
Hemostasis	1	36.0×	0.042	ALDOA
Innate Immune System	1	25.5×	0.052	ALDOA
Neutrophil degranulation	1	23.1×	0.052	ALDOA
Immune System	1	13.0×	0.084	ALDOA
Metabolism	1	11.6×	0.086	ALDOA

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
fructose 1,6-bisphosphate metabolic process	1	702.2×	0.014	ALDOA
fructose metabolic process	1	561.7×	0.014	ALDOA
termination of RNA polymerase II transcription	1	432.1×	0.014	MAZ
ATP biosynthetic process	1	330.4×	0.014	ALDOA
striated muscle contraction	1	280.9×	0.014	ALDOA
canonical glycolysis	1	234.1×	0.014	ALDOA
muscle cell cellular homeostasis	1	216.1×	0.014	ALDOA
fusion of sperm to egg plasma membrane involved in single fertilization	1	187.2×	0.014	FIMP1
negative regulation of apoptotic signaling pathway	1	187.2×	0.014	MAZ
binding of sperm to zona pellucida	1	140.4×	0.015	ALDOA
glycolytic process	1	127.7×	0.015	ALDOA
transcription initiation at RNA polymerase II promoter	1	124.8×	0.015	MAZ
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	124.8×	0.015	ALDOA
fertilization	1	104.0×	0.016	FIMP1
protein homotetramerization	1	79.1×	0.020	ALDOA
regulation of cell shape	1	41.0×	0.035	ALDOA
actin filament organization	1	39.6×	0.035	ALDOA
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	26.1×	0.050	MAZ
positive regulation of cell migration	1	20.6×	0.060	MAZ
positive regulation of gene expression	1	12.9×	0.091	MAZ
positive regulation of cell population proliferation	1	11.2×	0.099	MAZ
positive regulation of DNA-templated transcription	1	9.3×	0.113	MAZ
negative regulation of transcription by RNA polymerase II	1	5.9×	0.167	MAZ
regulation of transcription by RNA polymerase II	1	3.9×	0.236	MAZ

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDOA	1	2
FIMP1	0	0
MAZ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ALDOA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALDOA	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDOA	4.1.2.13	fructose-bisphosphate aldolase

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

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)
MOLIBRESIB	2	ALDOA

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	ALDOA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FIMP1, MAZ

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)
FIMP1	0	—
MAZ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.