Glycogen Storage Disease Due To Aldolase A Deficiency

Mendelian MONDO:0012747 Pathograph 23 Show in embeddings browser Glycogen storage disease Inborn error of glycolysis

Glycogen storage disease type XII is an autosomal recessive glycolytic enzymopathy caused by biallelic ALDOA variants. Aldolase A is the only fructose-bisphosphate aldolase isozyme in erythrocytes and skeletal muscle, so one enzymatic lesion produces a two-organ disease: chronic non-spherocytic haemolytic anaemia and episodic rhabdomyolysis, classically triggered by fever. The mechanism that makes this disease distinctive is thermolability rather than simple loss of activity. Aldolase A is an unusually stable homotetramer, and the tetramer is what confers both thermal stability and the loop dynamics catalysis needs. Destabilizing missense alleles do not abolish catalysis; the crystal structure of a mimic of the clinical Asp128 mutation is a catalytically active dimer that has simply lost one of the tetramer's two subunit interfaces. The enzyme therefore works at normal body temperature and fails when the patient has a fever, which is why the episodes are triggered rather than continuous. That temperature dependence is also tissue-selective. In one family a thermolabile allele caused fever-induced rhabdomyolysis with no haemolytic anaemia at all, because the thermolability affected myoblasts and not erythrocytes. So the two-organ picture is a tendency of the disease, not a requirement of it, and an entry that treats haemolysis as obligatory would mis-describe the reported spectrum. The name is a historical artifact worth flagging: this is an enzymopathy of glycolysis rather than of glycogen breakdown, and it is grouped with the glycogen storage diseases because glycogen accumulates in muscle downstream of the block.

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1
Inheritance
7
Pathophys.
10
Phenotypes
2
Gaps
23
Pathograph
1
Genes
4
Variants
6
Medical Actions
2
Differentials
13
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry two pathogenic ALDOA alleles, homozygous in consanguineous or founder settings and compound heterozygous otherwise. Heterozygous parents are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:39223030 SUPPORT Human Clinical
"being homozygous,and the genotypes in the parents were heterozygous"
Homozygous affected brothers with heterozygous unaffected parents is the recessive segregation pattern.
PMID:2825199 SUPPORT Human Clinical
"Southern blot analysis of the genomic DNA showed the patient carried a homozygous mutation inherited from his parents."
The first molecularly defined case, homozygous and inherited from both parents.
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Discussions and Knowledge Gaps

2
By what mechanism does arginine rescue aldolase A deficiency in patient myoblasts, and does it work in patients?
KNOWLEDGE GAP gsd12_arginine_rescue_mechanism
Attached to
pathophysiology#Thermolability of Residual Aldolase A Activity
Arginine restored aldolase A activity in patient myoblasts while three other established chemical chaperones did not, which the authors take as evidence that it is not acting as a chaperone. What it is doing instead is unknown, and the result has not been tested in a patient. This is the only reported lead toward a mechanism-directed therapy for the disease, so the gap is worth naming rather than folding into supportive care.
Show evidence (1 reference)
PMID:25392908 SUPPORT In Vitro
"The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning."
The rescue, the negative controls, and the authors' own statement that the mechanism is not chaperoning.
Why is the thermolability of a mutant aldolase A tissue-selective, sparing erythrocytes in some families?
KNOWLEDGE GAP gsd12_tissue_selective_thermolability
Attached to
pathophysiology#Thermolability of Residual Aldolase A Activity
The same protein is expressed in both affected tissues, so a purely intrinsic thermodynamic defect should affect both. One family had thermolability that affected myoblasts but not erythrocytes, which implies that something about the cellular context modulates the mutant enzyme's stability. Nothing in the reported literature identifies what. Until it is known, an entry cannot predict from genotype which of the two organs a given patient will present with.
Show evidence (1 reference)
PMID:25392908 SUPPORT In Vitro
"Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific."
The authors state the tissue specificity as a suggestion, which is the uncertainty this gap records.
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Pathophysiology

7
Biallelic ALDOA Loss-of-Function or Destabilizing Variants
Two classes of allele converge on the same disease. Null alleles such as the active-site nonsense Arg303X remove the enzyme outright, while destabilizing missense alleles leave a catalytically competent but conformationally fragile protein. The second class is the more informative one, because it is what produces the triggered, episodic clinical course.
ALDOA hgnc:414 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALDOA (hgnc:414), qualified as loss of function. hgnc:414 is a gene from the HUGO Gene Nomenclature Committee. ⇓ LOSS OF FUNCTION
fructose-bisphosphate aldolase activity GO:0004332 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased fructose-bisphosphate aldolase activity (GO:0004332). GO:0004332 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Aldolase A Tetramer Destabilization
Show evidence (1 reference)
PMID:14615364 SUPPORT Human Clinical
"The paternal allele encoded a nonsense mutation, Arg303X, in the enzyme-active site. The maternal allele encoded a missense mutation, Cys338Tyr, predicted to cause enzyme instability."
One patient carrying one allele of each class, which is what shows the two classes converge.
Aldolase A Tetramer Destabilization
Aldolase A is normally an unusually stable tetramer of TIM-barrel subunits. A destabilizing substitution at the subunit interface yields a dimer that still turns substrate over, so the primary consequence is a loss of assembly rather than of chemistry. That matters because oligomerization is what stabilizes the enzyme and preserves the mobility of the catalytic loops, so losing an interface costs stability first and dynamics second.
protein homotetramerization GO:0051289 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein homotetramerization (GO:0051289). GO:0051289 is a biological process from the Gene Ontology. ↓ DECREASED
fructose-bisphosphate aldolase activity GO:0004332 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves fructose-bisphosphate aldolase activity (GO:0004332). GO:0004332 is a molecular function from the Gene Ontology.
Downstream
Thermolability of Residual Aldolase A Activity
Show evidence (3 references)
PMID:2335208 SUPPORT In Vitro
"The active protein is a tetramer of 4 identical subunits each of which is composed of an eight-stranded alpha/beta-barrel structure."
Establishes the normal quaternary structure that the destabilizing alleles disrupt.
PMID:18453690 SUPPORT In Vitro
"The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase."
The dimer is catalytically competent, which is why the defect presents as instability rather than as a constant enzymatic block.
PMID:25982518 SUPPORT INDIRECT Computational
"oligomerization not only stabilizes the aldolase structures, showing fewer fluctuations at the subunit interfaces, but also allows the enzyme to achieve the required dynamics for its functional loops"
Normal-mode analysis giving the general principle that links interface loss to both instability and impaired loop dynamics. It is indirect because the simulations are of bacterial class II aldolases, not of the human disease protein.
Thermolability of Residual Aldolase A Activity
The mutant enzyme is functional at normal body temperature and destabilizes as temperature rises. This is the node that converts a constitutive genetic lesion into an episodic clinical disease, and it is why the triggers are febrile rather than dietary.
protein stabilization GO:0050821 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein stabilization (GO:0050821). GO:0050821 is a biological process from the Gene Ontology. ↓ DECREASED
fructose-bisphosphate aldolase activity GO:0004332 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased fructose-bisphosphate aldolase activity (GO:0004332). GO:0004332 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Block at Step Four of Glycolysis
Show evidence (2 references)
PMID:2825199 SUPPORT In Vitro
"The results of E. coli expression of the mutated aldolase A enzyme confirmed the thermolabile nature of the abnormal enzyme."
Recombinant confirmation that the thermolability belongs to the mutant protein rather than to the patient's cellular context.
PMID:25392908 SUPPORT In Vitro
"We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes."
Demonstrates the temperature dependence directly, and that it can be restricted to one of the two affected tissues.
Block at Step Four of Glycolysis
Loss of aldolase A activity halts the cleavage of fructose-1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, cutting glycolytic ATP output in the two tissues that have no other aldolase isozyme. The consequences then split by tissue, because erythrocytes have no alternative to glycolysis at all while muscle depends on it only under stress.
glycolytic process GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Erythrocyte ATP Depletion and Membrane Instability
Skeletal Myocyte Energy Failure Under Catabolic Stress
Muscle Glycogen Accumulation
Show evidence (1 reference)
PMID:14615364 SUPPORT Human Clinical
"converts fructose-1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate"
The reaction that the block interrupts.
Erythrocyte ATP Depletion and Membrane Instability
Red cells have no mitochondria, so glycolysis is their only ATP source and an aldolase block is not survivable by any alternative route. The result is oxidative stress, membrane instability and shortened red cell lifespan.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
glycolytic process GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↓ DECREASED response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Chronic Non-Spherocytic Hemolytic Anemia
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"leads to oxidative stress, membrane instability, and chronic non-spherocytic hemolytic anemia due to impaired ATP production in erythrocytes"
The three-step erythrocyte mechanism this node asserts, and the sentence that supports both processes bound here: the glycolytic block that is the disorder-specific substitution, and the oxidative-stress response the module's own node carries.
Skeletal Myocyte Energy Failure Under Catabolic Stress
Muscle tolerates reduced aldolase activity at rest and fails when demand rises, which is why the episodes are provoked by fever or exertion rather than being continuous. Patient myoblasts also accumulate lipid droplets, and that accumulation is increased by cytokines and reduced by dexamethasone, which places the inflammatory context of a febrile illness inside the mechanism rather than beside it.
myoblast CL:0000056 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myoblast (CL:0000056). CL:0000056 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
glycolytic process GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↓ DECREASED
skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Episodic Rhabdomyolysis
Show evidence (2 references)
PMID:25392908 SUPPORT In Vitro
"Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone."
A measured cellular abnormality in patient myoblasts, modulated in the direction the febrile trigger predicts.
PMID:25392908 SUPPORT Human Clinical
"Myoglobinuria was always triggered by febrile illnesses."
Establishes that the muscle episodes are provoked rather than spontaneous.
Muscle Glycogen Accumulation
Glycogen accumulates in muscle downstream of the glycolytic block, which is the reason the disorder is classified among the glycogen storage diseases despite being an enzymopathy of glycolysis rather than of glycogenolysis. The nosology follows the storage product, not the lesion.
skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:35246226 SUPPORT Human Clinical
"a rare metabolic disease resulting from Aldolase A deficiency that causes muscle glycogen accumulation"
The accumulation this node records, and the basis of the disease's classification.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Glycogen Storage Disease Due To Aldolase A Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Blood 1
Chronic Non-Spherocytic Hemolytic Anemia FREQUENT HP:0001930 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic non-spherocytic hemolytic anemia, annotated with Nonspherocytic hemolytic anemia (HP:0001930), qualified as temporality chronic. HP:0001930 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:14615364 SUPPORT Human Clinical
"Clinical manifestations included transfusion-dependent anemia until splenectomy at age 3 and increasing muscle weakness, with death at age 4 associated with rhabdomyolysis and hyperkalemia."
Transfusion-dependent anaemia and its response to splenectomy in a molecularly confirmed patient.
PMID:25392908 REFUTE Human Clinical
"We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia."
Three siblings with molecularly confirmed disease and no haemolytic anaemia, which refutes treating this phenotype as obligatory.
Cardiovascular 1
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"On examination, she had pallor, icterus, hepatosplenomegaly, and skeletal abnormalities"
Hepatosplenomegaly on examination in a molecularly confirmed patient.
Genitourinary 1
Myoglobinuria HP:0002913 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoglobinuria (HP:0002913). HP:0002913 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25392908 SUPPORT Human Clinical
"Myoglobinuria was always triggered by febrile illnesses."
The observed myoglobinuria and its invariable trigger in this family.
Limbs 1
Brachymesophalangy and Symphalangism VERY_RARE Short middle phalanx of the 5th finger HP:0004220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachymesophalangy type A3 with symphalangism, annotated with Short middle phalanx of the 5th finger (HP:0004220). HP:0004220 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41199518 SUPPORT Human Clinical
"X-rays revealed bilateral symphalangism of the second digits and clinodactyly of the fifth digits, indicating brachymesophalangy type A3"
The radiographic finding and its type designation.
PMID:41199518 SUPPORT Human Clinical
"Our patient had intellectual delay along with the skeletal anomalies of brachymesophalangy and symphalangism, previously unreported in this condition."
The authors' own statement of novelty, which is why the frequency band is the lowest available and why the description says single observation.
Metabolism 1
Elevated Creatine Kinase Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated serum creatine kinase, annotated with Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"CK-MB (5911 U/L) was significantly higher."
A measured value in a molecularly confirmed patient.
Musculoskeletal 2
Episodic Rhabdomyolysis FREQUENT HP:0003201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhabdomyolysis (HP:0003201), qualified as temporality recurrent. HP:0003201 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Sequelae: Myoglobinuria
Show evidence (2 references)
PMID:33665120 SUPPORT Human Clinical
"cause hemolytic anemia and/or recurrent episodes of rhabdomyolysis, usually precipitated by fever"
The recurrent, fever-precipitated character of the episodes across the reviewed cases.
PMID:34171939 SUPPORT Human Clinical
"Here, we first report a patient with dermatological findings, hemodialysis requirement for rhabdomyolysis"
Documents the severity an episode can reach.
Muscle Weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14615364 SUPPORT Human Clinical
"transfusion-dependent anemia until splenectomy at age 3 and increasing muscle weakness"
Documents weakness that increased over time rather than only during episodes.
Nervous System 2
Seizure VERY_RARE HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35246226 SUPPORT Human Clinical
"we describe a new phenotype of the disease in a 14-year-old boy, characterized by seizures and rhabdomyolysis"
The single report from which this phenotype is curated, and it is labelled a new phenotype by its own authors.
Global Developmental Delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41199518 SUPPORT Human Clinical
"described a child with hemolytic anemia, developmental delay, and dysmorphism but no rhabdomyolysis"
Names developmental delay directly. The entry previously quoted a sentence about mild intellectual disability, which is a distinct HPO concept from global developmental delay and did not support this binding.
PMID:41199518 SUPPORT Human Clinical
"She had delayed motor milestones and, by the age of 3 years, she had proximal muscular discomfort and high creatinine kinase (CK)."
The index case's own milestone delay, which is what the description's "delayed milestones" claim rests on.
Growth 1
Short Stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"Patients may also show metabolic abnormalities, short stature, or mild intellectual disability."
Short stature named among the additional features seen in a subset.
🧬

Genetic Associations

1
ALDOA (ALDOA encodes fructose-bisphosphate aldolase A, the sole aldolase isozyme of erythrocytes and skeletal muscle. Biallelic loss-of-function or destabilizing variants cause GSD XII.)
Gene: ALDOA hgnc:414 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALDOA (hgnc:414). hgnc:414 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:14615364 SUPPORT Human Clinical
"The sole aldolase present in red blood cells and skeletal muscle is the A isozyme."
The isozyme restriction is what confines the disease to those two tissues and is the reason the phenotype pairs anaemia with myopathy.
PMID:33665120 SUPPORT Human Clinical
"Autosomal recessive mutations in ALDOA, are extremely rare and cause hemolytic anemia and/or recurrent episodes of rhabdomyolysis, usually precipitated by fever."
The review's summary of the gene-disease relationship, including the and/or that this entry treats as the reported spectrum.
Variants (4)
ALDOA c.386A>G p.Asp128Gly Pathogenic
The first molecularly defined allele, homozygous in a patient with haemolytic anaemia. Asp128 is conserved across aldolases A, B and C from humans to Drosophila.
Show evidence (1 reference)
PMID:2825199 SUPPORT Human Clinical
"As a result, the 128th amino acid, aspartic acid, was replaced with glycine (GAT to GGT)."
Identifies the substitution at the nucleotide and protein level.
ALDOA p.Arg303X and p.Cys338Tyr, compound heterozygous Pathogenic
A nonsense allele in the enzyme active site in trans with a destabilizing missense allele, in the most severely affected patient reported.
Show evidence (1 reference)
PMID:14615364 SUPPORT Human Clinical
"The paternal allele encoded a nonsense mutation, Arg303X, in the enzyme-active site. The maternal allele encoded a missense mutation, Cys338Tyr, predicted to cause enzyme instability."
Names both alleles and their predicted mechanisms.
ALDOA c.619G>A p.Glu207Lys Pathogenic
Homozygous in two brothers with neonatal-onset disease, the most severe end of the reported spectrum.
Show evidence (1 reference)
PMID:39223030 SUPPORT Human Clinical
"The results of gene detection showed that nucleotide and amino acid alterations (c.619G>A,p.E207K) of the ALDOA gene existed in the two brothers"
The allele and its homozygous state in the two neonatal-onset brothers.
ALDOA c.971C>T p.Ala324Val Likely Pathogenic
A likely pathogenic allele reported in a patient whose rhabdomyolysis required haemodialysis.
Show evidence (1 reference)
PMID:34171939 SUPPORT Human Clinical
"hemodialysis requirement for rhabdomyolysis, and a novel likely pathogenic c.971C>T (p.A324V) mutation in the ALDOA gene"
The allele, its ACMG classification and the severity of the episode it accompanied.
💊

Medical Actions

6
Antipyresis During Febrile Illness
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
The mechanistically motivated intervention, and a drug one. Because the enzyme fails as temperature rises, bringing a fever down acts on the lesion rather than only on symptoms. The cited source prescribes antipyretics without naming an agent or class, so none is asserted here.
Mechanism Target:
INHIBITS Thermolability of Residual Aldolase A Activity — Lowering body temperature removes the condition under which the residual enzyme unfolds.
Show evidence (1 reference)
PMID:34171939 SUPPORT Human Clinical
"Treatment includes management of hemolytic anemia and administration of antipyretics during febrile episodes to avoid hemolysis and rhabdomyolysis."
States antipyresis during fever as the preventive measure for both arms of the disease. Split out from trigger avoidance because this half is a drug intervention and the modality slot should say so.
Fever and Exertion Trigger Avoidance
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
The non-pharmacological half: avoiding the exposures that precipitate decompensation, which for this disease are febrile illness and strenuous exercise. Both are curated as environmental triggers in this entry, so the avoidance is directed at named exposures rather than at general caution. No cited source evaluates avoidance as an intervention; it follows from the triggers.
Mechanism Target:
INHIBITS Thermolability of Residual Aldolase A Activity — Keeps the residual enzyme out of the temperature range in which it unfolds, by removing the exposure rather than by treating the fever.
Show evidence (1 reference)
PMID:34171939 SUPPORT INDIRECT Human Clinical
"Treatment includes management of hemolytic anemia and administration of antipyretics during febrile episodes to avoid hemolysis and rhabdomyolysis."
Indirect. The sentence establishes that fever is the exposure to be prevented, which is what makes avoidance sensible, but it prescribes a drug rather than avoidance and says nothing about exertion.
Blood Transfusion
Action: Blood TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Blood Transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. NCIT:C15192
Platform: Other
Supportive management of the haemolytic anaemia, which is transfusion dependent in a substantial share of reported patients.
Mechanism Target:
RESTORES Chronic Non-Spherocytic Hemolytic Anemia — Transfusion replaces the red cell mass the haemolysis removes, without acting on the enzymatic lesion that causes it.
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"The patient remains on intermittent transfusion support, folate supplementation, and physiotherapy."
Documents ongoing transfusion support as the management of the anaemia.
Splenectomy
Action: SplenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Splenectomy (NCIT:C15328). NCIT:C15328 is a clinical intervention from the NCI Thesaurus. NCIT:C15328
Platform: Surgery
Considered for transfusion-dependent haemolysis. In the one detailed report it ended transfusion dependence, though the patient's muscle disease continued to progress and was ultimately fatal.
Mechanism Target:
INHIBITS Chronic Non-Spherocytic Hemolytic Anemia — Removing the spleen removes the site at which the fragile red cells are preferentially destroyed.
Show evidence (1 reference)
PMID:14615364 SUPPORT Human Clinical
"transfusion-dependent anemia until splenectomy at age 3"
Records the point at which transfusion dependence ended.
Ketogenic Diet
Action: Ketogenic DietNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Ketogenic Diet (NCIT:C173168). NCIT:C173168 is a clinical intervention from the NCI Thesaurus. NCIT:C173168
Platform: Behavioral / lifestyle
Proposed as a way to supply an energy substrate that bypasses the glycolytic block for muscle and brain. The evidence is a single patient, in whom it was combined with antiepileptic treatment and followed by no further episodes, so the two interventions cannot be separated.
Mechanism Target:
BYPASSES Skeletal Myocyte Energy Failure Under Catabolic Stress — Ketone bodies enter energy metabolism downstream of the aldolase step, so they are proposed as a substrate that does not require the blocked reaction.
Show evidence (2 references)
PMID:35246226 SUPPORT INDIRECT Human Clinical
"we propose a new therapeutic approach based on ketogenic diet in order to supply an energetic substrate for skeletal muscle and neurons"
The proposal and its rationale. It is indirect because the reported outcome follows a combined dietary and antiepileptic regimen in one patient, so the diet's own contribution is not isolated.
PMID:35246226 SUPPORT Human Clinical
"This led to a deceleration of the disease with no other acute episodes of seizures and rhabdomyolysis, without any side effects observed."
The reported outcome, which the entry describes as attributable to the combined regimen rather than the diet alone.
Exercise Adaptation and Caution With Pre-Exercise Carbohydrate
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Lifestyle adaptation with carefully titrated exercise. The point worth flagging is that immediate pre-exercise carbohydrate, which helps in the glycogenolytic defects such as McArdle disease, can make glycolytic defects worse, and aldolase A deficiency is a glycolytic defect. The intuitive advice for a glycogen storage disease is the wrong advice here.
Mechanism Target:
INHIBITS Skeletal Myocyte Energy Failure Under Catabolic Stress — Titrating exertion keeps demand below the point at which the residual glycolytic capacity fails.
Show evidence (2 references)
PMID:30397902 SUPPORT INDIRECT Human Clinical
"Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK)."
The review states the principle for glycolytic defects using PFK as its example rather than ALDOA, so applying it here is an inference from the shared class of lesion.
PMID:30397902 SUPPORT Human Clinical
"Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise."
The general management principle for this disease group.
🌍

Environmental Factors

2
Febrile illness
febrile illness Relation: this environmental factor is this exposure This environmental factor is febrile illness.
Left unbound to an ontology term deliberately. ECTO models exposures to things in the environment, and its temperature terms (for example ECTO:4000001, exposure to increased temperature) describe ambient temperature rather than endogenous fever. Binding one of those here would assert the wrong exposure.
The characteristic trigger. Fever raises tissue temperature past the point at which the thermolabile enzyme holds together, so an intercurrent infection converts a compensated metabolic state into an acute crisis. This is why antipyresis is treatment rather than comfort care here.
Show evidence (1 reference)
PMID:34171939 SUPPORT Human Clinical
"Episodes of rhabdomyolysis can be triggered by febrile illnesses and catabolic processes."
An independent report naming febrile illness as a trigger.
Mechanism Target:
TRIGGERS Thermolability of Residual Aldolase A Activity — The exposure acts on the temperature-dependence node directly, by supplying the temperature.
Show evidence (1 reference)
PMID:25392908 SUPPORT Human Clinical
"Myoglobinuria was always triggered by febrile illnesses."
In three siblings every episode followed a febrile illness, which is as close to a controlled trigger as this literature offers.
Strenuous exercise
exposure to strenuous exercise ECTO:6000031 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to strenuous exercise (ECTO:6000031). ECTO:6000031 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
The second reported trigger, acting through metabolic demand rather than temperature. It matters clinically because the standard advice for glycogenolytic myopathies does not transfer.
Show evidence (1 reference)
PMID:35246226 SUPPORT Human Clinical
"rhabdomyolysis crises are caused by fever and/or exercise and can accompany acute hemolytic anemia"
Names exercise alongside fever as a crisis trigger in this disease specifically.
Mechanism Target:
TRIGGERS Skeletal Myocyte Energy Failure Under Catabolic Stress
Show evidence (1 reference)
PMID:30397902 SUPPORT INDIRECT Human Clinical
"Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise"
Places exercise-induced rhabdomyolysis in the muscle glycogen and glycolysis disorder group that includes ALDOA.
🔬

Diagnosis

2
Molecular sequencing of ALDOA
Definitive diagnosis. The erythrocyte aldolase activity assay exists but is not widely available, so in practice a metabolic-myopathy or hereditary-anaemia panel or exome sequencing is the route.
Show evidence (2 references)
PMID:34171939 SUPPORT Human Clinical
"Diagnosis should be confirmed by the mutation analysis of ALDOA gene."
States that molecular confirmation is required.
PMID:41199518 SUPPORT Human Clinical
"Clinical exome sequencing revealed compound heterozygous pathogenic mutations in the ALDOA gene"
Exome sequencing as the route that reached the diagnosis in practice.
Recognizing the anaemia-plus-myopathy combination
The diagnostic problem is that each half is unremarkable on its own. In one reported patient years passed under a working diagnosis of inflammatory myositis, treated with steroids and methotrexate, before the combination was read as a single metabolic disease.
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"With a provisional diagnosis of inflammatory myositis, she was given a trial treatment of steroids and methotrexate, but the symptoms persisted."
The misdiagnosis and its cost, which is what makes recognizing the combination a diagnostic step in its own right.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Roughly a dozen families have been reported since the first clinical description in 1977. No prevalence or incidence estimate exists, and none can be normalized from case reports.
Show evidence (1 reference)
PMID:34171939 SUPPORT Human Clinical
"Aldolase A deficiency also known as glycogen storage disease (GSD) XII, is an ultra rare autosomal recessively inherited GSD"
The ultra-rare classification; no numeric estimate is available in the cited literature.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Glycogen Storage Disease Due To Aldolase A Deficiency:

Other glycolytic and glycogenolytic myopathies
Overlapping Features Phosphofructokinase deficiency, phosphoglycerate mutase deficiency and beta-enolase deficiency share the exercise-induced rhabdomyolysis, and McArdle disease shares it from the glycogenolytic side. The discriminator that matters clinically is the response to pre-exercise carbohydrate, which separates the two halves of the group in opposite directions.
Show evidence (1 reference)
PMID:30397902 SUPPORT Human Clinical
"Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis"
Places ALDOA within a group defined by shared clinical presentation but split by which half of the pathway is affected.
Inflammatory myositis
Overlapping Features The label a patient with unexplained myopathy and raised creatine kinase receives by default, and the one that delayed a molecular diagnosis by years in a reported case.
Show evidence (1 reference)
PMID:41199518 SUPPORT Human Clinical
"With a provisional diagnosis of inflammatory myositis, she was given a trial treatment of steroids and methotrexate, but the symptoms persisted."
Documents the misdiagnosis this differential exists to prevent.
{ }

Source YAML

click to show 
name: Glycogen Storage Disease Due To Aldolase A Deficiency
creation_date: "2026-09-05T10:00:00Z"
category: Mendelian
synonyms:
- GSD XII
- GSD12
- aldolase A deficiency
- ALDOA deficiency
- glycogen storage disease type XII
description: >-
  Glycogen storage disease type XII is an autosomal recessive glycolytic
  enzymopathy caused by biallelic ALDOA variants. Aldolase A is the only
  fructose-bisphosphate aldolase isozyme in erythrocytes and skeletal muscle, so
  one enzymatic lesion produces a two-organ disease: chronic non-spherocytic
  haemolytic anaemia and episodic rhabdomyolysis, classically triggered by
  fever.

  The mechanism that makes this disease distinctive is thermolability rather
  than simple loss of activity. Aldolase A is an unusually stable homotetramer,
  and the tetramer is what confers both thermal stability and the loop dynamics
  catalysis needs. Destabilizing missense alleles do not abolish catalysis; the
  crystal structure of a mimic of the clinical Asp128 mutation is a catalytically
  active dimer that has simply lost one of the tetramer's two subunit
  interfaces. The enzyme therefore works at normal body temperature and fails
  when the patient has a fever, which is why the episodes are triggered rather
  than continuous.

  That temperature dependence is also tissue-selective. In one family a
  thermolabile allele caused fever-induced rhabdomyolysis with no haemolytic
  anaemia at all, because the thermolability affected myoblasts and not
  erythrocytes. So the two-organ picture is a tendency of the disease, not a
  requirement of it, and an entry that treats haemolysis as obligatory would
  mis-describe the reported spectrum.

  The name is a historical artifact worth flagging: this is an enzymopathy of
  glycolysis rather than of glycogen breakdown, and it is grouped with the
  glycogen storage diseases because glycogen accumulates in muscle downstream of
  the block.
disease_term:
  preferred_term: glycogen storage disease type XII
  term:
    id: MONDO:0012747
    label: glycogen storage disease due to aldolase A deficiency
parents:
- Glycogen storage disease
- Inborn error of glycolysis
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry two pathogenic ALDOA alleles, homozygous in
    consanguineous or founder settings and compound heterozygous otherwise.
    Heterozygous parents are unaffected.
  evidence:
  - reference: PMID:39223030
    reference_title: "[Onset of Glycogen Storage Disease Type Ⅻ in Two Brothers in the Neonatal Period]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "being homozygous,and the genotypes in the parents were heterozygous"
    explanation: Homozygous affected brothers with heterozygous unaffected parents is the recessive segregation pattern.
  - reference: PMID:2825199
    reference_title: "Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Southern blot analysis of the genomic DNA showed the patient carried a homozygous mutation inherited from his parents."
    explanation: The first molecularly defined case, homozygous and inherited from both parents.
genetic:
- name: ALDOA
  gene_term:
    preferred_term: ALDOA
    term:
      id: hgnc:414
      label: ALDOA
  association: >-
    ALDOA encodes fructose-bisphosphate aldolase A, the sole aldolase isozyme of
    erythrocytes and skeletal muscle. Biallelic loss-of-function or
    destabilizing variants cause GSD XII.
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:14615364
    reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sole aldolase present in red blood cells and skeletal muscle is the A isozyme."
    explanation: The isozyme restriction is what confines the disease to those two tissues and is the reason the phenotype pairs anaemia with myopathy.
  - reference: PMID:33665120
    reference_title: "Aldolase A deficiency: Report of new cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive mutations in ALDOA, are extremely rare and cause hemolytic anemia and/or recurrent episodes of rhabdomyolysis, usually precipitated by fever."
    explanation: The review's summary of the gene-disease relationship, including the and/or that this entry treats as the reported spectrum.
  variants:
  - name: ALDOA c.386A>G p.Asp128Gly
    description: >-
      The first molecularly defined allele, homozygous in a patient with
      haemolytic anaemia. Asp128 is conserved across aldolases A, B and C from
      humans to Drosophila.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:2825199
      reference_title: "Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As a result, the 128th amino acid, aspartic acid, was replaced with glycine (GAT to GGT)."
      explanation: Identifies the substitution at the nucleotide and protein level.
  - name: ALDOA p.Arg303X and p.Cys338Tyr, compound heterozygous
    description: >-
      A nonsense allele in the enzyme active site in trans with a destabilizing
      missense allele, in the most severely affected patient reported.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:14615364
      reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The paternal allele encoded a nonsense mutation, Arg303X, in the enzyme-active site. The maternal allele encoded a missense mutation, Cys338Tyr, predicted to cause enzyme instability."
      explanation: Names both alleles and their predicted mechanisms.
  - name: ALDOA c.619G>A p.Glu207Lys
    description: >-
      Homozygous in two brothers with neonatal-onset disease, the most severe
      end of the reported spectrum.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:39223030
      reference_title: "[Onset of Glycogen Storage Disease Type Ⅻ in Two Brothers in the Neonatal Period]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The results of gene detection showed that nucleotide and amino acid alterations (c.619G>A,p.E207K) of the ALDOA gene existed in the two brothers"
      explanation: The allele and its homozygous state in the two neonatal-onset brothers.
  - name: ALDOA c.971C>T p.Ala324Val
    description: >-
      A likely pathogenic allele reported in a patient whose rhabdomyolysis
      required haemodialysis.
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:34171939
      reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hemodialysis requirement for rhabdomyolysis, and a novel likely pathogenic c.971C>T (p.A324V) mutation in the ALDOA gene"
      explanation: The allele, its ACMG classification and the severity of the episode it accompanied.
pathophysiology:
- name: Biallelic ALDOA Loss-of-Function or Destabilizing Variants
  biological_scale: MOLECULAR
  description: >-
    Two classes of allele converge on the same disease. Null alleles such as the
    active-site nonsense Arg303X remove the enzyme outright, while destabilizing
    missense alleles leave a catalytically competent but conformationally fragile
    protein. The second class is the more informative one, because it is what
    produces the triggered, episodic clinical course.
  gene:
    preferred_term: ALDOA
    modifier: LOSS_OF_FUNCTION
    term:
      id: hgnc:414
      label: ALDOA
  molecular_functions:
  - preferred_term: fructose-bisphosphate aldolase activity
    modifier: DECREASED
    term:
      id: GO:0004332
      label: fructose-bisphosphate aldolase activity
  evidence:
  - reference: PMID:14615364
    reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The paternal allele encoded a nonsense mutation, Arg303X, in the enzyme-active site. The maternal allele encoded a missense mutation, Cys338Tyr, predicted to cause enzyme instability."
    explanation: One patient carrying one allele of each class, which is what shows the two classes converge.
  downstream:
  - target: Aldolase A Tetramer Destabilization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18453690
      reference_title: "Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer."
      explanation: A crystal structure showing the substitution acting on the tetramer interface rather than on the active site.
- name: Aldolase A Tetramer Destabilization
  biological_scale: MOLECULAR
  description: >-
    Aldolase A is normally an unusually stable tetramer of TIM-barrel subunits.
    A destabilizing substitution at the subunit interface yields a dimer that
    still turns substrate over, so the primary consequence is a loss of assembly
    rather than of chemistry. That matters because oligomerization is what
    stabilizes the enzyme and preserves the mobility of the catalytic loops, so
    losing an interface costs stability first and dynamics second.
  molecular_functions:
  - preferred_term: fructose-bisphosphate aldolase activity
    term:
      id: GO:0004332
      label: fructose-bisphosphate aldolase activity
  biological_processes:
  - preferred_term: protein homotetramerization
    modifier: DECREASED
    term:
      id: GO:0051289
      label: protein homotetramerization
  evidence:
  - reference: PMID:2335208
    reference_title: "The crystal structure of human muscle aldolase at 3.0 A resolution."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The active protein is a tetramer of 4 identical subunits each of which is composed of an eight-stranded alpha/beta-barrel structure."
    explanation: Establishes the normal quaternary structure that the destabilizing alleles disrupt.
  - reference: PMID:18453690
    reference_title: "Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase."
    explanation: The dimer is catalytically competent, which is why the defect presents as instability rather than as a constant enzymatic block.
  - reference: PMID:25982518
    reference_title: "Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "oligomerization not only stabilizes the aldolase structures, showing fewer fluctuations at the subunit interfaces, but also allows the enzyme to achieve the required dynamics for its functional loops"
    explanation: Normal-mode analysis giving the general principle that links interface loss to both instability and impaired loop dynamics. It is indirect because the simulations are of bacterial class II aldolases, not of the human disease protein.
  downstream:
  - target: Thermolability of Residual Aldolase A Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2229018
      reference_title: "Human aldolase A of a hemolytic anemia patient with Asp-128----Gly substitution: characteristics of an enzyme generated in E. coli transfected with the expression plasmid pHAAD128G."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Conversion of Asp to Gly at the 128th position in the enzyme rendered the enzyme thermolabile and susceptible to tryptic digestion."
      explanation: Recombinant expression of the patient allele demonstrating that the substitution is what makes the enzyme thermolabile.
- name: Thermolability of Residual Aldolase A Activity
  biological_scale: MOLECULAR
  description: >-
    The mutant enzyme is functional at normal body temperature and destabilizes
    as temperature rises. This is the node that converts a constitutive genetic
    lesion into an episodic clinical disease, and it is why the triggers are
    febrile rather than dietary.
  molecular_functions:
  - preferred_term: fructose-bisphosphate aldolase activity
    modifier: DECREASED
    term:
      id: GO:0004332
      label: fructose-bisphosphate aldolase activity
  biological_processes:
  - preferred_term: protein stabilization
    modifier: DECREASED
    term:
      id: GO:0050821
      label: protein stabilization
  evidence:
  - reference: PMID:2825199
    reference_title: "Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results of E. coli expression of the mutated aldolase A enzyme confirmed the thermolabile nature of the abnormal enzyme."
    explanation: Recombinant confirmation that the thermolability belongs to the mutant protein rather than to the patient's cellular context.
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes."
    explanation: Demonstrates the temperature dependence directly, and that it can be restricted to one of the two affected tissues.
  downstream:
  - target: Block at Step Four of Glycolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33665120
      reference_title: "Aldolase A deficiency: Report of new cases and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ALDOA is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate"
      explanation: Names the reaction that the destabilized enzyme fails to sustain.
- name: Block at Step Four of Glycolysis
  biological_scale: CELLULAR
  description: >-
    Loss of aldolase A activity halts the cleavage of fructose-1,6-bisphosphate
    into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, cutting
    glycolytic ATP output in the two tissues that have no other aldolase
    isozyme. The consequences then split by tissue, because erythrocytes have no
    alternative to glycolysis at all while muscle depends on it only under
    stress.
  biological_processes:
  - preferred_term: glycolytic process
    modifier: DECREASED
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:14615364
    reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "converts fructose-1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate"
    explanation: The reaction that the block interrupts.
  downstream:
  - target: Erythrocyte ATP Depletion and Membrane Instability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41199518
      reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Its deficiency leads to oxidative stress, membrane instability, and chronic non-spherocytic hemolytic anemia due to impaired ATP production in erythrocytes"
      explanation: States the erythrocyte arm from the enzymatic block to the anaemia.
  - target: Skeletal Myocyte Energy Failure Under Catabolic Stress
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41199518
      reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In muscle, especially under anaerobic stress, impaired energy metabolism results in rhabdomyolysis, muscle pain, and elevated CK"
      explanation: States the muscle arm and its dependence on stress conditions.
  - target: Muscle Glycogen Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35246226
      reference_title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Glycogen storage disease type XII is a rare metabolic disease resulting from Aldolase A deficiency that causes muscle glycogen accumulation"
      explanation: The accumulation is asserted as a consequence of the deficiency; the intervening steps between a glycolytic block and net glycogen storage are not spelled out in the cited sources.
- name: Erythrocyte ATP Depletion and Membrane Instability
  biological_scale: CELLULAR
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Reduced Erythrocyte Integrity"
  description: >-
    Red cells have no mitochondria, so glycolysis is their only ATP source and
    an aldolase block is not survivable by any alternative route. The result is
    oxidative stress, membrane instability and shortened red cell lifespan.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: glycolytic process
    modifier: DECREASED
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: response to oxidative stress
    modifier: DYSREGULATED
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "leads to oxidative stress, membrane instability, and chronic non-spherocytic hemolytic anemia due to impaired ATP production in erythrocytes"
    explanation: >-
      The three-step erythrocyte mechanism this node asserts, and the sentence
      that supports both processes bound here: the glycolytic block that is the
      disorder-specific substitution, and the oxidative-stress response the
      module's own node carries.
  downstream:
  - target: Chronic Non-Spherocytic Hemolytic Anemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33665120
      reference_title: "Aldolase A deficiency: Report of new cases and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive mutations in ALDOA, are extremely rare and were originally reported to cause hemolytic anemia by impairing thermostability of the enzyme"
      explanation: Ties the haemolytic anaemia to the thermostability defect rather than to a separate mechanism.
- name: Skeletal Myocyte Energy Failure Under Catabolic Stress
  biological_scale: CELLULAR
  description: >-
    Muscle tolerates reduced aldolase activity at rest and fails when demand
    rises, which is why the episodes are provoked by fever or exertion rather
    than being continuous. Patient myoblasts also accumulate lipid droplets, and
    that accumulation is increased by cytokines and reduced by dexamethasone,
    which places the inflammatory context of a febrile illness inside the
    mechanism rather than beside it.
  cell_types:
  - preferred_term: myoblast
    term:
      id: CL:0000056
      label: myoblast
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  biological_processes:
  - preferred_term: glycolytic process
    modifier: DECREASED
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone."
    explanation: A measured cellular abnormality in patient myoblasts, modulated in the direction the febrile trigger predicts.
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myoglobinuria was always triggered by febrile illnesses."
    explanation: Establishes that the muscle episodes are provoked rather than spontaneous.
  downstream:
  - target: Episodic Rhabdomyolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41199518
      reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired energy metabolism results in rhabdomyolysis, muscle pain, and elevated CK"
      explanation: States the step from myocyte energy failure to clinical rhabdomyolysis.
- name: Muscle Glycogen Accumulation
  biological_scale: TISSUE
  description: >-
    Glycogen accumulates in muscle downstream of the glycolytic block, which is
    the reason the disorder is classified among the glycogen storage diseases
    despite being an enzymopathy of glycolysis rather than of glycogenolysis.
    The nosology follows the storage product, not the lesion.
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:35246226
    reference_title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare metabolic disease resulting from Aldolase A deficiency that causes muscle glycogen accumulation"
    explanation: The accumulation this node records, and the basis of the disease's classification.
environmental:
- name: Febrile illness
  description: >-
    The characteristic trigger. Fever raises tissue temperature past the point
    at which the thermolabile enzyme holds together, so an intercurrent
    infection converts a compensated metabolic state into an acute crisis. This
    is why antipyresis is treatment rather than comfort care here.
  exposure_term:
    preferred_term: febrile illness
  influences_mechanisms:
  - target: Thermolability of Residual Aldolase A Activity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The exposure acts on the temperature-dependence node directly, by
      supplying the temperature.
    evidence:
    - reference: PMID:25392908
      reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Myoglobinuria was always triggered by febrile illnesses."
      explanation: In three siblings every episode followed a febrile illness, which is as close to a controlled trigger as this literature offers.
  evidence:
  - reference: PMID:34171939
    reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Episodes of rhabdomyolysis can be triggered by febrile illnesses and catabolic processes."
    explanation: An independent report naming febrile illness as a trigger.
  notes: >-
    Left unbound to an ontology term deliberately. ECTO models exposures to
    things in the environment, and its temperature terms (for example
    ECTO:4000001, exposure to increased temperature) describe ambient
    temperature rather than endogenous fever. Binding one of those here would
    assert the wrong exposure.
- name: Strenuous exercise
  description: >-
    The second reported trigger, acting through metabolic demand rather than
    temperature. It matters clinically because the standard advice for
    glycogenolytic myopathies does not transfer.
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  influences_mechanisms:
  - target: Skeletal Myocyte Energy Failure Under Catabolic Stress
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30397902
      reference_title: "Myopathies Related to Glycogen Metabolism Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise"
      explanation: Places exercise-induced rhabdomyolysis in the muscle glycogen and glycolysis disorder group that includes ALDOA.
  evidence:
  - reference: PMID:35246226
    reference_title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rhabdomyolysis crises are caused by fever and/or exercise and can accompany acute hemolytic anemia"
    explanation: Names exercise alongside fever as a crisis trigger in this disease specifically.
phenotypes:
- name: Chronic Non-Spherocytic Hemolytic Anemia
  category: Hematological
  description: >-
    Often present from infancy and frequently transfusion-dependent, with
    reticulocytosis, indirect hyperbilirubinaemia and raised lactate
    dehydrogenase. It is not obligatory: one reported family had thermolabile
    disease with no haemolysis at all.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic non-spherocytic hemolytic anemia
    term:
      id: HP:0001930
      label: Nonspherocytic hemolytic anemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:14615364
    reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations included transfusion-dependent anemia until splenectomy at age 3 and increasing muscle weakness, with death at age 4 associated with rhabdomyolysis and hyperkalemia."
    explanation: Transfusion-dependent anaemia and its response to splenectomy in a molecularly confirmed patient.
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia."
    explanation: Three siblings with molecularly confirmed disease and no haemolytic anaemia, which refutes treating this phenotype as obligatory.
- name: Episodic Rhabdomyolysis
  category: Musculoskeletal
  description: >-
    Acute muscle breakdown provoked by fever or exertion, severe enough in
    reported cases to require haemodialysis and, in one patient, to be the
    terminal event.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
    temporality: RECURRENT
  evidence:
  - reference: PMID:33665120
    reference_title: "Aldolase A deficiency: Report of new cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cause hemolytic anemia and/or recurrent episodes of rhabdomyolysis, usually precipitated by fever"
    explanation: The recurrent, fever-precipitated character of the episodes across the reviewed cases.
  - reference: PMID:34171939
    reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we first report a patient with dermatological findings, hemodialysis requirement for rhabdomyolysis"
    explanation: Documents the severity an episode can reach.
  sequelae:
  - target: Myoglobinuria
    description: >-
      Myoglobin released by muscle breakdown appears in the urine and is the
      route to the renal risk that makes hydration urgent.
    evidence:
    - reference: PMID:25392908
      reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Myoglobinuria was always triggered by febrile illnesses."
      explanation: Myoglobinuria as the recorded manifestation of the episodes.
- name: Myoglobinuria
  category: Renal
  description: >-
    The urinary manifestation of an acute episode, and the finding that drives
    the renal-protective part of management.
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  evidence:
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myoglobinuria was always triggered by febrile illnesses."
    explanation: The observed myoglobinuria and its invariable trigger in this family.
- name: Elevated Creatine Kinase
  category: Biochemical
  description: >-
    Raised during and after episodes; in one reported patient the CK-MB fraction
    reached 5911 U/L.
  phenotype_term:
    preferred_term: Elevated serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CK-MB (5911 U/L) was significantly higher."
    explanation: A measured value in a molecularly confirmed patient.
- name: Muscle Weakness
  category: Musculoskeletal
  description: >-
    Present between episodes in some patients. Progression is documented in one
    severely affected case, whose weakness increased until death at age four;
    clinical_course is deliberately not set on the term, because a qualifier
    there would read as a property of the phenotype in general rather than of
    that single course.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:14615364
    reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transfusion-dependent anemia until splenectomy at age 3 and increasing muscle weakness"
    explanation: Documents weakness that increased over time rather than only during episodes.
- name: Seizure
  category: Neurological
  description: >-
    Reported in a 14-year-old as part of a newly described phenotype combining
    epilepsy with rhabdomyolysis.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35246226
    reference_title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe a new phenotype of the disease in a 14-year-old boy, characterized by seizures and rhabdomyolysis"
    explanation: The single report from which this phenotype is curated, and it is labelled a new phenotype by its own authors.
- name: Global Developmental Delay
  category: Neurodevelopmental
  description: >-
    Delayed milestones and intellectual delay have been reported in a subset of
    patients, alongside short stature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "described a child with hemolytic anemia, developmental delay, and dysmorphism but no rhabdomyolysis"
    explanation: >-
      Names developmental delay directly. The entry previously quoted a sentence
      about mild intellectual disability, which is a distinct HPO concept from
      global developmental delay and did not support this binding.
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had delayed motor milestones and, by the age of 3 years, she had proximal muscular discomfort and high creatinine kinase (CK)."
    explanation: >-
      The index case's own milestone delay, which is what the description's
      "delayed milestones" claim rests on.
- name: Brachymesophalangy and Symphalangism
  category: Skeletal
  description: >-
    Short middle phalanges with fused interphalangeal joints and fifth-digit
    clinodactyly, radiographically typed as brachymesophalangy A3. Reported in
    one patient and stated by that paper's authors to be previously unreported
    in this condition, so it is curated as a single novel observation rather
    than as an established feature. The binding names the middle phalanx of the
    fifth finger, which is what brachydactyly type A3 is by definition and what
    the exam and radiographs describe: short fifth fingers on examination and
    fifth-digit clinodactyly on X-ray. No HPO term for symphalangism of the hand
    is bound, so the name carries that half of the finding.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Brachymesophalangy type A3 with symphalangism
    term:
      id: HP:0004220
      label: Short middle phalanx of the 5th finger
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-rays revealed bilateral symphalangism of the second digits and clinodactyly of the fifth digits, indicating brachymesophalangy type A3"
    explanation: The radiographic finding and its type designation.
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient had intellectual delay along with the skeletal anomalies of brachymesophalangy and symphalangism, previously unreported in this condition."
    explanation: >-
      The authors' own statement of novelty, which is why the frequency band is
      the lowest available and why the description says single observation.
- name: Short Stature
  category: Growth
  description: >-
    Reported in a subset of patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients may also show metabolic abnormalities, short stature, or mild intellectual disability."
    explanation: Short stature named among the additional features seen in a subset.
- name: Hepatosplenomegaly
  category: Gastrointestinal
  description: >-
    Enlargement of liver and spleen, the latter consistent with chronic
    haemolysis.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination, she had pallor, icterus, hepatosplenomegaly, and skeletal abnormalities"
    explanation: Hepatosplenomegaly on examination in a molecularly confirmed patient.
treatments:
- name: Antipyresis During Febrile Illness
  description: >-
    The mechanistically motivated intervention, and a drug one. Because the
    enzyme fails as temperature rises, bringing a fever down acts on the lesion
    rather than only on symptoms. The cited source prescribes antipyretics
    without naming an agent or class, so none is asserted here.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:34171939
    reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment includes management of hemolytic anemia and administration of antipyretics during febrile episodes to avoid hemolysis and rhabdomyolysis."
    explanation: >-
      States antipyresis during fever as the preventive measure for both arms of
      the disease. Split out from trigger avoidance because this half is a drug
      intervention and the modality slot should say so.
  target_mechanisms:
  - target: Thermolability of Residual Aldolase A Activity
    treatment_effect: INHIBITS
    description: >-
      Lowering body temperature removes the condition under which the residual
      enzyme unfolds.
- name: Fever and Exertion Trigger Avoidance
  description: >-
    The non-pharmacological half: avoiding the exposures that precipitate
    decompensation, which for this disease are febrile illness and strenuous
    exercise. Both are curated as environmental triggers in this entry, so the
    avoidance is directed at named exposures rather than at general caution. No
    cited source evaluates avoidance as an intervention; it follows from the
    triggers.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34171939
    reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Treatment includes management of hemolytic anemia and administration of antipyretics during febrile episodes to avoid hemolysis and rhabdomyolysis."
    explanation: >-
      Indirect. The sentence establishes that fever is the exposure to be
      prevented, which is what makes avoidance sensible, but it prescribes a
      drug rather than avoidance and says nothing about exertion.
  target_mechanisms:
  - target: Thermolability of Residual Aldolase A Activity
    treatment_effect: INHIBITS
    description: >-
      Keeps the residual enzyme out of the temperature range in which it
      unfolds, by removing the exposure rather than by treating the fever.
- name: Blood Transfusion
  description: >-
    Supportive management of the haemolytic anaemia, which is transfusion
    dependent in a substantial share of reported patients.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Blood Transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient remains on intermittent transfusion support, folate supplementation, and physiotherapy."
    explanation: Documents ongoing transfusion support as the management of the anaemia.
  target_mechanisms:
  - target: Chronic Non-Spherocytic Hemolytic Anemia
    treatment_effect: RESTORES
    description: >-
      Transfusion replaces the red cell mass the haemolysis removes, without
      acting on the enzymatic lesion that causes it.
- name: Splenectomy
  description: >-
    Considered for transfusion-dependent haemolysis. In the one detailed report
    it ended transfusion dependence, though the patient's muscle disease
    continued to progress and was ultimately fatal.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  evidence:
  - reference: PMID:14615364
    reference_title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transfusion-dependent anemia until splenectomy at age 3"
    explanation: Records the point at which transfusion dependence ended.
  target_mechanisms:
  - target: Chronic Non-Spherocytic Hemolytic Anemia
    treatment_effect: INHIBITS
    description: >-
      Removing the spleen removes the site at which the fragile red cells are
      preferentially destroyed.
- name: Ketogenic Diet
  description: >-
    Proposed as a way to supply an energy substrate that bypasses the glycolytic
    block for muscle and brain. The evidence is a single patient, in whom it was
    combined with antiepileptic treatment and followed by no further episodes,
    so the two interventions cannot be separated.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Ketogenic Diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  evidence:
  - reference: PMID:35246226
    reference_title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "we propose a new therapeutic approach based on ketogenic diet in order to supply an energetic substrate for skeletal muscle and neurons"
    explanation: The proposal and its rationale. It is indirect because the reported outcome follows a combined dietary and antiepileptic regimen in one patient, so the diet's own contribution is not isolated.
  - reference: PMID:35246226
    reference_title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This led to a deceleration of the disease with no other acute episodes of seizures and rhabdomyolysis, without any side effects observed."
    explanation: The reported outcome, which the entry describes as attributable to the combined regimen rather than the diet alone.
  target_mechanisms:
  - target: Skeletal Myocyte Energy Failure Under Catabolic Stress
    treatment_effect: BYPASSES
    description: >-
      Ketone bodies enter energy metabolism downstream of the aldolase step, so
      they are proposed as a substrate that does not require the blocked
      reaction.
- name: Exercise Adaptation and Caution With Pre-Exercise Carbohydrate
  description: >-
    Lifestyle adaptation with carefully titrated exercise. The point worth
    flagging is that immediate pre-exercise carbohydrate, which helps in the
    glycogenolytic defects such as McArdle disease, can make glycolytic defects
    worse, and aldolase A deficiency is a glycolytic defect. The intuitive
    advice for a glycogen storage disease is the wrong advice here.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:30397902
    reference_title: "Myopathies Related to Glycogen Metabolism Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK)."
    explanation: The review states the principle for glycolytic defects using PFK as its example rather than ALDOA, so applying it here is an inference from the shared class of lesion.
  - reference: PMID:30397902
    reference_title: "Myopathies Related to Glycogen Metabolism Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise."
    explanation: The general management principle for this disease group.
  target_mechanisms:
  - target: Skeletal Myocyte Energy Failure Under Catabolic Stress
    treatment_effect: INHIBITS
    description: >-
      Titrating exertion keeps demand below the point at which the residual
      glycolytic capacity fails.
diagnosis:
- name: Molecular sequencing of ALDOA
  description: >-
    Definitive diagnosis. The erythrocyte aldolase activity assay exists but is
    not widely available, so in practice a metabolic-myopathy or
    hereditary-anaemia panel or exome sequencing is the route.
  evidence:
  - reference: PMID:34171939
    reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis should be confirmed by the mutation analysis of ALDOA gene."
    explanation: States that molecular confirmation is required.
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical exome sequencing revealed compound heterozygous pathogenic mutations in the ALDOA gene"
    explanation: Exome sequencing as the route that reached the diagnosis in practice.
- name: Recognizing the anaemia-plus-myopathy combination
  description: >-
    The diagnostic problem is that each half is unremarkable on its own. In one
    reported patient years passed under a working diagnosis of inflammatory
    myositis, treated with steroids and methotrexate, before the combination was
    read as a single metabolic disease.
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With a provisional diagnosis of inflammatory myositis, she was given a trial treatment of steroids and methotrexate, but the symptoms persisted."
    explanation: The misdiagnosis and its cost, which is what makes recognizing the combination a diagnostic step in its own right.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Roughly a dozen families have been reported since the first clinical
    description in 1977. No prevalence or incidence estimate exists, and none
    can be normalized from case reports.
  evidence:
  - reference: PMID:34171939
    reference_title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldolase A deficiency also known as glycogen storage disease (GSD) XII, is an ultra rare autosomal recessively inherited GSD"
    explanation: The ultra-rare classification; no numeric estimate is available in the cited literature.
differential_diagnoses:
- name: Other glycolytic and glycogenolytic myopathies
  description: >-
    Phosphofructokinase deficiency, phosphoglycerate mutase deficiency and
    beta-enolase deficiency share the exercise-induced rhabdomyolysis, and
    McArdle disease shares it from the glycogenolytic side. The discriminator
    that matters clinically is the response to pre-exercise carbohydrate, which
    separates the two halves of the group in opposite directions.
  evidence:
  - reference: PMID:30397902
    reference_title: "Myopathies Related to Glycogen Metabolism Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis"
    explanation: Places ALDOA within a group defined by shared clinical presentation but split by which half of the pathway is affected.
- name: Inflammatory myositis
  description: >-
    The label a patient with unexplained myopathy and raised creatine kinase
    receives by default, and the one that delayed a molecular diagnosis by years
    in a reported case.
  evidence:
  - reference: PMID:41199518
    reference_title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With a provisional diagnosis of inflammatory myositis, she was given a trial treatment of steroids and methotrexate, but the symptoms persisted."
    explanation: Documents the misdiagnosis this differential exists to prevent.
discussions:
- discussion_id: gsd12_arginine_rescue_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    By what mechanism does arginine rescue aldolase A deficiency in patient
    myoblasts, and does it work in patients?
  attaches_to:
  - pathophysiology#Thermolability of Residual Aldolase A Activity
  rationale: >-
    Arginine restored aldolase A activity in patient myoblasts while three other
    established chemical chaperones did not, which the authors take as evidence
    that it is not acting as a chaperone. What it is doing instead is unknown,
    and the result has not been tested in a patient. This is the only reported
    lead toward a mechanism-directed therapy for the disease, so the gap is
    worth naming rather than folding into supportive care.
  evidence:
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning."
    explanation: The rescue, the negative controls, and the authors' own statement that the mechanism is not chaperoning.
- discussion_id: gsd12_tissue_selective_thermolability
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is the thermolability of a mutant aldolase A tissue-selective, sparing
    erythrocytes in some families?
  attaches_to:
  - pathophysiology#Thermolability of Residual Aldolase A Activity
  rationale: >-
    The same protein is expressed in both affected tissues, so a purely
    intrinsic thermodynamic defect should affect both. One family had
    thermolability that affected myoblasts but not erythrocytes, which implies
    that something about the cellular context modulates the mutant enzyme's
    stability. Nothing in the reported literature identifies what. Until it is
    known, an entry cannot predict from genotype which of the two organs a given
    patient will present with.
  evidence:
  - reference: PMID:25392908
    reference_title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific."
    explanation: The authors state the tissue specificity as a suggestion, which is the uncertainty this gap records.
references:
- reference: PMID:2825199
  title: "Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation."
- reference: PMID:2229018
  title: "Human aldolase A of a hemolytic anemia patient with Asp-128----Gly substitution: characteristics of an enzyme generated in E. coli transfected with the expression plasmid pHAAD128G."
- reference: PMID:14615364
  title: "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)."
- reference: PMID:25392908
  title: "A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia."
- reference: PMID:33665120
  title: "Aldolase A deficiency: Report of new cases and literature review."
- reference: PMID:34171939
  title: "Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report."
- reference: PMID:35246226
  title: "A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report."
- reference: PMID:39223030
  title: "[Onset of Glycogen Storage Disease Type Ⅻ in Two Brothers in the Neonatal Period]."
- reference: PMID:41199518
  title: "Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII."
- reference: PMID:2335208
  title: "The crystal structure of human muscle aldolase at 3.0 A resolution."
- reference: PMID:18453690
  title: "Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant."
- reference: PMID:25982518
  title: "Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics."
- reference: PMID:30397902
  title: "Myopathies Related to Glycogen Metabolism Disorders."
notes: >-
  Deep-research provenance. Curated alongside an OpenScientist report
  (research/Glycogen_Storage_Disease_Due_To_Aldolase_A_Deficiency-deep-research-openscientist.md),
  whose structural-biology thread was its most useful contribution: the crystal
  structure of the D128V dimer variant and the normal-mode analysis of aldolase
  oligomeric states together explain why a substitution away from the active
  site produces a thermolabile enzyme, which is the mechanistic core of this
  entry. The report's causal chain was otherwise consistent with the primary
  literature.

  Two things in the report were not carried across. It cites Lowry and Hanson
  1977 (PMID:890096), the earliest clinical description, for the developmental
  and dysmorphic features. That record has no abstract available in PubMed, so
  no evidence item is drawn from it here and the subset features are evidenced
  from PMID:41199518 instead. The report also devotes a finding to ALDOA
  overexpression in cancer under HIF-1alpha; that is a gain-of-expression
  context in the opposite direction from this loss-of-function disease and is
  deliberately absent from the entry.

  Ontology labels. The report suggested HP:0003236 under the label "Elevated
  circulating creatine kinase activity", which is correct and is the label used
  here. An earlier version of this note had that backwards, asserting HPO had
  renamed the term to "Elevated circulating creatine kinase concentration": that
  was the stale string in `cache/hp/terms.csv`, which term validation reads
  first, so the report was overruled by a snapshot rather than by the ontology.
  Corrected corpus-wide under issue #12358. Several of its other suggested HPO labels were table column values such
  as "Lab / clinical sign" rather than term names, which is why its own term
  validation reported ten label mismatches without any of the CURIEs being
  wrong.

  The febrile trigger is deliberately left unbound. ECTO's temperature terms
  describe ambient exposure rather than endogenous fever, and binding one would
  assert the wrong exposure; the reasoning is recorded on the environmental
  entry itself.

  Related work. ALDOA appears in the IEMbase WP-007 package tracked in
  monarch-initiative/dismech#5562, whose repository audit in
  monarch-initiative/dismech#7801 lists it among the rows genuinely absent from
  the knowledge base. This entry covers that row.
📚

References & Deep Research

References

13
PMID:2825199
Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation.
No top-level findings curated for this source.
PMID:2229018
Human aldolase A of a hemolytic anemia patient with Asp-128----Gly substitution: characteristics of an enzyme generated in E. coli transfected with the expression plasmid pHAAD128G.
No top-level findings curated for this source.
PMID:14615364
Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr).
No top-level findings curated for this source.
PMID:25392908
A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia.
No top-level findings curated for this source.
PMID:33665120
Aldolase A deficiency: Report of new cases and literature review.
No top-level findings curated for this source.
PMID:34171939
Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report.
No top-level findings curated for this source.
PMID:35246226
A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report.
No top-level findings curated for this source.
PMID:39223030
[Onset of Glycogen Storage Disease Type Ⅻ in Two Brothers in the Neonatal Period].
No top-level findings curated for this source.
PMID:41199518
Beyond the Usual Suspects: Unexplained Childhood Hemolytic Anemia with Myopathy Unveiled as Glycogen Storage Disease Type XII.
No top-level findings curated for this source.
PMID:2335208
The crystal structure of human muscle aldolase at 3.0 A resolution.
No top-level findings curated for this source.
PMID:18453690
Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant.
No top-level findings curated for this source.
PMID:25982518
Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics.
No top-level findings curated for this source.
PMID:30397902
Myopathies Related to Glycogen Metabolism Disorders.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Deep-research provenance. Curated alongside an OpenScientist report (research/Glycogen_Storage_Disease_Due_To_Aldolase_A_Deficiency-deep-research-openscientist.md), whose structural-biology thread was its most useful contribution: the crystal structure of the D128V dimer variant and the normal-mode analysis of aldolase oligomeric states together explain why a substitution away from the active site produces a thermolabile enzyme, which is the mechanistic core of this entry. The report's causal chain was otherwise consistent with the primary literature. Two things in the report were not carried across. It cites Lowry and Hanson 1977 (PMID:890096), the earliest clinical description, for the developmental and dysmorphic features. That record has no abstract available in PubMed, so no evidence item is drawn from it here and the subset features are evidenced from PMID:41199518 instead. The report also devotes a finding to ALDOA overexpression in cancer under HIF-1alpha; that is a gain-of-expression context in the opposite direction from this loss-of-function disease and is deliberately absent from the entry. Ontology labels. The report suggested HP:0003236 under the label "Elevated circulating creatine kinase activity", which is correct and is the label used here. An earlier version of this note had that backwards, asserting HPO had renamed the term to "Elevated circulating creatine kinase concentration": that was the stale string in `cache/hp/terms.csv`, which term validation reads first, so the report was overruled by a snapshot rather than by the ontology. Corrected corpus-wide under issue #12358. Several of its other suggested HPO labels were table column values such as "Lab / clinical sign" rather than term names, which is why its own term validation reported ten label mismatches without any of the CURIEs being wrong. The febrile trigger is deliberately left unbound. ECTO's temperature terms describe ambient exposure rather than endogenous fever, and binding one would assert the wrong exposure; the reasoning is recorded on the environmental entry itself. Related work. ALDOA appears in the IEMbase WP-007 package tracked in monarch-initiative/dismech#5562, whose repository audit in monarch-initiative/dismech#7801 lists it among the rows genuinely absent from the knowledge base. This entry covers that row.

Create: Glycogen Storage Disease Due To Aldolase A Deficiency (GSD XII, ALDOA) · 2026-09-05T15:05:56Z · View source

New kb/disorders entry for GSD XII (MONDO:0012747), claimed via issue #11106. Curated around thermolability rather than simple enzyme loss: biallelic ALDOA variants destabilize the homotetramer (the D128V crystal structure is a catalytically active dimer that has lost one subunit interface), which makes residual activity temperature-dependent, which is why the disease is episodic and fever-triggered. The block at glycolysis step four then splits by tissue into an erythrocyte arm (no mitochondria, so no alternative ATP route, giving chronic non-spherocytic haemolytic anaemia) and a muscle arm (glycolysis-dependent only under stress, giving episodic rhabdomyolysis), with muscle glycogen accumulation recorded as the reason for the GSD nosology. Nine HPO-bound phenotypes, four variants, two environmental triggers with influences_mechanisms links, five treatments, and two KNOWLEDGE_GAP discussions (the unexplained non-chaperone arginine rescue; the unexplained tissue selectivity of thermolability). Deliberate negative evidence: the haemolytic anaemia phenotype carries a REFUTE item citing three siblings with molecularly confirmed disease and no anaemia, so the entry does not treat it as obligatory. Deep research: OpenScientist report committed; its structural-biology thread was the substantive contribution. Not carried across: PMID:890096 (Lowry 1977) has no PubMed abstract so no evidence item is drawn from it, and the report's ALDOA-in-cancer finding is a gain-of-expression context in the opposite direction and is excluded. The report's suggested HPO label for HP:0003236 was the retired 'activity' form; the current 'concentration' label is used. The febrile trigger is left unbound because ECTO's temperature terms describe ambient exposure, not endogenous fever, with the reasoning recorded on the environmental entry. Validation: schema pass, term validation pass, 58/58 snippets verified, check-entity-refs / check-causal-targets / check-duplicate-keys / check-enum-values / check-environmental-evidence clean.

OpenScientist ▸
Key Findings
openscientist-autonomous 16 citations 2026-09-05T14:26:06.249650

Key Findings

Finding 1 — GSD XII is caused by biallelic ALDOA mutations producing a thermolabile aldolase A enzyme

GSD XII is inherited in an autosomal-recessive manner; affected individuals carry two pathogenic ALDOA alleles while heterozygous parents are clinically unaffected. The first molecularly defined case, reported by Kishi and colleagues in 1987 (PMID: 2825199), carried a homozygous c.386A>G (p.Asp128Gly) substitution. This variant produces a highly thermolabile erythrocyte enzyme, a conclusion confirmed by recombinant expression in E. coli: "the 128th amino acid, aspartic acid, was replaced with glycine (GAT to GGT)." Subsequent site-directed-mutagenesis work (PMID: 2229018) established that aspartate at position 128 is required for thermal stability, since substitution rendered the enzyme thermolabile and susceptible to tryptic digestion, with CD spectra revealing conformational change.

The variant spectrum has since broadened. Yao et al. (2004; PMID: 14615364) described a severe compound-heterozygous case: "The paternal allele encoded a nonsense mutation, Arg303X, in the enzyme-active site. The maternal allele encoded a missense mutation, Cys338Tyr, predicted to cause enzyme instability." More recent reports added c.971C>T (p.Ala324Val) (Kara 2021; PMID: 34171939) and homozygous c.619G>A (p.Glu207Lys) in two affected brothers (Sun 2024; PMID: 39223030), where "the genotypes in the parents were heterozygous."

Variant table (reported pathogenic ALDOA alleles):

Variant (protein) cDNA Type Zygosity reported Key phenotype Reference
p.Asp128Gly c.386A>G Missense (thermolabile) Homozygous Hemolytic anemia PMID: 2825199
p.Glu207Lys c.619G>A Missense Homozygous Severe neonatal, multi-organ PMID: 39223030
p.Arg303X c.907C>T Nonsense (active site) Compound het Severe, fatal rhabdomyolysis PMID: 14615364
p.Cys338Tyr c.1013G>A Missense (destabilizing) Compound het Severe PMID: 14615364
p.Ala324Val c.971C>T Missense — Hemolytic anemia + rhabdomyolysis PMID: 34171939

Because loss-of-function and instability are the shared functional theme, the classification of these variants under ACMG/AMP criteria is pathogenic/likely pathogenic, supported by functional evidence (recombinant thermolability assays) and, for p.Arg303X, a null mechanism (nonsense at the active site).

Finding 2 — Aldolase A is a homotetrameric TIM-barrel enzyme; destabilizing mutations disrupt tetramer assembly

Human muscle aldolase A is a tetramer of four identical subunits, each folded as an eight-stranded α/β (TIM) barrel with an active-site Schiff-base lysine near the barrel center. The crystal structure of human muscle aldolase (Gamblin 1990; PMID: 2335208) established this architecture: "The active protein is a tetramer of 4 identical subunits each of which is composed of an eight-stranded alpha/beta-barrel structure."

The structural basis of disease was illuminated by the crystal structure of the D128V variant (an engineered mimic of the clinical D128G mutation) in rabbit muscle aldolase (Sherawat 2008; PMID: 18453690): "The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer." The mutation yields a catalytically active but destabilized dimer rather than the normal tetramer. This is consistent with the broader biophysical principle that oligomerization stabilizes aldolase and preserves the mobility of catalytic loops (elastic-network normal-mode analysis, PMID: 25982518): oligomeric assembly "not only stabilizes the aldolase structures… but also allows the enzyme to achieve the required dynamics for its functional loops." Loss of a subunit interface therefore both destabilizes the protein (explaining thermolability) and can impair catalytic dynamics.

Finding 3 — Clinical spectrum: fever/exercise-triggered rhabdomyolysis and hemolytic anemia with variable multisystem involvement

Across roughly ten published families, the recurring features are:

  • Chronic non-spherocytic hemolytic anemia — often transfusion-dependent, frequently improved by splenectomy (Yao 2004; PMID: 14615364: "transfusion-dependent anemia until splenectomy at age 3 and increasing muscle weakness, with death at age 4 associated with rhabdomyolysis and hyperkalemia").
  • Episodic rhabdomyolysis / myoglobinuria — triggered by febrile illness or exercise (Mamoune 2014; PMID: 25392908: "Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes.").
  • Muscle weakness, sometimes progressive (Yao 2004; PMID: 14615364).
  • Developmental/neurological features — developmental delay, intellectual disability, short stature, dysmorphic (midfacial hypoplasia) facies, hepatomegaly (Lowry 1977; PMID: 890096).
  • Newly expanded phenotypes — epilepsy/seizures (Santoro 2022; PMID: 35246226) and severe neonatal onset with asphyxia, myasthenia, myocardial damage, and anemia (Sun 2024; PMID: 39223030).

Crucially, the phenotype can dissociate: a thermolabile mutant caused isolated fever-induced recurrent rhabdomyolysis without hemolytic anemia (PMID: 25392908), because thermolability affected myoblasts but not erythrocytes — direct evidence of tissue-specific vulnerability and of variable expressivity.

Phenotype table with suggested HPO terms:

Phenotype Type HPO term Onset / severity Frequency (qualitative)
Non-spherocytic hemolytic anemia Lab / clinical sign HP:0004804 Childhood; mild–severe (transfusion-dependent) Common (cardinal)
Rhabdomyolysis (fever/exercise) Clinical event HP:0003201 Childhood; episodic, severe Common (cardinal)
Elevated creatine kinase Lab abnormality HP:0003236 With episodes Common
Myoglobinuria Lab / sign HP:0002913 With episodes Common
Muscle weakness Physical sign HP:0001324 Childhood; variable/progressive Variable
Developmental delay / intellectual disability Neurodevelopmental HP:0001263 / HP:0001249 Childhood Subset
Short stature Physical HP:0004322 Childhood Subset
Seizures / epilepsy Neurological HP:0001250 Childhood Rare/newly reported
Hepatomegaly Sign HP:0002240 Childhood Subset
Facial dysmorphism / midface hypoplasia Physical HP:0011800 Congenital Subset

Finding 4 — Pathophysiology: aldolase A deficiency blocks step 4 of glycolysis, causing ATP-depletion energy failure

Aldolase A (EC 4.1.2.13) catalyzes the reversible cleavage of fructose-1,6-bisphosphate into DHAP and glyceraldehyde-3-phosphate — the fourth step of glycolysis (Yao 2004; PMID: 14615364: "converts fructose-1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate"; Papadopoulos 2021; PMID: 33665120). Because it is the sole aldolase isozyme in erythrocytes and skeletal muscle, its deficiency directly lowers glycolytic ATP output in those tissues.

  • Red blood cells depend entirely on glycolysis for ATP (they lack mitochondria). Reduced/thermolabile aldolase shortens red-cell lifespan → chronic non-spherocytic hemolytic anemia.
  • Skeletal muscle relies heavily on glycolysis during febrile or exertional catabolic states. Thermolabile enzyme collapse during fever produces acute energy failure → rhabdomyolysis (PMID: 25392908).

Upstream substrate (F-1,6-BP) and glycolytic intermediates accumulate, and glycogen accumulates in muscle — the reason the disorder is classified as a glycogen storage disease (GSD XII) despite being an enzymopathy of glycolysis rather than glycogen breakdown per se. GSD XII sits within the broader family of muscle glycolytic-defect myopathies (PFK/Tarui, PGAM2, β-enolase, aldolase A) reviewed by Vissing and colleagues (PMID: 30397902), in which higher-intensity exercise provokes cramps and rhabdomyolysis and pre-exercise carbohydrate can worsen glycolytic (as opposed to glycogenolytic) defects.

Finding 5 — ALDOA gene identity, tissue expression, and a distinct oncologic (gain-of-expression) context

ALDOA (HGNC:414; NCBI Gene 226; chromosome 16p11.2; UniProt P04075; EC 4.1.2.13) encodes fructose-bisphosphate aldolase A, the predominant/sole isozyme in skeletal muscle and erythrocytes; ALDOB (liver/kidney) and ALDOC (brain) are the paralogous isozymes (PMID: 33665120: "Aldolase A (ALDOA), is the predominant isoform of aldolase in skeletal muscle and erythrocytes that catalyzes the reversible…").

Importantly, the Mendelian loss-of-function disease is mechanistically opposite to the gain-of-expression role of ALDOA in cancer. Under hypoxia, HIF-1α drives ALDOA overexpression, which acts as a glycolytic driver and "moonlighting" protein interacting with Wnt/β-catenin, EGFR/MAPK, Akt, and cytoskeletal partners, correlating with poor prognosis (Niu 2021; PMID: 33813748: "we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia"; Tang 2024; PMID: 39120781: "these enzymes also have various pathological and physiological functions through distinct signaling pathways such as Wnt/β-catenin, EGFR/MAPK, Akt, and HIF-1α"). This cancer literature is included for gene-annotation completeness only; it is not part of the GSD XII disease mechanism.

Finding 6 — Diagnosis relies on molecular ALDOA sequencing after a suggestive biochemical picture

Diagnostic clues combine (1) chronic non-spherocytic hemolytic anemia (reticulocytosis, low haptoglobin, elevated LDH and unconjugated bilirubin) and (2) episodic rhabdomyolysis with elevated creatine kinase and myoglobinuria during fever/exercise (PMID: 14615364; PMID: 34171939; PMID: 25392908). Reduced/thermolabile erythrocyte aldolase A activity can be demonstrated biochemically but the assay is not widely available. Definitive diagnosis is by molecular sequencing of ALDOA (Kara 2021; PMID: 34171939: "Diagnosis should be confirmed by the mutation analysis of ALDOA gene."). In practice, whole-exome sequencing or hereditary-anemia / metabolic-myopathy gene panels are the pragmatic route.

Differential diagnosis spans the other glycolytic erythroenzymopathies and metabolic myopathies:

Condition Gene Distinguishing feature
Pyruvate kinase deficiency PKLR Most common glycolytic hemolytic anemia; no rhabdomyolysis (PMID: 30681718)
Phosphofructokinase / Tarui (GSD VII) PFKM Exertional myopathy + hemolysis; carbohydrate worsens (PMID: 30397902)
Triosephosphate isomerase deficiency TPI1 Hemolysis + severe neurological disease
Phosphoglycerate kinase deficiency PGK1 X-linked; hemolysis + myopathy + CNS
Hexokinase deficiency HK1 Hemolysis ± neurological (PMID: 33361148)
McArdle disease (GSD V) PYGM Exertional rhabdomyolysis; no hemolysis (PMID: 30397902)
CPT II deficiency CPT2 Fasting/exercise rhabdomyolysis; no hemolysis

Finding 7 — Inheritance, epidemiology, and management

Inheritance is autosomal recessive: affected individuals carry two mutant alleles and heterozygous parents are unaffected (PMID: 39223030; consanguineous parents in PMID: 890096). The disorder is ultra-rare — fewer than ~15 families reported worldwide since 1977, and Orphanet classifies it as ultra-rare (Kara 2021; PMID: 34171939: "an ultra rare autosomal recessively inherited GSD"). No true prevalence or incidence figures are available. Both sexes are affected; consanguinity and founder homozygosity are noted in several families.

Management is entirely supportive — there is no curative therapy:

  • Aggressive fever control / antipyresis and avoidance of fasting and strenuous exercise (the main triggers).
  • Red-cell transfusions and splenectomy for hemolytic anemia.
  • Aggressive hydration and renal protection during rhabdomyolysis episodes.
  • Experimental/nutritional strategies: a ketogenic diet has been proposed to supply an alternative energy substrate to muscle and neurons (Santoro 2022; PMID: 35246226: "we propose a new therapeutic approach based on ketogenic diet in order to supply an energetic substrate for skeletal muscle and neurons"); and arginine rescued mutant enzyme activity in vitro as a chemical chaperone (PMID: 25392908).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic ALDOA mutation (missense/nonsense; e.g., D128G, E207K, R303X, C338Y, A324V) → altered aldolase A polypeptide. (demonstrated: sequencing across families)
  2. The mutation disrupts an intersubunit interface / destabilizes the fold → the enzyme fails to assemble a stable homotetramer, forming a destabilized dimer, and/or is intrinsically thermolabile. (demonstrated structurally for D128V, PMID: 18453690; biochemically for D128G, PMID: 2229018)
  3. Thermolability leads to loss of catalytic activity, worsened at elevated temperature (fever) → the fourth step of glycolysis (F-1,6-BP → DHAP + GAP) is blocked. (demonstrated: PMID: 25392908)
  4. Blocked glycolysis results in reduced ATP production in the two tissues where ALDOA is the only aldolase — erythrocytes and skeletal muscle. (inferred from enzymology + tissue expression)

Branch A — erythrocytes: ATP depletion shortens red-cell lifespan → chronic non-spherocytic hemolytic anemia → reticulocytosis, low haptoglobin, high LDH/bilirubin; splenic clearance of damaged cells (splenectomy helps). (demonstrated clinically)

Branch B — skeletal muscle: during fever or exercise, thermolabile-enzyme collapse causes acute energy failure and myofiber breakdown → rhabdomyolysis, elevated CK, myoglobinuria → risk of hyperkalemia and acute kidney injury. Glycogen accumulates upstream (hence "GSD"). (demonstrated clinically; PMID: 14615364)

Branch C — variable multisystem: in severe genotypes, energy failure may extend to neurons (developmental delay, seizures), heart (myocardial damage), and growth (short stature, dysmorphism). (inferred / associative; PMID: 39223030, PMID: 35246226)

   ALDOA mutation (biallelic)
    │
    ▼
   Destabilized / thermolabile aldolase A
   (tetramer → dimer; loss of interface)
    │  worsens with fever ↑T
    ▼
   Glycolysis step 4 blocked
   (F-1,6-BP ⟶ DHAP + GAP fails)
    │
    ▼
   ATP depletion in ALDOA-only tissues
┌───────────────┼─────────────────┐
▼               ▼                 ▼
   RBC (no mito)   Skeletal muscle    CNS/heart/growth
   hemolytic       fever/exercise-    (severe genotypes)
   anemia          triggered          DD, seizures,
   (HP:0004804)    rhabdomyolysis     myocardial damage
           (HP:0003201)

Upstream vs downstream

  • Upstream (initiating): ALDOA genotype and the resulting protein-stability defect.
  • Central node: temperature-dependent glycolytic block and ATP depletion.
  • Downstream (clinical): hemolysis, rhabdomyolysis, and secondary organ effects — all consequences of the same energetic lesion but with tissue-specific thresholds that explain phenotypic dissociation (e.g., muscle-only disease when a variant is thermolabile in myoblasts but not erythrocytes).

Ontology annotations

  • Gene/protein: ALDOA (HGNC:414), UniProt P04075.
  • GO biological process: glycolytic process (GO:0006096), canonical glycolysis (GO:0061621), fructose-bisphosphate aldolase activity (GO:0004332).
  • GO cellular component: cytosol (GO:0005829).
  • Cell types (CL): erythrocyte (CL:0000232), skeletal muscle fiber / myoblast (CL:0000188, CL:0000515).
  • Anatomy (UBERON): blood (UBERON:0000178), skeletal muscle tissue (UBERON:0001134); secondary — spleen (UBERON:0002106), kidney (UBERON:0002113), liver (UBERON:0002107), heart (UBERON:0000948), brain (UBERON:0000955).
  • Chemical entities (CHEBI): fructose-1,6-bisphosphate (CHEBI:78682), dihydroxyacetone phosphate (CHEBI:57642), glyceraldehyde-3-phosphate (CHEBI:59776), ATP (CHEBI:30616).
  • Treatment (NCIT): blood transfusion (NCIT:C15326), splenectomy (NCIT:C51749), ketogenic diet (NCIT:C92955).

Section-by-Section Detail

1. Disease Information

Aldolase A deficiency (GSD XII) is a Mendelian metabolic disorder defined by biallelic ALDOA pathogenic variants. Identifiers: MONDO:0012747; OMIM #611881; ORPHA:57; ICD-10 E74.0. Synonyms: "glycogen storage disease type XII", "GSD 12", "ALDOA deficiency", "red-cell/muscle aldolase deficiency", "hereditary aldolase A deficiency". Information is derived from aggregated disease-level resources plus individual case reports (there is no EHR-scale dataset given the rarity).

2. Etiology

The sole cause is genetic — biallelic loss-of-function/destabilizing ALDOA variants. There is no environmental or infectious cause. Recognized triggers of acute episodes (a true gene–environment interaction) are febrile illness, strenuous exercise, and fasting, which precipitate rhabdomyolysis by exacerbating the enzyme's thermolability/energetic marginality (PMID: 25392908). Consanguinity is a risk factor for homozygosity (PMID: 890096). No protective genetic or environmental factors are established.

3. Phenotypes

See Finding 3 and the HPO table above.

4. Genetic / Molecular Information

Causal gene ALDOA (16p11.2). Pathogenic variants are predominantly missense (thermolabile/destabilizing) with at least one nonsense allele (R303X). Functional consequence is loss of function via protein instability / impaired tetramer assembly. No modifier genes, epigenetic mechanisms, or chromosomal abnormalities are implicated. Allele frequencies for these private variants are effectively absent from gnomAD.

5. Environmental Information

None causal. Fever, exercise, and fasting are episode triggers (see Etiology). No toxins, radiation, occupational exposures, or infectious agents are involved.

6. Mechanism / Pathophysiology

See the ordered causal chain above.

7. Anatomical Structures Affected

  • Primary organs/tissues: blood/erythrocytes (UBERON:0000178; CL:0000232) and skeletal muscle (UBERON:0001134; CL:0000188).
  • Secondary involvement: spleen (hemolysis sequestration; UBERON:0002106), kidney (myoglobinuric AKI; UBERON:0002113), liver (hepatomegaly; UBERON:0002107), heart (myocardial damage in severe cases; UBERON:0000948), brain (developmental delay/seizures; UBERON:0000955).
  • Body systems: hematologic, musculoskeletal; secondarily renal, hepatic, cardiovascular, nervous.
  • Subcellular: cytosol (GO:0005829), where glycolysis occurs.
  • Lateralization: systemic/bilateral (not applicable as a focal lesion).

8. Temporal Development

Onset ranges from neonatal/congenital (severe multi-organ cases; PMID: 39223030) to childhood. Course is chronic and lifelong, punctuated by episodic acute rhabdomyolytic crises triggered by fever/exercise. Hemolytic anemia is chronic and may be transfusion-dependent until splenectomy. Critical intervention windows are during febrile illnesses (antipyresis) and metabolic stress.

9. Inheritance and Population

Autosomal recessive; ultra-rare (<15 families). No prevalence/incidence, sex ratio, or founder-population data beyond scattered consanguineous families. Penetrance appears complete in biallelic carriers; expressivity is highly variable. Carrier frequency is unknown but presumed very low.

10. Diagnostics

Biochemistry: hemolysis panel (reticulocytes↑, haptoglobin↓, LDH↑, bilirubin↑) and, during crises, CK↑↑ and myoglobinuria. Erythrocyte aldolase activity/thermolability assay (specialized). Confirmatory test: ALDOA sequencing (WES or hereditary-anemia/metabolic-myopathy panels). Differential diagnosis table above.

11. Outcome / Prognosis

Highly variable. Mild cases survive into adulthood with supportive care; severe compound-heterozygous or neonatal-onset cases can be fatal in early childhood (e.g., death at age 4 from rhabdomyolysis/hyperkalemia, PMID: 14615364). No quantitative survival statistics exist. Main morbidity drivers: recurrent rhabdomyolysis (renal risk), transfusion-dependent anemia, and neurodevelopmental impairment in a subset.

12. Treatment

Entirely supportive (see Finding 7). NCIT: blood transfusion (C15326), splenectomy (C51749), ketogenic diet (C92955). Experimental: ketogenic diet (PMID: 35246226), arginine chemical chaperone (PMID: 25392908). No approved pharmacotherapy, gene therapy, or enzyme replacement.

13. Prevention

Primary prevention is genetic counseling for at-risk/consanguineous families, with carrier testing and prenatal/preimplantation options once familial variants are known. Tertiary prevention (preventing crises/complications): antipyresis, trigger avoidance, prompt hydration during illness. No immunization or population screening applies.

14. Other Species / Natural Disease

Human orthologue Aldoa exists in mouse (NCBI Gene 11674) and other vertebrates, but no naturally occurring animal disease is documented. Aldolase is broadly conserved (structural/mechanistic studies exist in rabbit, parasites, bacteria, and yeast), but these are enzymology surrogates, not disease models. No zoonotic relevance.

15. Model Organisms

No faithful published knock-in mouse recapitulating the deficiency. Experimental systems: (1) recombinant human aldolase A variants in E. coli (thermolability characterization; PMID: 2229018), (2) patient-derived myoblasts (PMID: 25392908), and (3) rabbit muscle aldolase D128V crystal structures as a structural surrogate (PMID: 18453690). A constitutive Aldoa knockout is predicted to be embryonic-lethal, limiting straightforward whole-animal modeling.

Evidence Base

PMID Study / type How it supports the profile
2825199 Kishi 1987 — first molecular case (human clinical + in vitro) First pathogenic ALDOA missense (D128G) causing a thermolabile enzyme
2229018 Recombinant D128G characterization (in vitro) Asp128 required for thermal stability; mutant thermolabile, trypsin-susceptible, conformationally altered
14615364 Yao 2004 — compound het case (human clinical) R303X/C338Y; severe transfusion-dependent anemia + fatal rhabdomyolysis; defines enzymatic reaction
25392908 Mamoune 2014 (human clinical + in vitro) Thermolabile mutant → fever-induced rhabdomyolysis without hemolysis; tissue-specific thermolability; arginine rescue
34171939 Kara 2021 — new case + review (human clinical) Novel A324V; ultra-rare AR; molecular ALDOA testing is confirmatory
39223030 Sun 2024 — two brothers (human clinical) Homozygous E207K; severe neonatal multi-organ phenotype; AR inheritance confirmed in parents
35246226 Santoro 2022 — new phenotype (human clinical) Epilepsy + rhabdomyolysis; proposes ketogenic-diet therapy
890096 Lowry 1977 — first clinical description Growth/developmental retardation, midface hypoplasia, hepatomegaly; consanguineous parents
2335208 Gamblin 1990 — human aldolase crystal structure Homotetrameric TIM-barrel architecture
18453690 Sherawat 2008 — D128V variant structure Structural mechanism: mutation abolishes a tetramer interface → destabilized dimer
25982518 Aldolase dynamics (computational) Oligomerization stabilizes structure and preserves catalytic-loop dynamics
33665120 Papadopoulos 2021 — review Gene/protein identity, tissue distribution, reaction
30397902 Vissing — glycogen-metabolism myopathies review Places GSD XII in the glycolytic-myopathy family; management principles
33813748 / 39120781 ALDOA in cancer Contrasting gain-of-expression context (gene annotation only)

Evidence-source composition: the GSD XII literature is dominated by single-family human clinical case reports supplemented by in-vitro recombinant enzyme studies and X-ray crystallography (largely on rabbit muscle aldolase as a structural surrogate). No population cohorts, natural-history studies, or faithful animal models of the deficiency exist.

Limitations and Knowledge Gaps

  1. Extreme rarity → weak epidemiology. With <15 families, all prevalence, penetrance, expressivity, carrier-frequency, and sex-ratio statements are qualitative. Penetrance appears complete for biallelic carriers, but expressivity is highly variable and genotype–phenotype correlation is only partially defined.
  2. Genotype–phenotype correlation is incomplete. Why some variants cause muscle-only disease, others hemolysis-only, and others severe multisystem disease is only partly explained by tissue-specific thermolability; the biophysical determinants deserve systematic study.
  3. No approved disease-directed therapy. Ketogenic diet and arginine chaperone rescue are hypotheses from single reports and in-vitro work, not trial-validated.
  4. No faithful animal model, limiting mechanistic and preclinical therapeutic work.
  5. Diagnostic biochemistry is not standardized/widely available (erythrocyte aldolase thermolability assay), so diagnosis depends on access to sequencing.
  6. Literature retrieval limitation: several relevant case reports lacked machine-readable abstracts, so some clinical details rest on secondary review summaries rather than primary abstract quotes.

Proposed Follow-up Experiments / Actions

  1. Curate an international variant/phenotype registry. Systematically collect all published ALDOA deficiency cases into a ClinVar-linked table with per-variant thermostability (Tm), tissue-specific activity, and phenotype, to build genotype–phenotype and thermolability–severity correlations.
  2. Recombinant thermostability panel. Express each clinical variant (D128G, E207K, C338Y, A324V, R303X-null) and measure Tm, tetramer/dimer equilibrium (SEC-MALS), and activity at 37 °C vs 40 °C to quantitatively test the thermolability model and rank variant severity.
  3. Chemical-chaperone screen. Extend the arginine finding (PMID: 25392908) by screening osmolytes/pharmacological chaperones on patient myoblasts and recombinant enzyme, measuring rescue of activity and thermostability — a plausible repurposing route.
  4. Isogenic iPSC / knock-in model. Introduce patient variants into iPSCs and differentiate to erythroid and myogenic lineages to model tissue-specific ATP failure and test ketogenic/substrate-supplementation and chaperone interventions.
  5. Small pilot of ketogenic diet or trigger-avoidance protocols in known patients, with CK, hemolysis markers, and quality-of-life endpoints, coordinated through rare-disease networks.
  6. Structural work on the human (not rabbit) variants to confirm interface disruption for E207K, C338Y, and A324V and to guide chaperone design.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 17
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 35
Resolved 33
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 11
Terms named correctly 0
Terms named as a different term 10
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0004804 (2 mentions) - the report calls it "Lab / clinical sign"; HP calls it Congenital hemolytic anemia
  • HP:0003201 (2 mentions) - the report calls it "Clinical event"; HP calls it Rhabdomyolysis
  • HP:0003236 (1 mention) - the report calls it "Lab abnormality"; HP calls it Elevated circulating creatine kinase activity
  • HP:0002913 (1 mention) - the report calls it "Lab / sign"; HP calls it Myoglobinuria
  • HP:0001324 (1 mention) - the report calls it "Physical sign"; HP calls it Muscle weakness
  • HP:0004322 (1 mention) - the report calls it "Physical"; HP calls it Short stature
  • HP:0001250 (1 mention) - the report calls it "Neurological"; HP calls it Seizure
  • HP:0002240 (1 mention) - the report calls it "Sign"; HP calls it Hepatomegaly
  • HP:0011800 (1 mention) - the report calls it "Physical"; HP calls it Midface retrusion
  • GO:0005829 (2 mentions) - the report calls it "GO cellular component: cytosol", "Subcellular: cytosol"; GO calls it cytosol

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006096 (1 mention) - the report calls it "GO biological process: glycolytic process"; GO calls it glycolytic process**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HGNC:414 - called "ALDOA", "Gene/protein:* ALDOA"
  • GO:0005829 - called "GO cellular component: cytosol", "Subcellular: cytosol"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.