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Classifications

ICIMD (Inherited Metabolic Disorders)

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Mappings

MONDO

MONDO:0013047 glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals carry two loss-of-function LDHA alleles. Heterozygous parents and siblings have a partial reduction in M-subunit-containing isoenzymes on erythrocyte electrophoresis but are clinically asymptomatic, so carrier detection is biochemically possible. Expressivity among homozygotes for the same allele is variable: in one series four patients from two families carrying the identical 20-base-pair deletion differed markedly in symptom severity.

Autosomal recessive inheritance Penetrance: UNKNOWN Expressivity: VARIABLE

Show evidence (3 references)

PMID:36292720 SUPPORT Human Clinical

"LDH-A deficiency is an autosomal recessive disorder (glycogenosis type XI, OMIM#612933) caused by mutations in the LDHA gene."

States the mode of inheritance and the gene.

PMID:7449146 SUPPORT Human Clinical

"The ratio between H-subunit and M-subunit (H/M) in erythrocyte LDH suggested a partial absence of the M-subunit in two siblings and in the parents."

Documents the intermediate carrier state in obligate heterozygotes, the family-study evidence for recessive transmission.

PMID:7630349 SUPPORT Human Clinical

"We report the glycolytic features of 4 patients from 2 families in whom the severity of the disease differed. There was no difference in the gene abnormality."

Same genotype, different severity — the basis for recording variable expressivity.

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Discussions and Knowledge Gaps

2

How does loss of the LDH M subunit produce psoriasiform and pustular skin disease, and why only in some patients?

KNOWLEDGE GAP ldha_skin_mechanism

Attached to

pathophysiology#Epidermal and Follicular Glycolytic Failure phenotypes#Psoriasiform dermatitis

What is established is that the enzyme is missing from lesional epidermis and hair follicles, and that the eruption occurs in a minority of patients, sometimes decades after the muscle phenotype. What is not established is the step between the two. Keratinocytes are highly glycolytic, but no study has shown that a keratinocyte ATP or redox deficit drives the inflammatory phenotype, and the pustular cases were specifically reported as not carrying IL36RN variants, which excludes the obvious alternative explanation of coincidental generalised pustular psoriasis. The seasonal pattern — flares in warm months, remission in autumn — is unexplained by any current model.

Proposed experiments

Redox and inflammatory profiling of LDHA-null keratinocytes

ldha_keratinocyte_redox

Generate LDHA-null human keratinocytes by gene editing, culture them as organotypic epidermal equivalents under normal and raised temperature, and measure cytosolic NADH/NAD+ ratio, ATP, and release of psoriasis-associated cytokines including IL-36 family members and IL-17-inducing signals, comparing against isogenic controls.

Would support

pathophysiology#Epidermal and Follicular Glycolytic Failure

Would refute

pathophysiology#Epidermal and Follicular Glycolytic Failure

Supporting outcome

LDHA-null keratinocytes show a raised NADH/NAD+ ratio and lower ATP, and release psoriasis-associated cytokines in excess of isogenic controls, with the difference widening at raised temperature.

Refuting outcome

LDHA-null keratinocytes maintain normal redox state, ATP and cytokine output, which would mean the skin phenotype is not a direct keratinocyte energy or redox failure and some other cell type or systemic factor mediates it.

Is glycerol-3-phosphate dehydrogenase capacity the modifier that sets severity among patients with identical LDHA genotypes?

KNOWLEDGE GAP ldha_severity_modifier

Attached to

pathophysiology#Glycerol-3-Phosphate Shunt Compensation

Four patients from two families carrying the same 20-base-pair deletion differed markedly in severity, and the group that reported them found threefold higher muscle glycerol-3-phosphate dehydrogenase activity in the mildly affected patients. That is a plausible modifier and it is the only one proposed, but it rests on four patients and a correlation, with no genetic variant identified in GPD1 or elsewhere and no independent replication in the thirty years since. The alternative offered by the same group — that severity tracks muscle oxidative capacity — has the same evidential standing, and the two have never been separated.

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Pathophysiology

7

LDHA Loss and Muscle Lactate Dehydrogenase Deficiency

Biallelic LDHA variants abolish the M subunit of lactate dehydrogenase. The reported alleles are nulls — a recurrent 20-base-pair frameshifting deletion in exon 6, nonsense variants such as p.Ser137Ter and p.Trp250Ter, and a frameshifting deletion in exon 7 — and the truncated protein is degraded rather than made. Because functional LDH is a tetramer assembled from M and H subunits, losing M removes four of the five isoenzymes: only H4 (LDH-1) survives, so the serum isoenzyme pattern collapses to a single band. Residual LDH activity in skeletal muscle, where the M subunit normally predominates, falls below 5% of control.

skeletal muscle fiber CL:0008002

LDHA hgnc:6535

Genetic context LDHA hgnc:6535 allele_type: FRAMESHIFT variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Null alleles on both chromosomes. The most prevalent variant is a 20-base-pair deletion in exon 6 producing a premature stop; nonsense and other frameshifting alleles have the same consequence.

L-lactate dehydrogenase (NAD+) activity GO:0004459 ↓ DECREASED

Downstream

Cytosolic NADH Reoxidation Failure Loss of the pyruvate-to-lactate step removes the reaction that regenerates cytosolic NAD+ during anaerobic work.

Epidermal and Follicular Glycolytic Failure The same null alleles remove M-subunit LDH from epidermis and hair follicle, where enzyme histochemistry finds the tissue virtually devoid of activity. The edge is drawn from the enzyme loss itself rather than from the muscle ATP deficit, because no measurement establishes an ATP deficit in keratinocytes.

Show evidence (3 references)

PMID:2334430 SUPPORT Human Clinical

"The nucleotide sequences of seven protein-coding exons were determined and a deletion of 20 base-pairs in exon 6 was found. This mutation results in a frame-shift translation and premature termination."

Identifies the recurrent null allele and its frameshift consequence.

PMID:2334430 SUPPORT Human Clinical

"The predicted incomplete LDH-A (M) subunit containing only 259 instead of 331 amino acids appears to be degraded rapidly, since no protein was detected immunologically"

Establishes that the allele is a true null at the protein level rather than a hypomorph.

PMID:7630349 SUPPORT Human Clinical

"The enzyme activity of LDH in the muscle was less than 5% that of the control value."

Quantifies residual LDH activity in the target tissue.

Cytosolic NADH Reoxidation Failure

During high-intensity exercise, mitochondrial NADH oxidation cannot keep pace with glycolytic flux, and the LDH reaction is what regenerates cytosolic NAD+. Without it NADH accumulates and glyceraldehyde-3-phosphate dehydrogenase, which requires NAD+, is inhibited. Glycolysis is therefore retarded at that step, and the metabolites immediately above it — glyceraldehyde 3-phosphate, dihydroxyacetone phosphate and fructose 1,6-bisphosphate — accumulate. This is the reason the lactate curve on a forearm exercise test is flat while pyruvate rises steeply: pyruvate is produced but cannot be reduced.

glycolytic process GO:0006096 ↓ DECREASED pyruvate metabolic process GO:0006090 ⚠ ABNORMAL

Downstream

Glycerol-3-Phosphate Shunt Compensation Accumulating NADH is partly reoxidized by cytosolic alpha-glycerophosphate dehydrogenase instead.

Abortive Glycolysis and Muscle ATP Deficit A retarded pathway yields less ATP per unit time under anaerobic conditions.

Show evidence (3 references)

PMID:3383424 SUPPORT Human Clinical

"Glycolysis was markedly retarded in the patient's muscle in the glyceraldehyde 3-phosphate dehydrogenase (GA3PD) step."

Locates the block in the pathway, measured in patient muscle.

PMID:3383424 SUPPORT Human Clinical

"The glycolysis retardation may be attributed to the impaired reoxidation of NADH produced by GA3PD action."

States the redox mechanism by which loss of LDH inhibits the upstream dehydrogenase step.

PMID:3383424 SUPPORT Human Clinical

"The response to ischemic forearm work is characteristic in these three families: an increase of venous lactate concentration after ischemic work was not observed and a marked increase of venous pyruvate was found."

The in vivo consequence of the block, and the basis of the diagnostic exercise test.

Glycerol-3-Phosphate Shunt Compensation

Skeletal muscle cytosol is rich in alpha-glycerophosphate (glycerol 3-phosphate) dehydrogenase, which reoxidizes NADH by reducing dihydroxyacetone phosphate. This partially rescues the redox imbalance, but at a cost: it drains triose phosphates out of glycolysis, so the pathway becomes abortive rather than merely slow. How much of this shunt a patient has appears to set how severe the disease is — muscle glycerol-3-phosphate dehydrogenase activity was three times control in mildly affected patients and the sum of muscle pyruvate plus lactate was 65% of control in the mild group against 35% in the severe group, despite an identical LDHA genotype.

glycerol-3-phosphate metabolic process GO:0006072 ↑ INCREASED

Downstream

Abortive Glycolysis and Muscle ATP Deficit Draining triose phosphates makes the glycolytic pathway abortive, lowering ATP yield even as it relieves the redox block.

Show evidence (2 references)

PMID:3383424 SUPPORT Human Clinical

"This enzyme reoxidizes the excess NADH and drains triose phosphates from the glycolytic pathway under anaerobic conditions."

Describes both halves of the compensation: redox rescue and loss of glycolytic intermediates.

PMID:7630349 SUPPORT Human Clinical

"These findings suggest that the disease severity in our patients may be related to the degree of NADH reoxidation by glycerol 3-phosphate dehydrogenase substituting for LDH."

Links the size of the shunt to clinical severity, which is why this compensation is modelled as its own node rather than folded into the block.

Abortive Glycolysis and Muscle ATP Deficit

The net result is that skeletal muscle cannot generate ATP anaerobically at the rate that brief maximal effort demands. Oxidative metabolism is intact — maximal oxygen uptake is 73-92% of control and the respiratory exchange ratio rises normally above 1.0 — so endurance activity is tolerated and the deficit is specific to short, high-intensity, anaerobic work. Muscle compensates by activating AMP deaminase, which is why the ammonium response to a forearm exercise test is exaggerated to 25-30 times baseline while the lactate response is flat.

skeletal muscle fiber CL:0008002

ATP metabolic process GO:0046034 ↓ DECREASED

Animal models

Drosophila Ldh null larva (Ldh16/Ldh17) Drosophila melanogaster partially recapitulates Loss of LDH leaves the animal normal at rest and failing under sustained physical demand, which is the defining shape of the human node: an ATP deficit that appears only when glycolytic flux must be sustained anaerobically.

Downstream

Exercise intolerance The ATP deficit at maximal anaerobic effort is what limits short, high-intensity work, whether or not any fibre is injured.

Exertional Myocyte Injury Energy failure during maximal contraction damages the sarcolemma.

Uterine Smooth Muscle Energy Failure The same anaerobic deficit in myometrium during sustained labour contractions.

Show evidence (3 references)

PMID:3383424 SUPPORT Human Clinical

"For this reason, ATP production was significantly impaired and muscle cells were damaged in these patients."

States the energetic deficit and its immediate cellular consequence.

PMID:7549132 SUPPORT Human Clinical

"These findings suggest that in these patients, the oxidative functions of glycogenolysis in which pyruvate is required for fuel of maximal oxidative metabolism are preserved, and that disease severity may be related to the degree of muscle oxidative capacity."

Establishes that oxidative metabolism is preserved, which is why the deficit is confined to anaerobic effort.

PMID:36292720 SUPPORT Human Clinical

"The high increase in ammonium (Figure 2, ammonium increase of 25-30X, normal: 5-10X) can be explained as the result of the increased activity of AMPD, to compensate for the muscle energetic deficit during intense exertion in the context of LDH deficiency"

The purine-nucleotide-cycle compensation, and the second half of the characteristic exercise-test signature.

Exertional Myocyte Injury

Damaged fibres release their cytosolic contents — creatine kinase and myoglobin — into the circulation, producing the biochemical and clinical picture of rhabdomyolysis. The structural correlate on biopsy is subtle: rare subsarcolemmal vacuoles, with LDHA immunostaining showing intracytoplasmic aggregates instead of the normal diffuse pattern, which has been described as a metabolic-driven vacuolar myopathy. Crucially the injury is episodic and exertion-dependent; between episodes patients are neurologically and biochemically much closer to normal, and there is no fixed weakness or atrophy.

skeletal muscle fiber CL:0008002

Downstream

Rhabdomyolysis

Myoglobinuria

Elevated circulating creatine kinase concentration

Myalgia

Show evidence (3 references)

PMID:3383424 SUPPORT Human Clinical

"Consequently, the cytosolic enzymes and proteins such as creatine kinase and myoglobin were released into the blood stream."

Directly reports sarcolemmal leak of CK and myoglobin as the consequence of the energy deficit.

PMID:3383424 SUPPORT Human Clinical

"Otherwise, patients with a lactate dehydrogenase M-subunit deficiency do not show muscle stiffness and myoglobinuria under ordinary circumstances."

Establishes that injury is confined to anaerobic exertion, the defining episodic character of the myopathy.

PMID:40033989 SUPPORT Human Clinical

"Immunostaining with the antibody targeting LDHA showed intracytoplasmic aggregates of the protein unlike the normal control that presented a diffuse staining."

The histological correlate in patient muscle; note the aggregates are of the mutant protein product, not of glycogen.

Epidermal and Follicular Glycolytic Failure

The second affected tissue is skin. Epidermal keratinocytes and the hair follicle depend heavily on glycolysis, and direct enzyme histochemistry in an affected patient found the epidermis of the lesional skin and the scalp hair follicles virtually devoid of LDH activity. The clinical result is a psoriasis-like eruption — erythematosquamous plaques on extensor surfaces, annular erythema, or frankly pustular psoriasiform lesions — that characteristically flares in warm weather and remits in autumn. Not every patient develops it, and in some it appears decades after the muscle phenotype is diagnosed, so it is best treated as a late and variable manifestation of the same enzyme defect rather than an obligate feature. The mechanism connecting the LDH deficit to psoriasiform inflammation is not established.

keratinocyte CL:0000312 hair follicular keratinocyte CL:2000092

L-lactate dehydrogenase (NAD+) activity GO:0004459 ↓ DECREASED

Downstream

Psoriasiform dermatitis

Show evidence (2 references)

PMID:1999544 SUPPORT Human Clinical

"The epidermis of the diseased skin and scalp hair follicles of the patient were virtually devoid of LDH activity."

Direct tissue evidence that the enzyme defect is present in the affected skin, linking the cutaneous phenotype to the same deficiency.

PMID:27450766 SUPPORT Human Clinical

"These cases indicate that abnormal activity of LDH can induce pustular psoriatic lesions in the long term."

Supports the causal link from the enzyme defect to the pustular skin phenotype, with the authors' own long-latency caveat.

Uterine Smooth Muscle Energy Failure

Myometrial contraction in labour is sustained and substantially anaerobic, so the same ATP deficit appears in the uterus. Affected women report frequent uterine pains with raised serum pyruvate in the third trimester, and reported deliveries have required caesarean section because of the risk of dystocia from a uterus that stiffens rather than contracts effectively. This is the clearest example of the disorder affecting a muscle other than skeletal.

uterine smooth muscle cell CL:0002601

Downstream

Uterine stiffness and pain in pregnancy

Show evidence (2 references)

PMID:12078970 SUPPORT Human Clinical

"A woman with lactate dehydrogenase M-subunit deficiency underwent two cesarean sections because of the risk of dystocia due to decreased adenosine triphosphate production in anaerobic glycolysis including uterine muscles."

Attributes the obstetric complication to the same anaerobic ATP deficit in myometrium.

PMID:12078970 SUPPORT Human Clinical

"Frequent pains with increased serum pyruvate levels were observed during the third trimester of her pregnancies."

Couples the clinical uterine symptom to the biochemical signature of the block.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Genitourinary 2

Myoglobinuria FREQUENT HP:0002913

Band assigned from the three families of PMID:3383424 (3 of 3 with exertional myoglobinuria) together with cases reporting only a single or no pigmenturia episode; no pooled denominator exists.

Sequelae: Acute kidney injury

Show evidence (2 references)

PMID:7449146 SUPPORT Human Clinical

"The propositus was an 18-year-old male who complained of exertional pigmenturia and easy fatigue."

The index presentation of the disorder.

PMID:3383424 SUPPORT Human Clinical

"Three families with a complete deficiency of the lactate dehydrogenase M subunit show exertional myoglobinuria."

Exertional myoglobinuria in all three families of the defining series.

Acute kidney injury VERY_RARE HP:0001919

Reported as a possible complication in review, referenced to individual case reports; no published patient series reports a rate. Band reflects that it is the exception among reported myoglobinuric episodes rather than a counted proportion.

Show evidence (1 reference)

PMID:36292720 SUPPORT Human Clinical

"Myoglobinuria may lead to acute renal failure [7,8]."

Records acute renal failure as a recognised consequence of the myoglobinuric episodes.

Immune 1

Psoriasiform dermatitis OCCASIONAL HP:0003765

Temporal: RECURRENT

Band from PMID:27450766, which counted 2 of approximately 12 published cases with pustular psoriasis-like lesions, becoming 3 with that report; one of the two probands in PMID:36292720 had psoriasis-like dermatitis. Counting all reported cutaneous morphologies together would raise the estimate, and the true proportion is uncertain in so small a literature.

Show evidence (2 references)

PMID:36292720 SUPPORT Human Clinical

"Several skin lesions have been documented to be associated with the disease, such as desquamating erythematosquamous lesions, pustular psoriasis-like lesions, and annular erythematous plaques"

Enumerates the reported cutaneous morphologies of the disorder.

PMID:27450766 SUPPORT Human Clinical

"Hereditary lactate dehydrogenase (LDH) M-subunit deficiency is very rare and we have found reports of close to a dozen cases in the published work, two of which were associated with pustular psoriasis-like lesions."

Gives the numerator and denominator behind the frequency band: two of about a dozen published cases had pustular psoriasiform lesions at the time of that report.

Metabolism 1

Elevated circulating creatine kinase concentration VERY_FREQUENT Elevated circulating creatine kinase activity HP:0003236

Band assigned from both probands of PMID:36292720 having basal CK two to five times reference, plus the index family of PMID:7449146. No larger denominator is available.

Show evidence (1 reference)

PMID:7449146 SUPPORT Human Clinical

"Marked discrepancy was observed in the ratio between creatine kinase and lactate dehydrogenase (CK/LDH)."

The CK/LDH discrepancy that distinguishes this myopathy from other causes of raised CK.

Musculoskeletal 1

Rhabdomyolysis FREQUENT HP:0003201

Temporal: RECURRENT

Band reflects that recurrent rhabdomyolysis is reported in most but not all published patients; the 2025 case of PMID:40033989 had only one episode of dark urine. Numerators and denominators are per-family case reports rather than a series.

Show evidence (1 reference)

PMID:7630349 SUPPORT Human Clinical

"Recurrent rhabdomyolysis due to decreased glycolysis occurred during strenuous exercise by patients with lactate dehydrogenase-A subunit (LDH-A; muscle) deficiency."

States the recurrent, exertion-triggered character of the muscle breakdown.

Constitutional 2

Exercise intolerance VERY_FREQUENT HP:0003546

Band assigned from the review statement that exercise intolerance characterises the clinical presentation, and from its presence in both probands of PMID:36292720 (2 of 2). No cohort large enough to compute a real proportion has been published.

Show evidence (1 reference)

PMID:36292720 SUPPORT Human Clinical

"The clinical presentation of LDHA deficiency is characterized by exercise intolerance, with cramps, myalgia, and myoglobinuria due to rhabdomyolysis after strenuous exercise"

Names exercise intolerance as the leading clinical feature of the disorder.

Myalgia VERY_FREQUENT HP:0003326

Band assigned from the three families of PMID:3383424 and both probands of PMID:36292720, in all of whom exertional muscle pain or rigidity was present. No denominator large enough for a precise proportion exists.

Show evidence (1 reference)

PMID:3383424 SUPPORT Human Clinical

"They complain of muscle rigidity and sudden myoglobinuria after strenous exercise under anaerobic conditions."

Describes the exertional pain and stiffness in the three originally reported families.

Other 1

Uterine stiffness and pain in pregnancy OCCASIONAL

Only affected women who have been pregnant can express this, and the published pregnancies are few, so the band is a coarse statement about the whole patient population rather than a rate among pregnancies. Among reported pregnancies in affected women the feature appears to be usual, not occasional. No phenotype_term is bound because HPO was searched and has nothing for myometrial pain, uterine stiffness or dystocia from failed myometrial contraction: the nearest terms are Uterine rupture (HP:0100718), Uterine prolapse (HP:0000139) and Shoulder dystocia (HP:0011413), none of which name this finding, and there is no term for uterine atony, abnormal myometrial contraction or labour dystocia at all. This is a new-term-request candidate rather than an unfinished binding.

Show evidence (2 references)

PMID:36292720 SUPPORT Human Clinical

"Furthermore, uterine pain and stiffness have been reported in pregnant patients"

Reports uterine pain and stiffness as a recognised feature of pregnancy in this disorder.

PMID:36292720 SUPPORT Human Clinical

"and all labors were reported to require caesarean section."

Records the delivery outcome across the reported pregnancies, which is what makes this obstetrically actionable.

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Genetic Associations

1

LDHA

Gene: LDHA hgnc:6535 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:36292720 SUPPORT Human Clinical

"We identified in the LDHA gene a homozygous c.410C>A substitution that predicts a p.Ser137Ter nonsense mutation in Patient One and a compound heterozygous c.410C>A (p.Ser137Ter) and c.750G>A (p.Trp250Ter) nonsense mutation in Patient Two."

Documents two nonsense alleles segregating with the phenotype in two families.

PMID:40033989 SUPPORT Human Clinical

"Exome analysis revealed a novel bi-allelic frameshifting deletion in exon 7 of the LDHA gene; c.766_767delGT."

A further biallelic null allele, extending the mutational spectrum beyond the Japanese and Spanish families.

PMID:7603529 SUPPORT Human Clinical

"Genomic analysis revealed the heterogeneities of the mutations of this disease."

States that the disorder is allelically heterogeneous rather than caused by a single founder variant.

Variants (3)

20-base-pair deletion in exon 6

FRAMESHIFT

The most prevalent reported allele. Frameshift and premature termination yield a 259-residue product that is not detectable immunologically.

NM_005566:c.410C>A (p.Ser137Ter)

NONSENSE

Found homozygous in one Spanish proband and compound heterozygous with c.750G>A in a second, on a shared haplotype.

NM_005566:c.766_767delGT

FRAMESHIFT

Homozygous exon 7 frameshift in a consanguineous North African family, with myopathy and severe treatment-resistant acne.

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Medical Actions

3

Avoidance of maximal anaerobic exertion

Action: activity modification to avoid anaerobic exertion Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

The only management with a mechanistic rationale. Because the defect is confined to anaerobic ATP supply and oxidative capacity is preserved, endurance and moderate activity are tolerated while short maximal efforts — sprinting, competitive contact sport, isometric loading — are what precipitate rhabdomyolysis. Patients are advised to pace effort and to seek care for dark urine. This is standard metabolic myopathy advice rather than an LDHA-specific intervention tested in a trial.

Mechanism Target:

Exertional Myocyte Injury — Removing the anaerobic trigger prevents the energy failure that damages the fibre; it does not correct the enzyme deficiency.

Show evidence (1 reference)

PMID:3383424 SUPPORT INDIRECT Human Clinical

"Otherwise, patients with a lactate dehydrogenase M-subunit deficiency do not show muscle stiffness and myoglobinuria under ordinary circumstances."

Establishes that symptoms are confined to anaerobic exertion, from which avoidance follows as a mechanism-based measure; no trial has tested the advice itself, so the support is indirect.

Show evidence (1 reference)

PMID:7549132 SUPPORT Human Clinical

"Maximal oxygen uptake in the patients with severe and mild symptoms was approximately 73% and 92% of control."

Near-normal aerobic capacity is why the advice restricts anaerobic effort specifically rather than exercise in general.

Supportive management of rhabdomyolysis episodes

Action: Supportive Care NCIT:C15747

Platform: Other

Acute episodes are managed as rhabdomyolysis from any cause: intravenous fluids to protect renal function, monitoring of creatine kinase and renal function, and rest until recovery. There is no disease-specific acute therapy.

Target Phenotypes: Acute kidney injury HP:0001919

Show evidence (1 reference)

PMID:36292720 SUPPORT Human Clinical

"Myoglobinuria may lead to acute renal failure [7,8]."

The complication that supportive management of an episode is intended to prevent.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal recessive transmission with a 25% sibling recurrence risk. Counseling of affected women should also cover the obstetric risk, since reported pregnancies have involved third-trimester uterine pain and delivery by caesarean section.

Show evidence (1 reference)

PMID:12078970 SUPPORT Human Clinical

"A woman with lactate dehydrogenase M-subunit deficiency underwent two cesarean sections because of the risk of dystocia due to decreased adenosine triphosphate production in anaerobic glycolysis including uterine muscles."

The obstetric risk that counseling of affected women needs to cover.

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Biochemical Markers

1

Serum LDH isoenzyme pattern restricted to LDH-1 (H4)

Show evidence (2 references)

PMID:7449146 SUPPORT Human Clinical

"Electrophoretic analysis of serum LDH isoenzymes of the propositus demonstrated only one activity band of LDH H4."

The isoenzyme finding that defines M-subunit deficiency biochemically.

PMID:36292720 SUPPORT Human Clinical

"the isoenzyme pattern of the patients revealed a complete absence of the isoenzymes containing the M subunit, showing only one band of the LDH-1 (H4) isoenzyme"

Confirms the same isoenzyme signature in genetically characterised modern patients.

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Diagnosis

2

Forearm exercise test with lactate, pyruvate and ammonium

The functional test of choice. In an affected patient the venous lactate curve is flat, as it is in McArdle disease, but pyruvate rises steeply instead — that pyruvate rise is what separates a terminal glycolytic block from a glycogenolytic one. The ammonium response is exaggerated, around 25 to 30 times baseline against a normal 5 to 10 times, because AMP deaminase is recruited to compensate.

Show evidence (2 references)

PMID:3383424 SUPPORT Human Clinical

"The response to ischemic forearm work is characteristic in these three families: an increase of venous lactate concentration after ischemic work was not observed and a marked increase of venous pyruvate was found."

Describes the flat-lactate, high-pyruvate response that is the functional diagnostic signature.

PMID:36292720 SUPPORT Human Clinical

"Moreover, a flat lactate curve on the forearm exercise test, along with the clinical combination of myopathy and psoriatic-like dermatitis, can also lead to the diagnosis."

Confirms the exercise test plus the muscle-and-skin combination as the route to diagnosis in current practice.

LDHA sequencing

Biallelic LDHA variants confirm the diagnosis. In practice the gene is reached through a metabolic myopathy panel or exome; the common differential genes PYGM and CPT2 are excluded in the same test.

Show evidence (1 reference)

PMID:36292720 SUPPORT Human Clinical

"To identify the genetic causes of patient phenotypes, we performed a customized NGS panel including 32 genes associated with metabolic myopathies."

Describes the panel-based route by which the diagnosis is now made.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population rate has been estimated. Counting is by reported family: about 14 families with altered LDHA activity as of 2022, most of them Japanese, with the first description in 1980. Because affected individuals are well unless they exercise hard, and because serum total LDH can read normal, the condition is likely to be under-ascertained.

Show evidence (2 references)

PMID:36292720 SUPPORT Human Clinical

"14 different families with altered LDHA activity have been reported."

The published family count that supports the ultra-rare classification.

PMID:40033989 SUPPORT Human Clinical

"There are very few cases described in the literature and there is limited awareness of this condition that can easily be misdiagnosed or remain undiagnosed."

Supports both the rarity and the under-ascertainment caveat recorded in the notes.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Glycogen Storage Disease Due To Lactate Dehydrogenase M-subunit Deficiency:

McArdle disease (GSD V, PYGM)

Overlapping Features The closest mimic: exercise intolerance, exertional rhabdomyolysis and a flat lactate curve on the forearm test. The discriminator is pyruvate — it rises steeply in LDHA deficiency because the block is below pyruvate, and does not in McArdle disease because the block is at glycogen breakdown, above it. McArdle disease also shows a second-wind phenomenon, which LDHA deficiency does not, and has no cutaneous phenotype.

Show evidence (1 reference)

PMID:36292720 SUPPORT Human Clinical

"Overall, the main difference in the lactate stress test results of patients with LDHA deficiency compared with those with the very common glycogenosis (i.e., GSD V) is the high response of pyruvate, as the lactate response is similar in both diseases"

States exactly which measurement distinguishes the two disorders.

Fanconi-Bickel syndrome (SLC2A2)

Overlapping Features Not a clinical mimic but a nomenclature one: it also carries the label GSD XI in much of the literature. It is a hepatorenal glycogenosis with hepatomegaly, proximal tubulopathy and rickets, with no exertional myopathy. Any citation whose title says "glycogen storage disease XI" needs to be checked against the gene before use.

Carnitine palmitoyltransferase II deficiency

Overlapping Features Also causes recurrent exertional rhabdomyolysis, but triggered by prolonged endurance exercise, fasting or fever rather than brief maximal effort, with a normal lactate response to the forearm test and an abnormal acylcarnitine profile.

Complete LDH-B (H-subunit) deficiency

Overlapping Features The reciprocal enzyme defect. It also produces an abnormal serum isoenzyme pattern but is clinically silent, with no myopathy, and must not be conflated with M-subunit deficiency when an isoenzyme report is abnormal.

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Animal Models

1

Drosophila Ldh null larva (Ldh16/Ldh17)

Drosophila expresses a single LDH enzyme, so a trans-heterozygous null removes lactate dehydrogenase activity outright. Null larvae are viable at rest but die when forced to move continuously, and are slower in goal-directed crawling; a rescuing Ldh transgene abolishes both effects. This is currently the only published whole-organism model that reproduces the exertion-dependent character of the human disease.

Species

Drosophila melanogaster

Genotype

Ldh16/Ldh17 trans-heterozygous null

Publication

PMID:42465323

Pathograph links

Abortive Glycolysis and Muscle ATP Deficit partially recapitulates fidelity: moderate Loss of LDH leaves the animal normal at rest and failing under sustained physical demand, which is the defining shape of the human node: an ATP deficit that appears only when glycolytic flux must be sustained anaerobically.

Limitations: Drosophila has one LDH rather than the M/H subunit system, so the model cannot reproduce the tissue-restricted deficiency, the surviving H4 isoenzyme, or the diagnostic serum isoenzyme pattern that define the human disease. The endpoint is larval death during forced movement, which has no human counterpart -- LDHA-deficient people are exercise intolerant, not at risk of death from exertion -- and the authors report that muscle-specific rescue does not restore viability, so the fly phenotype is not muscle-autonomous in the way the human myopathy is. The NAD+-regeneration mechanism that would link this model to the node is offered as an interpretation, not measured. Neither rhabdomyolysis nor myoglobinuria is assayed.

Readouts

Survival during forced-movement exertion challenge

Direction: DECREASED

Interpretation: Exertion-dependent failure, absent at rest and absent in the transgenic rescue, is the model's closest correlate of the human exercise intolerance.

Show evidence (1 reference)

PMID:42465323 SUPPORT Model Organism

"Whereas controls and Ldh mutants expressing the rescuing transgene showed no lethality up to 40 minutes of stimulation, Ldh mutants began dying within 10 minutes, and all animals died by 50 minutes (Figure 4B)."

The measurement itself, with the rescue transgene as the internal control that ties it to Ldh loss.

Crawling speed and time to reach a food source

Direction: DECREASED

Interpretation: Baseline locomotor impairment, measured separately from the exertion challenge; it shows the deficit is not confined to extreme effort.

Show evidence (1 reference)

PMID:42465323 SUPPORT Model Organism

"In both assays, Ldh mutants were significantly delayed in reaching the yeast (Figure 4D) and crawled more slowly than control or rescue (Figure 4E)."

Quantifies the locomotor phenotype against both a genetic control and the rescue.

Show evidence (1 reference)

PMID:42465323 SUPPORT Model Organism

"This exertion-dependent phenotype closely parallels the clinical presentation of LDHA deficiency in humans, where symptoms such as muscle pain, weakness, and rhabdomyolysis are typically triggered by physical activity rather than evident at rest"

The authors' own statement of what the model is informative for, which is the exertion dependence rather than the myopathy itself.

Notes

PMID:42465323 is a bioRxiv preprint and has not been peer reviewed; the model is recorded with that caveat rather than withheld, because it is the only organism-level model of this disease in the literature. No mouse model of GSD XI exists: a PubMed search for Ldha-deficient mice with a muscle or exercise phenotype returns cancer and metabolism studies plus a 1987 hemolytic-anaemia mouse mutant (PMID:3315726), none of which model the human exertional myopathy.

{ }

Source YAML

click to show

name: Glycogen Storage Disease Due To Lactate Dehydrogenase M-subunit Deficiency
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: glycogen storage disease due to lactate dehydrogenase M-subunit deficiency
  term:
    id: MONDO:0013047
    label: glycogen storage disease due to lactate dehydrogenase M-subunit deficiency
synonyms:
- GSD XI
- GSD11
- glycogen storage disease type 11
- glycogenosis due to lactate dehydrogenase M-subunit deficiency
- lactate dehydrogenase A deficiency
- LDH-A deficiency
- LDHA deficiency
- hereditary lactate dehydrogenase M-subunit deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013047
      label: glycogen storage disease due to lactate dehydrogenase M-subunit deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- disorder of glycogen metabolism
- disorder of glycolysis
classifications:
  icimd_category:
  - classification_value: glycolysis
    notes: >-
      The enzymatic block is at the terminal step of anaerobic glycolysis rather
      than in glycogen synthesis or degradation, so the ICIMD placement is
      glycolysis even though the disorder carries a glycogen storage disease
      number.
    evidence:
    - reference: PMID:36292720
      reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        LDH plays a key role in anaerobic glycolysis as it regenerates
        nicotinamide adenine dinucleotide (NAD+) from NADH to provide ATP in
        situations where mitochondrial NADH oxidation cannot match the glycolysis
        rate
      explanation: >-
        Places the defective enzyme within anaerobic glycolysis, which is the
        basis for the ICIMD glycolysis category.
description: >-
  Lactate dehydrogenase M-subunit deficiency, numbered glycogen storage disease
  type XI, is an ultra-rare autosomal recessive metabolic myopathy caused by
  biallelic loss-of-function variants in LDHA. LDHA encodes the M (muscle)
  subunit of lactate dehydrogenase, the enzyme that closes anaerobic glycolysis
  by reducing pyruvate to lactate and, in doing so, regenerates the NAD+ that
  glyceraldehyde-3-phosphate dehydrogenase needs to keep the pathway running.
  Without it, muscle cannot sustain anaerobic ATP production: patients are
  entirely well at rest and during ordinary activity, but short bursts of
  high-intensity exercise produce myalgia, stiffness, and episodes of
  rhabdomyolysis with myoglobinuria. The diagnostic signature is a flat lactate
  curve on the forearm exercise test with a marked rise in pyruvate — the
  opposite of the substrate that accumulates in McArdle disease — together with
  a serum LDH isoenzyme pattern reduced to the single H4 (LDH-1) band. A minority
  of patients develop distinctive skin disease, most often erythematosquamous or
  pustular psoriasis-like lesions that flare in warm months, and affected women
  report uterine stiffness and pain in late pregnancy with dystocia at delivery.
  Fewer than twenty families have been reported since the first Japanese
  description in 1980.
notes: >-
  Numbering conflict. "GSD XI" denotes two different diseases in the literature.
  It was first applied to Fanconi-Bickel syndrome (SLC2A2/GLUT2), a hepatorenal
  glycogenosis with proximal tubulopathy, and was later reassigned to LDHA
  deficiency. This entry is the LDHA disease (OMIM 612933) and has nothing to do
  with SLC2A2. Papers titled "glycogen storage disease XI" must be checked for
  which of the two they mean before being cited here; at least one recent
  therapeutic paper using that exact title is about Fanconi-Bickel syndrome. The
  kb/groupings/Glycogen_Storage_Diseases.yaml grouping records the same conflict
  and currently lists only the Fanconi-Bickel entry; adding this entry as a
  member of that grouping is a reasonable follow-up but is deliberately not done
  in the same change.

  Scope. LDHB (the H subunit, heart type) and LDHC (testis) are separate genes
  and are not modelled here. Complete LDH-B deficiency is a distinct and largely
  asymptomatic biochemical trait.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  penetrance: UNKNOWN
  description: >-
    Affected individuals carry two loss-of-function LDHA alleles. Heterozygous
    parents and siblings have a partial reduction in M-subunit-containing
    isoenzymes on erythrocyte electrophoresis but are clinically asymptomatic,
    so carrier detection is biochemically possible. Expressivity among
    homozygotes for the same allele is variable: in one series four patients from
    two families carrying the identical 20-base-pair deletion differed markedly
    in symptom severity.
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LDH-A deficiency is an autosomal recessive disorder (glycogenosis type XI,
      OMIM#612933) caused by mutations in the LDHA gene.
    explanation: >-
      States the mode of inheritance and the gene.
  - reference: PMID:7449146
    reference_title: Hereditary deficiency of lactate dehydrogenase M-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ratio between H-subunit and M-subunit (H/M) in erythrocyte LDH
      suggested a partial absence of the M-subunit in two siblings and in the
      parents.
    explanation: >-
      Documents the intermediate carrier state in obligate heterozygotes, the
      family-study evidence for recessive transmission.
  - reference: PMID:7630349
    reference_title: Characterization of the glycolysis in lactate dehydrogenase-A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the glycolytic features of 4 patients from 2 families in whom the
      severity of the disease differed. There was no difference in the gene
      abnormality.
    explanation: >-
      Same genotype, different severity — the basis for recording variable
      expressivity.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population rate has been estimated. Counting is by reported family: about
    14 families with altered LDHA activity as of 2022, most of them Japanese,
    with the first description in 1980. Because affected individuals are well
    unless they exercise hard, and because serum total LDH can read normal, the
    condition is likely to be under-ascertained.
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      14 different families with altered LDHA activity have been reported.
    explanation: >-
      The published family count that supports the ultra-rare classification.
  - reference: PMID:40033989
    reference_title: "Glycogenosis type XI, a rare association between muscle and skin manifestations - the contribution of proteomics for the understanding of the underlying myopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are very few cases described in the literature and there is limited
      awareness of this condition that can easily be misdiagnosed or remain
      undiagnosed.
    explanation: >-
      Supports both the rarity and the under-ascertainment caveat recorded in the
      notes.
pathophysiology:
- name: LDHA Loss and Muscle Lactate Dehydrogenase Deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic LDHA variants abolish the M subunit of lactate dehydrogenase. The
    reported alleles are nulls — a recurrent 20-base-pair frameshifting deletion
    in exon 6, nonsense variants such as p.Ser137Ter and p.Trp250Ter, and a
    frameshifting deletion in exon 7 — and the truncated protein is degraded
    rather than made. Because functional LDH is a tetramer assembled from M and H
    subunits, losing M removes four of the five isoenzymes: only H4 (LDH-1)
    survives, so the serum isoenzyme pattern collapses to a single band. Residual
    LDH activity in skeletal muscle, where the M subunit normally predominates,
    falls below 5% of control.
  genes:
  - preferred_term: LDHA
    term:
      id: hgnc:6535
      label: LDHA
  genetic_context:
    gene:
      preferred_term: LDHA
      term:
        id: hgnc:6535
        label: LDHA
    allele_type: FRAMESHIFT
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Null alleles on both chromosomes. The most prevalent variant is a
      20-base-pair deletion in exon 6 producing a premature stop; nonsense and
      other frameshifting alleles have the same consequence.
  molecular_functions:
  - preferred_term: L-lactate dehydrogenase (NAD+) activity
    modifier: DECREASED
    term:
      id: GO:0004459
      label: L-lactate dehydrogenase (NAD+) activity
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:2334430
    reference_title: Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nucleotide sequences of seven protein-coding exons were determined and
      a deletion of 20 base-pairs in exon 6 was found. This mutation results in a
      frame-shift translation and premature termination.
    explanation: >-
      Identifies the recurrent null allele and its frameshift consequence.
  - reference: PMID:2334430
    reference_title: Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The predicted incomplete LDH-A (M) subunit containing only 259 instead of
      331 amino acids appears to be degraded rapidly, since no protein was
      detected immunologically
    explanation: >-
      Establishes that the allele is a true null at the protein level rather than
      a hypomorph.
  - reference: PMID:7630349
    reference_title: Characterization of the glycolysis in lactate dehydrogenase-A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The enzyme activity of LDH in the muscle was less than 5% that of the
      control value.
    explanation: >-
      Quantifies residual LDH activity in the target tissue.
  downstream:
  - target: Cytosolic NADH Reoxidation Failure
    causal_link_type: DIRECT
    description: >-
      Loss of the pyruvate-to-lactate step removes the reaction that regenerates
      cytosolic NAD+ during anaerobic work.
  - target: Epidermal and Follicular Glycolytic Failure
    causal_link_type: DIRECT
    description: >-
      The same null alleles remove M-subunit LDH from epidermis and hair follicle,
      where enzyme histochemistry finds the tissue virtually devoid of activity.
      The edge is drawn from the enzyme loss itself rather than from the muscle
      ATP deficit, because no measurement establishes an ATP deficit in
      keratinocytes.
- name: Cytosolic NADH Reoxidation Failure
  biological_scale: MOLECULAR
  description: >-
    During high-intensity exercise, mitochondrial NADH oxidation cannot keep pace
    with glycolytic flux, and the LDH reaction is what regenerates cytosolic
    NAD+. Without it NADH accumulates and glyceraldehyde-3-phosphate
    dehydrogenase, which requires NAD+, is inhibited. Glycolysis is therefore
    retarded at that step, and the metabolites immediately above it —
    glyceraldehyde 3-phosphate, dihydroxyacetone phosphate and fructose
    1,6-bisphosphate — accumulate. This is the reason the lactate curve on a
    forearm exercise test is flat while pyruvate rises steeply: pyruvate is
    produced but cannot be reduced.
  biological_processes:
  - preferred_term: glycolytic process
    modifier: DECREASED
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: pyruvate metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006090
      label: pyruvate metabolic process
  evidence:
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glycolysis was markedly retarded in the patient's muscle in the
      glyceraldehyde 3-phosphate dehydrogenase (GA3PD) step.
    explanation: >-
      Locates the block in the pathway, measured in patient muscle.
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The glycolysis retardation may be attributed to the impaired reoxidation of
      NADH produced by GA3PD action.
    explanation: >-
      States the redox mechanism by which loss of LDH inhibits the upstream
      dehydrogenase step.
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The response to ischemic forearm work is characteristic in these three
      families: an increase of venous lactate concentration after ischemic work
      was not observed and a marked increase of venous pyruvate was found.
    explanation: >-
      The in vivo consequence of the block, and the basis of the diagnostic
      exercise test.
  downstream:
  - target: Glycerol-3-Phosphate Shunt Compensation
    causal_link_type: DIRECT
    description: >-
      Accumulating NADH is partly reoxidized by cytosolic
      alpha-glycerophosphate dehydrogenase instead.
  - target: Abortive Glycolysis and Muscle ATP Deficit
    causal_link_type: DIRECT
    description: >-
      A retarded pathway yields less ATP per unit time under anaerobic
      conditions.
- name: Glycerol-3-Phosphate Shunt Compensation
  biological_scale: MOLECULAR
  description: >-
    Skeletal muscle cytosol is rich in alpha-glycerophosphate (glycerol
    3-phosphate) dehydrogenase, which reoxidizes NADH by reducing
    dihydroxyacetone phosphate. This partially rescues the redox imbalance, but at
    a cost: it drains triose phosphates out of glycolysis, so the pathway becomes
    abortive rather than merely slow. How much of this shunt a patient has appears
    to set how severe the disease is — muscle glycerol-3-phosphate dehydrogenase
    activity was three times control in mildly affected patients and the sum of
    muscle pyruvate plus lactate was 65% of control in the mild group against 35%
    in the severe group, despite an identical LDHA genotype.
  biological_processes:
  - preferred_term: glycerol-3-phosphate metabolic process
    modifier: INCREASED
    term:
      id: GO:0006072
      label: glycerol-3-phosphate metabolic process
  evidence:
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This enzyme reoxidizes the excess NADH and drains triose phosphates from
      the glycolytic pathway under anaerobic conditions.
    explanation: >-
      Describes both halves of the compensation: redox rescue and loss of
      glycolytic intermediates.
  - reference: PMID:7630349
    reference_title: Characterization of the glycolysis in lactate dehydrogenase-A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that the disease severity in our patients may be
      related to the degree of NADH reoxidation by glycerol 3-phosphate
      dehydrogenase substituting for LDH.
    explanation: >-
      Links the size of the shunt to clinical severity, which is why this
      compensation is modelled as its own node rather than folded into the block.
  downstream:
  - target: Abortive Glycolysis and Muscle ATP Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Draining triose phosphates makes the glycolytic pathway abortive, lowering
      ATP yield even as it relieves the redox block.
- name: Abortive Glycolysis and Muscle ATP Deficit
  biological_scale: CELLULAR
  description: >-
    The net result is that skeletal muscle cannot generate ATP anaerobically at
    the rate that brief maximal effort demands. Oxidative metabolism is intact —
    maximal oxygen uptake is 73-92% of control and the respiratory exchange ratio
    rises normally above 1.0 — so endurance activity is tolerated and the deficit
    is specific to short, high-intensity, anaerobic work. Muscle compensates by
    activating AMP deaminase, which is why the ammonium response to a forearm
    exercise test is exaggerated to 25-30 times baseline while the lactate
    response is flat.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: ATP metabolic process
    modifier: DECREASED
    term:
      id: GO:0046034
      label: ATP metabolic process
  evidence:
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For this reason, ATP production was significantly impaired and muscle cells
      were damaged in these patients.
    explanation: >-
      States the energetic deficit and its immediate cellular consequence.
  - reference: PMID:7549132
    reference_title: Characterization of the oxidative metabolism in lactate dehydrogenase A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that in these patients, the oxidative functions of
      glycogenolysis in which pyruvate is required for fuel of maximal oxidative
      metabolism are preserved, and that disease severity may be related to the
      degree of muscle oxidative capacity.
    explanation: >-
      Establishes that oxidative metabolism is preserved, which is why the deficit
      is confined to anaerobic effort.
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The high increase in ammonium (Figure 2, ammonium increase of 25-30X,
      normal: 5-10X) can be explained as the result of the increased activity of
      AMPD, to compensate for the muscle energetic deficit during intense exertion
      in the context of LDH deficiency
    explanation: >-
      The purine-nucleotide-cycle compensation, and the second half of the
      characteristic exercise-test signature.
  downstream:
  - target: Exercise intolerance
    causal_link_type: DIRECT
    description: >-
      The ATP deficit at maximal anaerobic effort is what limits short,
      high-intensity work, whether or not any fibre is injured.
  - target: Exertional Myocyte Injury
    causal_link_type: DIRECT
    description: >-
      Energy failure during maximal contraction damages the sarcolemma.
  - target: Uterine Smooth Muscle Energy Failure
    causal_link_type: DIRECT
    description: >-
      The same anaerobic deficit in myometrium during sustained labour
      contractions.
- name: Exertional Myocyte Injury
  biological_scale: TISSUE
  description: >-
    Damaged fibres release their cytosolic contents — creatine kinase and
    myoglobin — into the circulation, producing the biochemical and clinical
    picture of rhabdomyolysis. The structural correlate on biopsy is subtle:
    rare subsarcolemmal vacuoles, with LDHA immunostaining showing intracytoplasmic
    aggregates instead of the normal diffuse pattern, which has been described as a
    metabolic-driven vacuolar myopathy. Crucially the injury is episodic and
    exertion-dependent; between episodes patients are neurologically and
    biochemically much closer to normal, and there is no fixed weakness or
    atrophy.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consequently, the cytosolic enzymes and proteins such as creatine kinase
      and myoglobin were released into the blood stream.
    explanation: >-
      Directly reports sarcolemmal leak of CK and myoglobin as the consequence of
      the energy deficit.
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Otherwise, patients with a lactate dehydrogenase M-subunit deficiency do not
      show muscle stiffness and myoglobinuria under ordinary circumstances.
    explanation: >-
      Establishes that injury is confined to anaerobic exertion, the defining
      episodic character of the myopathy.
  - reference: PMID:40033989
    reference_title: "Glycogenosis type XI, a rare association between muscle and skin manifestations - the contribution of proteomics for the understanding of the underlying myopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunostaining with the antibody targeting LDHA showed intracytoplasmic
      aggregates of the protein unlike the normal control that presented a diffuse
      staining.
    explanation: >-
      The histological correlate in patient muscle; note the aggregates are of the
      mutant protein product, not of glycogen.
  downstream:
  - target: Rhabdomyolysis
  - target: Myoglobinuria
  - target: Elevated circulating creatine kinase concentration
  - target: Myalgia
- name: Epidermal and Follicular Glycolytic Failure
  biological_scale: TISSUE
  description: >-
    The second affected tissue is skin. Epidermal keratinocytes and the hair
    follicle depend heavily on glycolysis, and direct enzyme histochemistry in an
    affected patient found the epidermis of the lesional skin and the scalp hair
    follicles virtually devoid of LDH activity. The clinical result is a
    psoriasis-like eruption — erythematosquamous plaques on extensor surfaces,
    annular erythema, or frankly pustular psoriasiform lesions — that
    characteristically flares in warm weather and remits in autumn. Not every
    patient develops it, and in some it appears decades after the muscle
    phenotype is diagnosed, so it is best treated as a late and variable
    manifestation of the same enzyme defect rather than an obligate feature. The
    mechanism connecting the LDH deficit to psoriasiform inflammation is not
    established.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: hair follicular keratinocyte
    term:
      id: CL:2000092
      label: hair follicular keratinocyte
  molecular_functions:
  - preferred_term: L-lactate dehydrogenase (NAD+) activity
    modifier: DECREASED
    term:
      id: GO:0004459
      label: L-lactate dehydrogenase (NAD+) activity
  evidence:
  - reference: PMID:1999544
    reference_title: "Hereditary lactate dehydrogenase M-subunit deficiency: lactate dehydrogenase activity in skin lesions and in hair follicles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The epidermis of the diseased skin and scalp hair follicles of the patient
      were virtually devoid of LDH activity.
    explanation: >-
      Direct tissue evidence that the enzyme defect is present in the affected
      skin, linking the cutaneous phenotype to the same deficiency.
  - reference: PMID:27450766
    reference_title: Hereditary lactate dehydrogenase M-subunit deficiency with late-developing pustular psoriasis-like lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases indicate that abnormal activity of LDH can induce pustular
      psoriatic lesions in the long term.
    explanation: >-
      Supports the causal link from the enzyme defect to the pustular skin
      phenotype, with the authors' own long-latency caveat.
  downstream:
  - target: Psoriasiform dermatitis
- name: Uterine Smooth Muscle Energy Failure
  biological_scale: TISSUE
  description: >-
    Myometrial contraction in labour is sustained and substantially anaerobic, so
    the same ATP deficit appears in the uterus. Affected women report frequent
    uterine pains with raised serum pyruvate in the third trimester, and reported
    deliveries have required caesarean section because of the risk of dystocia
    from a uterus that stiffens rather than contracts effectively. This is the
    clearest example of the disorder affecting a muscle other than skeletal.
  cell_types:
  - preferred_term: uterine smooth muscle cell
    term:
      id: CL:0002601
      label: uterine smooth muscle cell
  evidence:
  - reference: PMID:12078970
    reference_title: "Pregnancy complicated with lactate dehydrogenase M-subunit deficiency: the first case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A woman with lactate dehydrogenase M-subunit deficiency underwent two
      cesarean sections because of the risk of dystocia due to decreased adenosine
      triphosphate production in anaerobic glycolysis including uterine muscles.
    explanation: >-
      Attributes the obstetric complication to the same anaerobic ATP deficit in
      myometrium.
  - reference: PMID:12078970
    reference_title: "Pregnancy complicated with lactate dehydrogenase M-subunit deficiency: the first case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frequent pains with increased serum pyruvate levels were observed during
      the third trimester of her pregnancies.
    explanation: >-
      Couples the clinical uterine symptom to the biochemical signature of the
      block.
  downstream:
  - target: Uterine stiffness and pain in pregnancy
phenotypes:
- name: Exercise intolerance
  category: Musculoskeletal
  description: >-
    Poor tolerance of short, high-intensity effort specifically. Patients are
    typically athletic and asymptomatic in ordinary life; symptoms appear with
    sprinting, judo, football, or a school exercise test. There is no second-wind
    phenomenon of the kind seen in McArdle disease.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation of LDHA deficiency is characterized by exercise
      intolerance, with cramps, myalgia, and myoglobinuria due to rhabdomyolysis
      after strenuous exercise
    explanation: >-
      Names exercise intolerance as the leading clinical feature of the disorder.
  notes: >-
    Band assigned from the review statement that exercise intolerance
    characterises the clinical presentation, and from its presence in both
    probands of PMID:36292720 (2 of 2). No cohort large enough to compute a real
    proportion has been published.
- name: Myalgia
  category: Musculoskeletal
  description: >-
    Muscle pain and stiffness during or immediately after intense exertion, often
    lasting days and eased by gentle movement of the affected segment.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They complain of muscle rigidity and sudden myoglobinuria after strenous
      exercise under anaerobic conditions.
    explanation: >-
      Describes the exertional pain and stiffness in the three originally
      reported families.
  notes: >-
    Band assigned from the three families of PMID:3383424 and both probands of
    PMID:36292720, in all of whom exertional muscle pain or rigidity was present.
    No denominator large enough for a precise proportion exists.
- name: Rhabdomyolysis
  category: Musculoskeletal
  description: >-
    Episodes of muscle breakdown triggered by anaerobic exertion, with markedly
    raised creatine kinase. Episodes are self-limited and recovery is complete
    between them.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:7630349
    reference_title: Characterization of the glycolysis in lactate dehydrogenase-A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent rhabdomyolysis due to decreased glycolysis occurred during
      strenuous exercise by patients with lactate dehydrogenase-A subunit (LDH-A;
      muscle) deficiency.
    explanation: >-
      States the recurrent, exertion-triggered character of the muscle breakdown.
  notes: >-
    Band reflects that recurrent rhabdomyolysis is reported in most but not all
    published patients; the 2025 case of PMID:40033989 had only one episode of
    dark urine. Numerators and denominators are per-family case reports rather
    than a series.
- name: Myoglobinuria
  category: Renal
  description: >-
    Dark or pigmented urine after strenuous exercise, the presenting complaint in
    the first reported patient and the feature that most often prompts referral.
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  frequency: FREQUENT
  evidence:
  - reference: PMID:7449146
    reference_title: Hereditary deficiency of lactate dehydrogenase M-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The propositus was an 18-year-old male who complained of exertional
      pigmenturia and easy fatigue.
    explanation: >-
      The index presentation of the disorder.
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three families with a complete deficiency of the lactate dehydrogenase M
      subunit show exertional myoglobinuria.
    explanation: >-
      Exertional myoglobinuria in all three families of the defining series.
  notes: >-
    Band assigned from the three families of PMID:3383424 (3 of 3 with exertional
    myoglobinuria) together with cases reporting only a single or no pigmenturia
    episode; no pooled denominator exists.
  sequelae:
  - target: Acute kidney injury
    causal_link_type: DIRECT
    description: >-
      Pigment nephropathy from a severe myoglobinuric episode; the complication
      is of the episode, not of the enzyme defect at rest.
- name: Elevated circulating creatine kinase concentration
  category: Musculoskeletal
  description: >-
    Creatine kinase is raised acutely during episodes and is often mildly raised
    at baseline (two to five times the upper reference limit), so
    hyper-CK-aemia can be the finding that starts the diagnostic workup. The
    ratio of creatine kinase to total LDH is characteristically discrepant,
    because total LDH stays deceptively normal.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:7449146
    reference_title: Hereditary deficiency of lactate dehydrogenase M-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Marked discrepancy was observed in the ratio between creatine kinase and
      lactate dehydrogenase (CK/LDH).
    explanation: >-
      The CK/LDH discrepancy that distinguishes this myopathy from other causes
      of raised CK.
  notes: >-
    Band assigned from both probands of PMID:36292720 having basal CK two to five
    times reference, plus the index family of PMID:7449146. No larger denominator
    is available.
- name: Psoriasiform dermatitis
  category: Integumentary
  description: >-
    A distinctive eruption reported in a minority of patients: desquamating
    erythematosquamous plaques on extensor surfaces, annular erythematous
    plaques, or pustular psoriasis-like lesions. It classically appears in spring
    and remits in autumn, and it can develop decades after the muscle diagnosis.
    A patient with treatment-resistant severe truncal acne has also been
    reported.
  phenotype_term:
    preferred_term: Psoriasiform dermatitis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
    temporality: RECURRENT
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several skin lesions have been documented to be associated with the
      disease, such as desquamating erythematosquamous lesions, pustular
      psoriasis-like lesions, and annular erythematous plaques
    explanation: >-
      Enumerates the reported cutaneous morphologies of the disorder.
  - reference: PMID:27450766
    reference_title: Hereditary lactate dehydrogenase M-subunit deficiency with late-developing pustular psoriasis-like lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary lactate dehydrogenase (LDH) M-subunit deficiency is very rare
      and we have found reports of close to a dozen cases in the published work,
      two of which were associated with pustular psoriasis-like lesions.
    explanation: >-
      Gives the numerator and denominator behind the frequency band: two of about
      a dozen published cases had pustular psoriasiform lesions at the time of
      that report.
  notes: >-
    Band from PMID:27450766, which counted 2 of approximately 12 published cases
    with pustular psoriasis-like lesions, becoming 3 with that report; one of the
    two probands in PMID:36292720 had psoriasis-like dermatitis. Counting all
    reported cutaneous morphologies together would raise the estimate, and the
    true proportion is uncertain in so small a literature.
- name: Uterine stiffness and pain in pregnancy
  category: Reproductive
  description: >-
    Frequent uterine pains in the third trimester with raised serum pyruvate, and
    a risk of dystocia in labour attributed to inadequate anaerobic ATP supply to
    the myometrium. Reported deliveries have been by caesarean section.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, uterine pain and stiffness have been reported in pregnant
      patients
    explanation: >-
      Reports uterine pain and stiffness as a recognised feature of pregnancy in
      this disorder.
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and all labors were reported to require caesarean section.
    explanation: >-
      Records the delivery outcome across the reported pregnancies, which is what
      makes this obstetrically actionable.
  notes: >-
    Only affected women who have been pregnant can express this, and the
    published pregnancies are few, so the band is a coarse statement about the
    whole patient population rather than a rate among pregnancies. Among reported
    pregnancies in affected women the feature appears to be usual, not
    occasional. No phenotype_term is bound because HPO was searched and has
    nothing for myometrial pain, uterine stiffness or dystocia from failed
    myometrial contraction: the nearest terms are Uterine rupture (HP:0100718),
    Uterine prolapse (HP:0000139) and Shoulder dystocia (HP:0011413), none of
    which name this finding, and there is no term for uterine atony, abnormal
    myometrial contraction or labour dystocia at all. This is a new-term-request candidate rather than an
    unfinished binding.
- name: Acute kidney injury
  category: Renal
  description: >-
    A complication of severe myoglobinuric episodes rather than a primary renal
    manifestation. Renal function is normal between episodes.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  frequency: VERY_RARE
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myoglobinuria may lead to acute renal failure [7,8].
    explanation: >-
      Records acute renal failure as a recognised consequence of the myoglobinuric
      episodes.
  notes: >-
    Reported as a possible complication in review, referenced to individual case
    reports; no published patient series reports a rate. Band reflects that it is
    the exception among reported myoglobinuric episodes rather than a counted
    proportion.
genetic:
- name: LDHA
  gene_term:
    preferred_term: LDHA
    term:
      id: hgnc:6535
      label: LDHA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    LDHA at 11p15.1 has seven protein-coding exons and encodes the 331-amino-acid
    M subunit of lactate dehydrogenase. Reported disease alleles are
    predominantly null: a recurrent 20-base-pair deletion in exon 6 (the most
    prevalent variant, truncating the protein at 259 residues), the nonsense
    variants c.410C>A (p.Ser137Ter) and c.750G>A (p.Trp250Ter), and a
    frameshifting c.766_767delGT in exon 7. A splice variant and a small
    insertion have also been described.
  variants:
  - name: 20-base-pair deletion in exon 6
    type: FRAMESHIFT
    description: >-
      The most prevalent reported allele. Frameshift and premature termination
      yield a 259-residue product that is not detectable immunologically.
  - name: NM_005566:c.410C>A (p.Ser137Ter)
    type: NONSENSE
    description: >-
      Found homozygous in one Spanish proband and compound heterozygous with
      c.750G>A in a second, on a shared haplotype.
  - name: NM_005566:c.766_767delGT
    type: FRAMESHIFT
    description: >-
      Homozygous exon 7 frameshift in a consanguineous North African family, with
      myopathy and severe treatment-resistant acne.
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified in the LDHA gene a homozygous c.410C>A substitution that
      predicts a p.Ser137Ter nonsense mutation in Patient One and a compound
      heterozygous c.410C>A (p.Ser137Ter) and c.750G>A (p.Trp250Ter) nonsense
      mutation in Patient Two.
    explanation: >-
      Documents two nonsense alleles segregating with the phenotype in two
      families.
  - reference: PMID:40033989
    reference_title: "Glycogenosis type XI, a rare association between muscle and skin manifestations - the contribution of proteomics for the understanding of the underlying myopathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome analysis revealed a novel bi-allelic frameshifting deletion in exon 7
      of the LDHA gene; c.766_767delGT.
    explanation: >-
      A further biallelic null allele, extending the mutational spectrum beyond
      the Japanese and Spanish families.
  - reference: PMID:7603529
    reference_title: "Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic background, and genetic heterogeneities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic analysis revealed the heterogeneities of the mutations of this
      disease.
    explanation: >-
      States that the disorder is allelically heterogeneous rather than caused by
      a single founder variant.
biochemical:
- name: Serum LDH isoenzyme pattern restricted to LDH-1 (H4)
  notes: >-
    Electrophoretic separation of serum or erythrocyte LDH isoenzymes shows a
    single band. Normally five tetramers are present (H4, H3M, H2M2, HM3, M4);
    with no M subunit, only H4 can be assembled. This is a cheap, decisive test,
    and it is diagnostic in a way that total LDH activity is not — total serum
    LDH is often normal or even raised, because the surviving H4 band is
    upregulated and because muscle damage releases what enzyme there is.
  evidence:
  - reference: PMID:7449146
    reference_title: Hereditary deficiency of lactate dehydrogenase M-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophoretic analysis of serum LDH isoenzymes of the propositus
      demonstrated only one activity band of LDH H4.
    explanation: >-
      The isoenzyme finding that defines M-subunit deficiency biochemically.
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the isoenzyme pattern of the patients revealed a complete absence of the
      isoenzymes containing the M subunit, showing only one band of the LDH-1
      (H4) isoenzyme
    explanation: >-
      Confirms the same isoenzyme signature in genetically characterised modern
      patients.
diagnosis:
- name: Forearm exercise test with lactate, pyruvate and ammonium
  description: >-
    The functional test of choice. In an affected patient the venous lactate
    curve is flat, as it is in McArdle disease, but pyruvate rises steeply
    instead — that pyruvate rise is what separates a terminal glycolytic block
    from a glycogenolytic one. The ammonium response is exaggerated, around 25 to
    30 times baseline against a normal 5 to 10 times, because AMP deaminase is
    recruited to compensate.
  evidence:
  - reference: PMID:3383424
    reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The response to ischemic forearm work is characteristic in these three
      families: an increase of venous lactate concentration after ischemic work
      was not observed and a marked increase of venous pyruvate was found.
    explanation: >-
      Describes the flat-lactate, high-pyruvate response that is the functional
      diagnostic signature.
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, a flat lactate curve on the forearm exercise test, along with the
      clinical combination of myopathy and psoriatic-like dermatitis, can also
      lead to the diagnosis.
    explanation: >-
      Confirms the exercise test plus the muscle-and-skin combination as the
      route to diagnosis in current practice.
- name: LDHA sequencing
  description: >-
    Biallelic LDHA variants confirm the diagnosis. In practice the gene is
    reached through a metabolic myopathy panel or exome; the common differential
    genes PYGM and CPT2 are excluded in the same test.
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To identify the genetic causes of patient phenotypes, we performed a
      customized NGS panel including 32 genes associated with metabolic
      myopathies.
    explanation: >-
      Describes the panel-based route by which the diagnosis is now made.
differential_diagnoses:
- name: McArdle disease (GSD V, PYGM)
  description: >-
    The closest mimic: exercise intolerance, exertional rhabdomyolysis and a flat
    lactate curve on the forearm test. The discriminator is pyruvate — it rises
    steeply in LDHA deficiency because the block is below pyruvate, and does not
    in McArdle disease because the block is at glycogen breakdown, above it.
    McArdle disease also shows a second-wind phenomenon, which LDHA deficiency
    does not, and has no cutaneous phenotype.
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, the main difference in the lactate stress test results of patients
      with LDHA deficiency compared with those with the very common glycogenosis
      (i.e., GSD V) is the high response of pyruvate, as the lactate response is
      similar in both diseases
    explanation: >-
      States exactly which measurement distinguishes the two disorders.
- name: Fanconi-Bickel syndrome (SLC2A2)
  description: >-
    Not a clinical mimic but a nomenclature one: it also carries the label GSD XI
    in much of the literature. It is a hepatorenal glycogenosis with
    hepatomegaly, proximal tubulopathy and rickets, with no exertional myopathy.
    Any citation whose title says "glycogen storage disease XI" needs to be
    checked against the gene before use.
- name: Carnitine palmitoyltransferase II deficiency
  description: >-
    Also causes recurrent exertional rhabdomyolysis, but triggered by prolonged
    endurance exercise, fasting or fever rather than brief maximal effort, with a
    normal lactate response to the forearm test and an abnormal acylcarnitine
    profile.
- name: Complete LDH-B (H-subunit) deficiency
  description: >-
    The reciprocal enzyme defect. It also produces an abnormal serum isoenzyme
    pattern but is clinically silent, with no myopathy, and must not be conflated
    with M-subunit deficiency when an isoenzyme report is abnormal.
treatments:
- name: Avoidance of maximal anaerobic exertion
  description: >-
    The only management with a mechanistic rationale. Because the defect is
    confined to anaerobic ATP supply and oxidative capacity is preserved,
    endurance and moderate activity are tolerated while short maximal efforts —
    sprinting, competitive contact sport, isometric loading — are what precipitate
    rhabdomyolysis. Patients are advised to pace effort and to seek care for dark
    urine. This is standard metabolic myopathy advice rather than an
    LDHA-specific intervention tested in a trial.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: activity modification to avoid anaerobic exertion
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Exertional Myocyte Injury
    description: >-
      Removing the anaerobic trigger prevents the energy failure that damages the
      fibre; it does not correct the enzyme deficiency.
    evidence:
    - reference: PMID:3383424
      reference_title: "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Otherwise, patients with a lactate dehydrogenase M-subunit deficiency do
        not show muscle stiffness and myoglobinuria under ordinary circumstances.
      explanation: >-
        Establishes that symptoms are confined to anaerobic exertion, from which
        avoidance follows as a mechanism-based measure; no trial has tested the
        advice itself, so the support is indirect.
  evidence:
  - reference: PMID:7549132
    reference_title: Characterization of the oxidative metabolism in lactate dehydrogenase A deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Maximal oxygen uptake in the patients with severe and mild symptoms was
      approximately 73% and 92% of control.
    explanation: >-
      Near-normal aerobic capacity is why the advice restricts anaerobic effort
      specifically rather than exercise in general.
  notes: >-
    No controlled study of activity modification in this disorder exists. The
    recommendation follows from the metabolic physiology and from the observation
    that patients are asymptomatic under ordinary circumstances.
- name: Supportive management of rhabdomyolysis episodes
  description: >-
    Acute episodes are managed as rhabdomyolysis from any cause: intravenous
    fluids to protect renal function, monitoring of creatine kinase and renal
    function, and rest until recovery. There is no disease-specific acute
    therapy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:36292720
    reference_title: "Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myoglobinuria may lead to acute renal failure [7,8].
    explanation: >-
      The complication that supportive management of an episode is intended to
      prevent.
- name: Genetic counseling
  description: >-
    Autosomal recessive transmission with a 25% sibling recurrence risk.
    Counseling of affected women should also cover the obstetric risk, since
    reported pregnancies have involved third-trimester uterine pain and delivery
    by caesarean section.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:12078970
    reference_title: "Pregnancy complicated with lactate dehydrogenase M-subunit deficiency: the first case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A woman with lactate dehydrogenase M-subunit deficiency underwent two
      cesarean sections because of the risk of dystocia due to decreased adenosine
      triphosphate production in anaerobic glycolysis including uterine muscles.
    explanation: >-
      The obstetric risk that counseling of affected women needs to cover.
animal_models:
- name: Drosophila Ldh null larva (Ldh16/Ldh17)
  species: Drosophila melanogaster
  genotype: Ldh16/Ldh17 trans-heterozygous null
  publication: PMID:42465323
  description: >-
    Drosophila expresses a single LDH enzyme, so a trans-heterozygous null
    removes lactate dehydrogenase activity outright. Null larvae are viable at
    rest but die when forced to move continuously, and are slower in
    goal-directed crawling; a rescuing Ldh transgene abolishes both effects.
    This is currently the only published whole-organism model that reproduces
    the exertion-dependent character of the human disease.
  modeled_mechanisms:
  - target: Abortive Glycolysis and Muscle ATP Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of LDH leaves the animal normal at rest and failing under sustained
      physical demand, which is the defining shape of the human node: an ATP
      deficit that appears only when glycolytic flux must be sustained
      anaerobically.
    limitations: >-
      Drosophila has one LDH rather than the M/H subunit system, so the model
      cannot reproduce the tissue-restricted deficiency, the surviving H4
      isoenzyme, or the diagnostic serum isoenzyme pattern that define the human
      disease. The endpoint is larval death during forced movement, which has no
      human counterpart -- LDHA-deficient people are exercise intolerant, not at
      risk of death from exertion -- and the authors report that muscle-specific
      rescue does not restore viability, so the fly phenotype is not
      muscle-autonomous in the way the human myopathy is. The NAD+-regeneration
      mechanism that would link this model to the node is offered as an
      interpretation, not measured. Neither rhabdomyolysis nor myoglobinuria is
      assayed.
    readouts:
    - name: Survival during forced-movement exertion challenge
      target: Abortive Glycolysis and Muscle ATP Deficit
      direction: DECREASED
      interpretation: >-
        Exertion-dependent failure, absent at rest and absent in the transgenic
        rescue, is the model's closest correlate of the human exercise
        intolerance.
      evidence:
      - reference: PMID:42465323
        reference_title: Drosophila melanogaster lactate dehydrogenase deficiency recapitulates the exercise intolerance of human glycogen storage disease type XI.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Whereas controls and Ldh mutants expressing the rescuing transgene
          showed no lethality up to 40 minutes of stimulation, Ldh mutants began
          dying within 10 minutes, and all animals died by 50 minutes (Figure
          4B).
        explanation: >-
          The measurement itself, with the rescue transgene as the internal
          control that ties it to Ldh loss.
    - name: Crawling speed and time to reach a food source
      target: Abortive Glycolysis and Muscle ATP Deficit
      direction: DECREASED
      interpretation: >-
        Baseline locomotor impairment, measured separately from the exertion
        challenge; it shows the deficit is not confined to extreme effort.
      evidence:
      - reference: PMID:42465323
        reference_title: Drosophila melanogaster lactate dehydrogenase deficiency recapitulates the exercise intolerance of human glycogen storage disease type XI.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In both assays, Ldh mutants were significantly delayed in reaching the
          yeast (Figure 4D) and crawled more slowly than control or rescue
          (Figure 4E).
        explanation: >-
          Quantifies the locomotor phenotype against both a genetic control and
          the rescue.
    evidence:
    - reference: PMID:42465323
      reference_title: Drosophila melanogaster lactate dehydrogenase deficiency recapitulates the exercise intolerance of human glycogen storage disease type XI.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This exertion-dependent phenotype closely parallels the clinical
        presentation of LDHA deficiency in humans, where symptoms such as muscle
        pain, weakness, and rhabdomyolysis are typically triggered by physical
        activity rather than evident at rest
      explanation: >-
        The authors' own statement of what the model is informative for, which is
        the exertion dependence rather than the myopathy itself.
  notes: >-
    PMID:42465323 is a bioRxiv preprint and has not been peer reviewed; the model
    is recorded with that caveat rather than withheld, because it is the only
    organism-level model of this disease in the literature. No mouse model of
    GSD XI exists: a PubMed search for Ldha-deficient mice with a muscle or
    exercise phenotype returns cancer and metabolism studies plus a 1987
    hemolytic-anaemia mouse mutant (PMID:3315726), none of which model the human
    exertional myopathy.
discussions:
- discussion_id: ldha_skin_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    How does loss of the LDH M subunit produce psoriasiform and pustular skin
    disease, and why only in some patients?
  attaches_to:
  - pathophysiology#Epidermal and Follicular Glycolytic Failure
  - phenotypes#Psoriasiform dermatitis
  rationale: >-
    What is established is that the enzyme is missing from lesional epidermis and
    hair follicles, and that the eruption occurs in a minority of patients,
    sometimes decades after the muscle phenotype. What is not established is the
    step between the two. Keratinocytes are highly glycolytic, but no study has
    shown that a keratinocyte ATP or redox deficit drives the inflammatory
    phenotype, and the pustular cases were specifically reported as not carrying
    IL36RN variants, which excludes the obvious alternative explanation of
    coincidental generalised pustular psoriasis. The seasonal pattern — flares in
    warm months, remission in autumn — is unexplained by any current model.
  proposed_experiments:
  - experiment_id: ldha_keratinocyte_redox
    name: Redox and inflammatory profiling of LDHA-null keratinocytes
    description: >-
      Generate LDHA-null human keratinocytes by gene editing, culture them as
      organotypic epidermal equivalents under normal and raised temperature, and
      measure cytosolic NADH/NAD+ ratio, ATP, and release of psoriasis-associated
      cytokines including IL-36 family members and IL-17-inducing signals,
      comparing against isogenic controls.
    would_support:
    - pathophysiology#Epidermal and Follicular Glycolytic Failure
    supporting_outcome:
    - >-
      LDHA-null keratinocytes show a raised NADH/NAD+ ratio and lower ATP, and
      release psoriasis-associated cytokines in excess of isogenic controls, with
      the difference widening at raised temperature.
    would_refute:
    - pathophysiology#Epidermal and Follicular Glycolytic Failure
    refuting_outcome:
    - >-
      LDHA-null keratinocytes maintain normal redox state, ATP and cytokine
      output, which would mean the skin phenotype is not a direct keratinocyte
      energy or redox failure and some other cell type or systemic factor
      mediates it.
- discussion_id: ldha_severity_modifier
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is glycerol-3-phosphate dehydrogenase capacity the modifier that sets
    severity among patients with identical LDHA genotypes?
  attaches_to:
  - pathophysiology#Glycerol-3-Phosphate Shunt Compensation
  rationale: >-
    Four patients from two families carrying the same 20-base-pair deletion
    differed markedly in severity, and the group that reported them found
    threefold higher muscle glycerol-3-phosphate dehydrogenase activity in the
    mildly affected patients. That is a plausible modifier and it is the only one
    proposed, but it rests on four patients and a correlation, with no genetic
    variant identified in GPD1 or elsewhere and no independent replication in the
    thirty years since. The alternative offered by the same group — that severity
    tracks muscle oxidative capacity — has the same evidential standing, and the
    two have never been separated.

📚

References & Deep Research

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 (1)

Review round 1: reconnect pathograph, specific cell type, animal model · 2026-09-04T06:16:01Z · View source

Addresses the CHANGES_REQUESTED review on PR #10896. (1) Reconnected the pathograph: added a downstream edge from LDHA Loss and Muscle Lactate Dehydrogenase Deficiency to Epidermal and Follicular Glycolytic Failure (drawn from the enzyme null itself, not from the skeletal-muscle ATP-deficit node, so no keratinocyte ATP mechanism is asserted); added Exercise intolerance as a downstream target of Abortive Glycolysis and Muscle ATP Deficit; added a sequelae edge from Myoglobinuria to Acute kidney injury. Every node except the root now has an incoming edge. (2) Replaced CL:0000192 smooth muscle cell with CL:0002601 uterine smooth muscle cell on Uterine Smooth Muscle Energy Failure. (3) No deep-research provider is reachable in this environment and CLAUDE.md forbids hand-writing files into research/, so the sweep was manual against PubMed: 25 hits for the disease name variants, 8 for LDHA deficiency with a myopathy term, and a separate search for Ldha-deficient mouse models. Confirmed no GeneReviews chapter exists for GSD XI. (4) Recorded in the uterine phenotype notes that HPO was searched and has no term for myometrial pain, uterine stiffness or labour dystocia, flagging it as an NTR candidate; the nearest terms are HP:0100718, HP:0000139 and HP:0011413. (5) The sweep found PMID:42465323, a Drosophila Ldh-null model that reproduces the exertion-dependent phenotype; added it as the entry's first animal_models entry with a PARTIALLY_RECAPITULATES link to Abortive Glycolysis and Muscle ATP Deficit, two readouts, and limitations covering the single-LDH fly enzyme, the non-muscle-autonomous rescue result and the lethality endpoint. Recorded that it is a preprint, and that no mouse model of GSD XI exists. Validated with just validate, validate-terms, count-verified-snippets (51/51), check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms and validate-disorders.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 24 citations 2026-09-03T23:56:05.664153

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Glycogen Storage Disease Due To Lactate Dehydrogenase M-subunit Deficiency
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Glycogen Storage Disease Due To Lactate Dehydrogenase M-subunit Deficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Glycogen Storage Disease Due to Lactate Dehydrogenase M-Subunit Deficiency

Executive summary

LDHA-related glycogen storage disease type XI (GSD XI) is an exceptionally rare autosomal-recessive metabolic myopathy caused by biallelic loss-of-function variants in LDHA, which encodes the muscle-type M subunit of lactate dehydrogenase. Loss of M-subunit-containing LDH isoenzymes limits lactate formation and NAD⁺ regeneration during high glycolytic demand. The characteristic phenotype is poor tolerance of short, intense, predominantly anaerobic exercise, with myalgia, cramps or stiffness, hyper-CK-emia, myoglobinuria, and episodic rhabdomyolysis. Psoriasiform dermatitis is an important but inconsistent extramuscular manifestation. Evidence remains almost entirely case-based: a 2021 synthesis found only 14 historical patients, and the most informative modern primary report described two additional Spanish patients in 2022. No population prevalence, standardized guideline, approved disease-modifying therapy, or disease-specific therapeutic trial was identified. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 1-2, serranolorenzo2022clinicalbiochemicaland pages 7-9, ariceta2021hepaticlactatedehydrogenase pages 2-4)

Domain	Established finding	Quantitative detail	Evidence level / caveat
Disease identity	LDHA-related glycogen storage disease type XI; synonyms include GSD XI, lactate dehydrogenase A deficiency, LDH-A deficiency, muscle LDH deficiency, and lactate dehydrogenase M-subunit deficiency	OMIM 612933; ORPHA 284426	Authoritative resource synthesis. “GSD XI” may also refer to GLUT2-deficient Fanconi–Bickel syndrome; specify LDHA-related GSD XI. (serranolorenzo2022clinicalbiochemicaland pages 1-2, ellingwood2018biochemicalandclinical pages 12-16)
Gene and inheritance	Biallelic germline loss-of-function variants in LDHA cause an autosomal-recessive metabolic myopathy	Chromosome 11p15.1; 7 exons; approximately 12 kb; protein 333 amino acids	Established through human pedigrees, segregation, molecular testing, and enzyme studies. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 1-2, kanungo2018glycogenmetabolismand pages 5-6)
Core muscle phenotype	Poor tolerance of short, high-intensity or predominantly anaerobic exercise, with exertional myalgia, cramps, stiffness, weakness, myoglobinuria, and episodic rhabdomyolysis	In the 2022 series, anaerobic-exercise intolerance and rhabdomyolysis occurred in 2/2 patients; basal CK was approximately 2–5 times the reference value	Demonstrated in two young women and consistent with historical cases; tiny, ascertainment-biased samples do not yield population frequencies. (serranolorenzo2022clinicalbiochemicaland pages 2-5, serranolorenzo2022clinicalbiochemicaland pages 5-7)
Aggregate phenotype data	Manifestations are predominantly muscular, but recurrent rhabdomyolysis is not universal	Review of 14 historical patients: 6 female and 8 male; 17/23 manifestations, or 74%, were muscular. A separate family-level synthesis reported recurrent rhabdomyolysis in 4/14 families	Aggregates use different denominators—patients, manifestations, and families—and must not be combined as prevalence estimates. (serranolorenzo2022clinicalbiochemicaland pages 7-9, ariceta2021hepaticlactatedehydrogenase pages 2-4)
Skin phenotype	Psoriasis-like or psoriasiform dermatitis may occur alone or with myopathy and may vary with stress or season	Present in 1/2 patients in the 2022 series and reported in 8/14 historical families	The human association is established; proposed causation through NAD⁺ or ATP depletion and inflammatory mediator release is not directly demonstrated. (serranolorenzo2022clinicalbiochemicaland pages 9-11, serranolorenzo2022clinicalbiochemicaland pages 7-9)
Exercise-test signature	Non-ischemic forearm exercise produces a flat or nearly flat lactate curve with exaggerated ammonium generation; elevated pyruvate may help distinguish LDHA deficiency from McArdle disease	In the 2022 cases, lactate lacked the normal 4–6-fold rise; ammonium increased approximately 25–30-fold, versus a normal 5–10-fold increase	Demonstrated human biochemical finding in two molecularly confirmed cases; provocative testing requires specialist supervision. (serranolorenzo2022clinicalbiochemicaland pages 2-5, serranolorenzo2022clinicalbiochemicaland pages 7-9, serranolorenzo2022clinicalbiochemicaland pages 5-7)
LDH isoenzymes	M-subunit-containing tetramers are absent, leaving LDH-1, the H4 homotetramer composed of LDHB subunits; total plasma LDH may remain normal or slightly increased	Complete absence of M-containing LDH isoenzymes in the 2022 cases	Strong functional evidence that the variants abolish LDHA M-subunit function; total LDH alone is an insensitive screen. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 7-9)
2022 pathogenic variants	Novel nonsense alleles LDHA c.410C>A, p.Ser137Ter, and c.750G>A, p.Trp250Ter	Patient 1 was homozygous for p.Ser137Ter; Patient 2 was compound heterozygous for p.Ser137Ter and p.Trp250Ter	Classified as pathogenic in the report; segregation, premature termination, and isoenzyme electrophoresis supported loss of function. A shared haplotype suggests, but does not prove, a founder allele. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 7-9)
Mechanism	Loss of LDHA-mediated pyruvate-to-lactate conversion impairs NAD⁺ regeneration, limits anaerobic glycolytic flux and rapid ATP production, and predisposes active myofibers to energetic failure and injury	Human evidence includes the flat lactate response and loss of M-containing isoenzymes; direct intramuscular NAD⁺ and ATP flux measurements are unavailable	The reaction defect and exercise phenotype are demonstrated; the complete NAD⁺ depletion to ATP failure to rhabdomyolysis chain remains partly inferred. (serranolorenzo2022clinicalbiochemicaland pages 1-2, rai2026drosophilamelanogasterlactate pages 20-24, serranolorenzo2022clinicalbiochemicaland pages 5-7)
Epidemiology	The disorder is extremely rare and has been reported in Japanese, Italian, U.S., and Spanish families	A 2021 review identified 14 unique historical patients; a 2022 report added two affected individuals from two Spanish families	No population-based prevalence, incidence, carrier frequency, or sex ratio is available; published counts are susceptible to underdiagnosis and reporting bias. (serranolorenzo2022clinicalbiochemicaland pages 1-2, ariceta2021hepaticlactatedehydrogenase pages 2-4)
Treatment	No approved disease-modifying pharmacotherapy, enzyme replacement, gene therapy, RNA therapy, or validated treatment algorithm was identified	No response-rate or comparative-treatment data are available	Management is supportive and focuses on avoiding intense anaerobic exertion and promptly treating rhabdomyolysis; disease-specific trials and formal guidelines are absent.
Clinical trials	No disease-specific therapeutic trial was identified; one observational study plans to assess home lactate and glucose meters in GSD types Ia, Ib, and XI	NCT07459582; planned enrollment 10; approximately 8 hours of hourly measurements	This is not a treatment trial and is not restricted to LDHA-related GSD XI; the registry record was first posted March 10, 2026. (NCT07459582 chunk 1)
Prognosis	Case reports suggest a chronic, episodic disorder compatible with survival into adulthood, with morbidity concentrated around exertional attacks and possible skin disease	No survival curves, mortality rate, life-expectancy estimate, renal-failure risk, or validated quality-of-life data are available	Adult survival is inferred from case reports. Acute renal failure is a possible complication of rhabdomyolysis, but its frequency is unknown. (serranolorenzo2022clinicalbiochemicaland pages 1-2)
Models	Drosophila Ldh loss-of-function mutants exhibit exercise intolerance, reduced mobility, and demand-dependent lethality; muscle and peripheral glial LDH are implicated	Reducing locomotor demand through altered food presentation can rescue viability	This disease-oriented model is reported in a 2026 non-peer-reviewed preprint, outside the 2023–2024 priority period. Mouse LDHA inhibition and conditional models generally address other diseases and do not fully reproduce congenital human GSD XI. (rai2026drosophilamelanogasterlactate pages 1-5, rai2026drosophilamelanogasterlactate pages 20-24, lai2018specificinhibitionof pages 10-11)

Table: Compact knowledge-base summary of LDHA-related GSD XI, separating demonstrated human findings from review aggregates, mechanistic inference, and unavailable evidence. Quantitative estimates retain their original denominators and key ascertainment caveats.

1. Disease information

Definition and identifiers

The disease is a disorder of terminal anaerobic glycolysis rather than a primary defect of glycogen synthesis or glycogenolysis. It is nevertheless conventionally classified among muscle glycogenoses because symptoms emerge when contracting muscle depends heavily on glycogen-derived glycolytic ATP.

Preferred unambiguous name: LDHA-related glycogen storage disease type XI.
OMIM: 612933.
Orphanet: ORPHA:284426.
Causal gene: LDHA; OMIM gene entry 150000.
Chromosomal locus: 11p15.1.
Synonyms: glycogenosis type XI; GSD XI/GSD 11; lactate dehydrogenase A deficiency; LDH-A deficiency; lactate dehydrogenase M-subunit deficiency; hereditary LDH-M deficiency; muscle lactate dehydrogenase deficiency; muscle LDH deficiency. (serranolorenzo2022clinicalbiochemicaland pages 1-2, ellingwood2018biochemicalandclinical pages 12-16, kanungo2018glycogenmetabolismand pages 5-6)
MONDO: a disease-specific MONDO identifier was not established by the retrieved evidence and should not be guessed. A database curator should reconcile the current MONDO release against OMIM 612933/ORPHA 284426.
MeSH: no specific LDHA-deficiency descriptor was established; broader indexing under glycogen storage disease, carbohydrate-metabolism inborn errors, metabolic myopathy, rhabdomyolysis, and lactate dehydrogenase is appropriate.
ICD: no validated disease-specific ICD-10/ICD-11 code was identified. A 2026 ClinicalTrials.gov protocol uses E74.09 for GSD XI, but this registry usage should not be treated as a universally authoritative disease-specific mapping. (NCT07459582 chunk 1)

Nomenclature warning: “GSD XI” has also been used for GLUT2/SLC2A2-deficient Fanconi–Bickel syndrome. Knowledge bases should therefore store the gene-qualified label “LDHA-related GSD XI” and should not merge it with Fanconi–Bickel syndrome. (ellingwood2018biochemicalandclinical pages 12-16)

The evidence is aggregated disease-level literature and individual published cases/families, not an EHR-derived cohort. The modern primary data are two index cases and their relatives; historical summaries aggregate published cases with substantial reporting bias. (serranolorenzo2022clinicalbiochemicaland pages 5-7, ariceta2021hepaticlactatedehydrogenase pages 2-4)

2. Etiology, risk, and protective factors

Causal factor

The established cause is biallelic germline LDHA loss of function. The 2022 pedigrees showed homozygosity or compound heterozygosity in affected individuals, heterozygosity in clinically unaffected relatives, and absence of M-containing LDH isoenzymes, supporting autosomal-recessive causation. (serranolorenzo2022clinicalbiochemicaland pages 5-7)

Genetic risk factors

A person is at risk when inheriting two pathogenic LDHA alleles. The best-characterized recent variants are:

NM-dependent genomic transcript notation: c.410C>A (p.Ser137Ter), homozygous in one patient.
c.410C>A (p.Ser137Ter) plus c.750G>A (p.Trp250Ter), compound heterozygous in the second.

Both are nonsense/null alleles predicted to truncate the 333-amino-acid protein. Segregation, Sanger confirmation, premature termination, and isoenzyme electrophoresis supported pathogenicity; the report classified them as pathogenic under ACMG criteria. A shared neighboring haplotype suggested a possible founder origin for p.Ser137Ter, but this was not proven epidemiologically. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 7-9)

Historical reports include a 20-bp exon-6 truncating/deletion allele and other molecularly heterogeneous LDHA mutations. Phenotypic severity can differ despite similar enzyme activity or genotype; no reliable genotype–phenotype relationship has been established. (serranolorenzo2022clinicalbiochemicaland pages 7-9, takahashi1995geneticanalysisof pages 4-4)

Population allele frequencies, carrier frequency, penetrance estimates, and complete ClinVar/gnomAD classifications were not available in the retrieved evidence. Somatic mutation is not the disease mechanism.

Environmental and lifestyle modifiers

Strenuous, short-duration, high-intensity or anaerobic exercise is the major trigger, not the primary cause. It exposes the limited capacity for glycolytic NAD⁺ recycling and can precipitate myalgia, pigmenturia, or rhabdomyolysis. Symptoms may occur in the days following medium-to-high-intensity exertion. Stress and season were reported to modify skin lesions. Pregnancy and sustained uterine contraction have precipitated uterine pain/stiffness in a historical case. (serranolorenzo2022clinicalbiochemicaland pages 9-11, serranolorenzo2022clinicalbiochemicaland pages 1-2, serranolorenzo2022clinicalbiochemicaland pages 2-5)

No toxin, radiation, pollution, smoking, alcohol, occupational exposure, or infectious agent has been shown to cause the disorder. No validated genetic protective allele or modifier gene is known. Avoidance of extreme anaerobic workload is plausibly protective against attacks, but no controlled prevention study exists.

3. Phenotypes

Phenotype	Type and characteristics	Frequency/evidence	Suggested HPO term
Exercise intolerance	Symptom; especially brief, intense anaerobic activity; episodic and workload-dependent	Core finding; 2/2 in the 2022 series	HP:0003546 Exercise intolerance
Myalgia/muscle pain	Symptom; exertional or post-exertional, variable severity	Common in cases; no patient-level population frequency	HP:0003326 Myalgia
Muscle cramps/contractures or stiffness	Symptom/sign; precipitated by intense exertion	Historical cases	HP:0003394 Muscle cramps; consider HP:0003552 Muscle stiffness
Rhabdomyolysis	Acute clinical/laboratory event; recurrent and exertional in some patients	2/2 modern cases; historical synthesis: 4/14 families	HP:0003201 Rhabdomyolysis
Myoglobinuria/dark urine	Symptom/laboratory sign after exertion	Reported in both modern families and historical cases	HP:0002913 Myoglobinuria
Hyper-CK-emia	Laboratory abnormality; may be mild at baseline and marked during attacks	Basal CK about 2–5× reference in the two modern cases	HP:0003236 Elevated circulating creatine kinase concentration
Muscle weakness	Sign; absent in one modern case but reported in the other/historical disease	Variable	HP:0001324 Muscle weakness
Psoriasiform dermatitis	Cutaneous sign; psoriasis-like, sometimes stress- or season-responsive; may occur with or without myopathy	1/2 modern cases; 8/14 historical families	HP:0003765 Psoriasiform dermatitis
Abnormal lactate response	Functional laboratory phenotype: absent/flat exercise-associated lactate rise	2/2 modern cases	HP:0011968 Abnormality of circulating lactate concentration; annotate test context explicitly
Exaggerated ammonia response	Functional laboratory abnormality after forearm exercise	About 25–30× increase in the modern cases	HP:0001987 Hyperammonemia only with caution; this is transient exercise-induced ammonium elevation, not necessarily resting hyperammonemia
Elevated pyruvate after exercise	Laboratory abnormality that may distinguish LDHA deficiency from McArdle disease	Historical/diagnostic literature; frequency unknown	HP:0011907 Abnormality of circulating pyruvate concentration
Acute kidney injury	Complication secondary to severe rhabdomyolysis	Reported as possible; frequency unknown	HP:0001919 Acute kidney injury
Uterine pain/stiffness in pregnancy	Smooth-muscle manifestation during labor/pregnancy	Isolated historical report	Use descriptive annotation; no confidently verified specific HPO mapping from retrieved evidence

The 2022 patients were 17 and 18 years old when characterized, but this does not establish typical onset. One reported no fixed weakness; the other described weakness and delayed symptoms after exercise. Severity and expression vary even among patients with comparable biochemical deficiency. (serranolorenzo2022clinicalbiochemicaland pages 2-5, serranolorenzo2022clinicalbiochemicaland pages 7-9)

Quantitative interpretation requires care. A 2021 review identified 14 historical patients—6 female and 8 male—and counted 23 reported manifestations, 17/23 (74%) of which were muscular. A separate 2022 family-level synthesis reported recurrent rhabdomyolysis in 4/14 and dermatitis in 8/14 families. These denominators represent manifestations, patients, and families and must not be combined into patient prevalence estimates. (serranolorenzo2022clinicalbiochemicaland pages 7-9, ariceta2021hepaticlactatedehydrogenase pages 2-4)

No EQ-5D, SF-36, PROMIS, disability scale, or disease-specific quality-of-life study was found. Likely burdens include restriction of vigorous activity, pain, fear of rhabdomyolysis, emergency care, and dermatologic morbidity, but these have not been formally quantified.

4. Genetic and molecular information

LDHA encodes the A/M subunit of tetrameric lactate dehydrogenase. LDHA and LDHB subunits form five isoenzymes; skeletal muscle is enriched for the M-containing LDH-4 and LDH-5 forms. The gene contains seven exons and spans approximately 12 kb at 11p15.1. (serranolorenzo2022clinicalbiochemicaland pages 1-2)

The established molecular consequence is loss of function. In the 2022 patients, electrophoresis showed absence of every M-containing tetramer and persistence only of LDH-1 (H4), composed solely of LDHB subunits. Total plasma LDH was normal or only slightly raised, demonstrating why total LDH concentration is an insensitive diagnostic screen. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 7-9)

No validated dominant-negative, gain-of-function, somatic, mosaic, chromosomal, copy-number, epigenetic, methylation, or imprinting mechanism was found. No disease-modifying gene has been established. The condition lies near an imprinted region of 11p15, but no evidence supports imprinting as its disease mechanism.

Suggested annotations include HGNC:6540 for LDHA, subject to database verification; GO molecular function L-lactate dehydrogenase activity; GO biological processes glycolytic process, NADH oxidation, pyruvate metabolic process, and lactate metabolic process; and GO cellular component cytosol. Exact GO identifiers should be resolved against the current GO release rather than inferred from names.

5. Environmental information

There is no evidence for environmental causation or an infectious trigger. Exercise, physiologic stress, and possibly temperature/season function as exposure-dependent modifiers of manifestations. High-intensity exercise increases ATP demand and dependence on anaerobic glycolysis; the inherited enzyme defect converts this otherwise normal exposure into a risk of muscle injury. (serranolorenzo2022clinicalbiochemicaland pages 9-11, serranolorenzo2022clinicalbiochemicaland pages 2-5)

No evidence supports smoking cessation, alcohol restriction, a specific macronutrient diet, supplements, or vaccination as disease-specific interventions, although general avoidance of dehydration and prompt management during rhabdomyolysis are clinically reasonable.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic pathogenic LDHA variants lead to absent or severely reduced functional LDH-A/M subunits.
Loss of M subunits leads to disappearance of M-containing LDH tetramers in skeletal muscle and blood isoenzyme profiles, leaving LDHB H4 activity. This is demonstrated in molecularly confirmed patients. (serranolorenzo2022clinicalbiochemicaland pages 5-7)
Loss of muscle-type LDH leads to impaired conversion of pyruvate + NADH to lactate + NAD⁺ during high glycolytic flux.
Impaired NAD⁺ regeneration leads to restriction of glycolytic throughput and rapid substrate-level ATP production during intense anaerobic contraction; this step is biochemically well grounded but direct intramuscular NAD⁺/ATP flux measurements in patients are unavailable. (serranolorenzo2022clinicalbiochemicaland pages 1-2, rai2026drosophilamelanogasterlactate pages 20-24)
Restricted anaerobic glycolysis leads to a flat exercise lactate curve and accumulation/diversion of pyruvate. The flat lactate response is demonstrated; the complete pyruvate-flux model is partly inferred. (serranolorenzo2022clinicalbiochemicaland pages 7-9, serranolorenzo2022clinicalbiochemicaland pages 5-7)
Reduced glycolytic ATP availability leads to compensatory adenylate-nucleotide degradation through AMP deaminase, resulting in exaggerated exercise-induced ammonium release; the 25–30-fold ammonium response is demonstrated, whereas the precise flux partition is inferred. (serranolorenzo2022clinicalbiochemicaland pages 7-9)
Energetic mismatch during contraction leads to exercise intolerance, myalgia, cramps/stiffness, membrane injury, CK/myoglobin release, and episodic rhabdomyolysis. Severe rhabdomyolysis can secondarily lead to acute kidney injury. (serranolorenzo2022clinicalbiochemicaland pages 1-2, serranolorenzo2022clinicalbiochemicaland pages 2-5)
Branch—skin: reduced LDHA-dependent NAD⁺/ATP homeostasis in keratinocytes may lead to disturbed calcium handling and release of IL-8, VEGF, and TNF-α, resulting in psoriasiform inflammation. This mechanism is proposed, not directly demonstrated in affected skin. (serranolorenzo2022clinicalbiochemicaland pages 9-11)
Branch—smooth muscle: increased glycolytic demand during uterine contraction may lead to uterine pain/stiffness and elevated pyruvate; evidence is limited to an isolated pregnancy-associated observation. (serranolorenzo2022clinicalbiochemicaland pages 1-2)

Cells, tissues, and pathways

The primary affected cell is the skeletal muscle fiber/myocyte; suggested Cell Ontology annotation is skeletal muscle fiber (CL:0000188, verify current release). Keratinocytes are implicated by the skin phenotype; smooth-muscle cells may be involved during uterine contraction. The disease is not primarily an mTOR, Wnt, MAPK, or PI3K-AKT signaling disorder. Its upstream lesion is metabolic/redox failure in glycolysis. Secondary inflammatory signaling in skin remains hypothetical.

Recent work refines general lactate biology but is not direct GSD-XI evidence. A 2024 mouse study found that MCT1-mediated lactate transport influences skeletal-muscle mitochondrial biogenesis and TCA flux, underscoring that lactate is a fuel and signaling metabolite rather than simply waste. A 2023 T-cell study showed that altering LDHA/LDHB isoenzyme composition changes glycolysis, NAD⁺/NADH balance, proliferation, and differentiation. These findings support broad roles for isoenzyme balance but cannot be used to assign immune or mitochondrial disease phenotypes to human GSD XI. (liang2016exerciseinduciblelactate pages 1-2)

No disease-specific human transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or multi-omics dataset from 2023–2024 was identified. Human biochemical profiling is currently limited chiefly to CK, LDH isoenzymes, lactate, pyruvate, and ammonium.

7. Anatomical structures affected

Primary organ/system: skeletal muscle and muscular system; suggested UBERON:0001134 skeletal muscle tissue and UBERON:0000383 skeletal musculature, subject to release verification.
Secondary tissue: skin/epidermis, particularly keratinocytes, in the psoriasiform phenotype; suggested UBERON:0002097 skin of body and CL:0000312 keratinocyte.
Possible smooth-muscle site: uterus/myometrium during pregnancy or labor; evidence is isolated and insufficient to call routine uterine disease.
Secondary complication: kidney injury from myoglobin released during rhabdomyolysis; the kidney is not established as a primary site of LDHA-deficiency pathology.
Subcellular compartment: cytosol, where the terminal glycolytic LDH reaction and redox coupling occur. Mitochondria are downstream users of pyruvate/reducing equivalents but are not the primary defective organelle.
Lateralization: diffuse/bilateral systemic muscle involvement; no consistent unilateral or asymmetric pattern.

8. Temporal development

The genetic defect is congenital and lifelong, but clinical manifestations can remain latent until sufficiently intense exertion. Published presentation spans youth and adulthood; the modern cases were evaluated at 17–18 years. The onset pattern is typically acute or subacute after exertion against a chronic inherited background. (serranolorenzo2022clinicalbiochemicaland pages 2-5)

The course is episodic rather than steadily progressive: patients may be relatively well between attacks, with recurrent exercise-triggered myalgia, pigmenturia, and rhabdomyolysis. Fixed weakness is variable. Dermatitis may fluctuate with season or stress. No validated stages, progression rate, remission definition, or longitudinal natural-history cohort exists. (serranolorenzo2022clinicalbiochemicaland pages 9-11, serranolorenzo2022clinicalbiochemicaland pages 7-9)

Critical vulnerability windows are periods of high anaerobic demand—sprinting, heavy resistance activity, strenuous unaccustomed exertion, and possibly sustained uterine contraction. Early molecular diagnosis permits trigger education and emergency planning, although benefit has not been quantified.

9. Inheritance and population

Inheritance is autosomal recessive. For two known heterozygous parents, standard Mendelian recurrence expectations are 25% affected, 50% carrier, and 25% unaffected/non-carrier per pregnancy, assuming no complicating factors. Heterozygous relatives in the 2022 pedigrees were clinically asymptomatic. (serranolorenzo2022clinicalbiochemicaland pages 5-7)

Penetrance among biallelic individuals cannot be estimated. Expressivity is variable, ranging from predominantly muscle disease to dermatitis, combined disease, or apparently milder manifestations. No anticipation or germline mosaicism has been reported. Consanguinity has occurred in historical families but is not required. (serranolorenzo2022clinicalbiochemicaland pages 7-9, takahashi1995geneticanalysisof pages 4-4)

A 2021 review identified 14 historical patients: 11 from seven Japanese families, one from an Italian family, and two from two U.S. families; six were female and eight male. The 2022 report added two young Spanish women from separate families. These observations show multinational occurrence but do not establish ethnic susceptibility or a sex ratio. (serranolorenzo2022clinicalbiochemicaland pages 1-2, ariceta2021hepaticlactatedehydrogenase pages 2-4)

No population prevalence per 100,000, annual incidence, carrier frequency, founder-population frequency, or geographic registry estimate is available. Published case counts suggest an ultra-rare and probably underdiagnosed disorder.

10. Diagnostics

Practical diagnostic approach

Clinical suspicion: recurrent exercise intolerance, myalgia, cramps, hyper-CK-emia, pigmenturia, or rhabdomyolysis after short intense exertion, especially with psoriasiform dermatitis.
Baseline/attack laboratories: CK, creatinine, electrolytes, urinalysis and urine/plasma myoglobin during attacks; total LDH may be normal and cannot exclude disease.
LDH isoenzyme electrophoresis: a highly informative functional test showing absence of M-containing LDH-2 through LDH-5 and persistence of LDH-1/H4. (serranolorenzo2022clinicalbiochemicaland pages 5-7, serranolorenzo2022clinicalbiochemicaland pages 7-9)
Non-ischemic forearm exercise testing: molecularly confirmed cases showed a flat lactate response rather than the normal 4–6-fold increase and ammonium increases of approximately 25–30-fold rather than 5–10-fold. Measuring pyruvate may help distinguish LDHA deficiency from McArdle disease, which can also produce a flat lactate curve. Testing should be conducted in a specialist metabolic/neuromuscular setting because exertion can provoke injury. (serranolorenzo2022clinicalbiochemicaland pages 2-5, serranolorenzo2022clinicalbiochemicaland pages 7-9)
Molecular confirmation: sequence LDHA, including exon–intron boundaries; deletion/duplication analysis should follow if sequencing finds fewer than two pathogenic alleles. Segregation testing is appropriate.

A metabolic-myopathy/rhabdomyolysis panel is efficient when the phenotype is nonspecific; the 2022 investigation used a 32-gene panel and excluded common PYGM and CPT2 disease-associated variants before confirming LDHA findings. WES or WGS is reasonable for unresolved cases, but RNA sequencing has no validated routine role. CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not first-line tests unless another phenotype suggests them. (serranolorenzo2022clinicalbiochemicaland pages 2-5)

Differential diagnosis

Important alternatives include McArdle disease/PYGM (GSD V), phosphofructokinase deficiency/PFKM (GSD VII), phosphoglycerate mutase deficiency, other glycolytic defects, CPT2 and other fatty-acid oxidation disorders, LPIN1-related rhabdomyolysis, RYR1-related exertional rhabdomyolysis, mitochondrial myopathy, inflammatory myopathy, and acquired toxic/exertional rhabdomyolysis. A high pyruvate response and LDH isoenzyme pattern favor LDHA deficiency over McArdle disease. (serranolorenzo2022clinicalbiochemicaland pages 7-9)

No standardized society diagnostic criteria or validated diagnostic score exists. There is no routine biochemical newborn screening program. Targeted genomic newborn screening could technically detect biallelic LDHA variants, but evidence of clinical utility is absent; the retrieved BabyDetect protocol screened broad panels of treatable diseases and did not establish LDHA-deficiency-specific outcomes. (NCT05687474 chunk 1)

11. Outcome and prognosis

Survival into adulthood is documented, and available cases suggest that the dominant morbidity is episodic rather than relentlessly degenerative. Nevertheless, attacks can involve severe rhabdomyolysis, myoglobinuria, and possible acute renal failure. The frequency of chronic weakness, renal sequelae, hospitalization, or disability is unknown. (serranolorenzo2022clinicalbiochemicaland pages 1-2)

No 5- or 10-year survival estimate, life expectancy, mortality rate, disease-specific death count, validated prognostic model, or prognostic biomarker exists. Attack severity, CK/myoglobin burden, renal function, hydration, and delay to treatment are clinically plausible acute prognostic factors but have not been validated in this disease. Genotype does not reliably predict phenotype. (serranolorenzo2022clinicalbiochemicaland pages 7-9)

12. Treatment

No approved disease-modifying treatment or evidence-based therapeutic algorithm was identified. Management is extrapolated from metabolic myopathy and rhabdomyolysis practice:

Avoid or carefully titrate brief maximal/anaerobic exertion and unaccustomed strenuous exercise.
Develop an individualized activity plan with metabolic/neuromuscular and rehabilitation specialists; activity should not be indiscriminately eliminated because controlled evidence defining safe training is absent.
Stop activity when severe pain, stiffness, weakness, or dark urine occurs.
During suspected rhabdomyolysis, urgently assess CK, renal function, potassium and other electrolytes, urine output, and myoglobin; provide hydration and standard acute management as clinically indicated.
Treat psoriasis-like dermatitis with dermatology input; no LDHA-specific dermatologic regimen or response rate is known.
Provide genetic counseling and cascade testing.

Suggested NCIT intervention concepts include Genetic Counseling, Genetic Testing, Physical Therapy, Supportive Care, and Intravenous Fluid Therapy; exact NCIT codes should be verified against the current thesaurus.

There is no established enzyme replacement, small molecule, gene replacement, genome editing, cell therapy, ASO, siRNA, or mRNA therapy for congenital LDHA deficiency. Importantly, hepatic LDHA inhibition is being developed for primary hyperoxaluria; that strategy models partial tissue-selective suppression and is not a treatment for systemic LDHA deficiency. (lai2018specificinhibitionof pages 10-11, ariceta2021hepaticlactatedehydrogenase pages 2-4)

No disease-specific therapeutic ClinicalTrials.gov study was found. NCT07459582, first posted 10 March 2026, is an observational study of home lactate and glucose meters in ten participants across GSD Ia, Ib, and XI; it is not a treatment trial and is not restricted to LDHA deficiency. (NCT07459582 chunk 1)

13. Prevention

Because the causal variants are inherited, primary prevention by lifestyle or vaccination is not possible.

Primary reproductive prevention/options: carrier testing in relatives, partner testing where appropriate, prenatal diagnosis, and preimplantation genetic testing when familial pathogenic variants are known. These are options requiring nondirective genetic counseling, not recommendations that affected pregnancies be avoided.
Secondary prevention: early diagnosis after characteristic exertional episodes; cascade testing of relatives; anticipatory education before severe attacks.
Tertiary prevention: avoid individually identified high-risk exertion, maintain hydration during illness/exercise, recognize pigmenturia promptly, and institute early rhabdomyolysis/renal monitoring.

No prophylactic drug, immunization, public-health screening recommendation, or controlled behavioral-prevention trial exists.

14. Other species and natural disease

No naturally occurring veterinary analogue, breed association, zoonotic potential, or cross-species transmission was identified. The disease is genetic and noncommunicable. Orthologous LDH genes are deeply conserved across animals, supporting comparative study, but conservation alone does not establish naturally occurring disease in another species.

Suggested taxonomy annotations include Homo sapiens, NCBI Taxon 9606 for the natural human disease, Mus musculus, Taxon 10090 for experimental mouse work, and Drosophila melanogaster, Taxon 7227 for the emerging invertebrate model. Exact ortholog gene identifiers should be imported directly from NCBI/Alliance releases.

15. Model organisms

No established animal model was found that fully reproduces the human congenital syndrome and has been validated for preclinical therapy.

Drosophila Ldh loss of function: a 2026 bioRxiv preprint reported reduced mobility, exercise intolerance, and food-consistency-dependent lethality. Tissue-specific work implicated muscle and peripheral glia; reducing the mechanical demand of feeding rescued viability. This supports a demand-dependent neuromuscular-energy model, but it is a non-peer-reviewed larval fly study and postdates the requested 2023–2024 priority window. It does not establish the human skin or rhabdomyolysis phenotype. (rai2026drosophilamelanogasterlactate pages 1-5, rai2026drosophilamelanogasterlactate pages 20-24)
Mouse LDHA inhibition/conditional deletion: available models primarily investigate liver-directed inhibition in primary hyperoxaluria, cardiac stress, cancer, or other metabolic questions. They clarify tissue-specific LDHA biology but are not validated GSD-XI models. Liver-directed siRNA studies measure lactate/pyruvate and exercise effects while intentionally sparing skeletal muscle, limiting disease relevance. (lai2018specificinhibitionof pages 10-11, dai2020lactatedehydrogenasea pages 11-12)
Cellular systems: LDHA knockout cells demonstrate effects on glycolysis and redox balance in several biological contexts, but no patient-derived myotube, iPSC-muscle, skin organoid, or CRISPR-corrected GSD-XI platform was identified in the retrieved literature.

Priority model-development needs are patient-derived myotubes and keratinocytes, conditional skeletal-muscle LDHA knockout models, isotope-resolved NAD⁺/NADH and pyruvate/lactate flux studies, and exercise paradigms that quantify CK, myoglobin, histologic injury, renal complications, and rescue.

Recent developments and expert assessment

The most disease-specific modern advance remains the 11 October 2022 Genes report, which added two Spanish families, two nonsense alleles, segregation data, a reproducible exercise-test signature, and functional isoenzyme confirmation. Its abstract states: “LDH-A deficiency is an autosomal recessive disorder (glycogenosis type XI, OMIM#612933) caused by mutations in the LDHA gene,” and reports “two young adult female patients presenting with intolerance to anaerobic exercise, episodes of rhabdomyolysis, and, in one of the patients, psoriasis-like dermatitis.” It concludes that “a flat lactate curve on the forearm exercise test, along with the clinical combination of myopathy and psoriatic-like dermatitis, can also lead to the diagnosis.” DOI: https://doi.org/10.3390/genes13101835. A PMID was not present in the retrieved record and is therefore not supplied. (serranolorenzo2022clinicalbiochemicaland pages 1-2, serranolorenzo2022clinicalbiochemicaland pages 9-11)

The authoritative 2023 Nature Reviews Disease Primers overview places GSDs within disorders of glycogen handling and emphasizes their organ-specific heterogeneity, but the retrieved evidence did not provide new GSD-XI patient data. Likewise, recent 2023–2024 work on muscle fatigue, lactate transport, mitochondrial adaptation, and LDH isoenzyme balance improves biological context rather than changing diagnosis or treatment. Thus, the current expert interpretation should remain conservative: the biochemical lesion and exercise phenotype are compelling, but epidemiology, penetrance, natural history, optimal exercise prescription, skin mechanism, and therapy remain unresolved.

Evidence limitations

The disease literature consists mainly of isolated families, retrospective descriptions, and reviews that reuse the same cases. Frequencies are highly vulnerable to ascertainment and publication bias. Family-level counts cannot be interpreted as patient prevalence; normal total LDH does not exclude disease; and mechanistic claims about NAD⁺, ATP, calcium, or inflammatory mediators should be labeled inferred unless measured in affected tissue. No verified disease-specific PMID was available from the retrieved full-text records, so DOI URLs and publication dates are supplied rather than fabricated PMID mappings.

References

(serranolorenzo2022clinicalbiochemicaland pages 5-7): Pablo Serrano-Lorenzo, María Rabasa, Jesús Esteban, Irene Hidalgo Mayoral, Cristina Domínguez-González, Agustín Blanco-Echevarría, Rocío Garrido-Moraga, Alejandro Lucia, Alberto Blázquez, Juan C. Rubio, Carmen Palma-Milla, Joaquín Arenas, and Miguel A. Martín. Clinical, biochemical, and molecular characterization of two families with novel mutations in the ldha gene (gsd xi). Oct 2022. URL: https://doi.org/10.3390/genes13101835, doi:10.3390/genes13101835. This article has 10 citations.
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(serranolorenzo2022clinicalbiochemicaland pages 7-9): Pablo Serrano-Lorenzo, María Rabasa, Jesús Esteban, Irene Hidalgo Mayoral, Cristina Domínguez-González, Agustín Blanco-Echevarría, Rocío Garrido-Moraga, Alejandro Lucia, Alberto Blázquez, Juan C. Rubio, Carmen Palma-Milla, Joaquín Arenas, and Miguel A. Martín. Clinical, biochemical, and molecular characterization of two families with novel mutations in the ldha gene (gsd xi). Oct 2022. URL: https://doi.org/10.3390/genes13101835, doi:10.3390/genes13101835. This article has 10 citations.
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Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
On topic	3
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	20
Resolved	18
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2

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.

18 of 20 terms resolved to a current term; the rest could not be looked up either way.

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Glycogen Storage Disease Due to Lactate Dehydrogenase M-Subunit Deficiency

Executive summary

1. Disease information

Definition and identifiers

2. Etiology, risk, and protective factors

Causal factor

Genetic risk factors

Environmental and lifestyle modifiers

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Cells, tissues, and pathways

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Practical diagnostic approach

Differential diagnosis

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Recent developments and expert assessment

Evidence limitations

Artifacts

Reference Validation

Term Validation

Prefixes with no resolver