| 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**. (pqac-00000002, pqac-00000006) |
| 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. (pqac-00000001, pqac-00000002, pqac-00000007) |
| 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. (pqac-00000003, pqac-00000021, pqac-00000022) |
| 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. (pqac-00000023, pqac-00000024) |
| 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. (pqac-00000000, pqac-00000004, pqac-00000011) |
| 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. (pqac-00000003, pqac-00000004, pqac-00000010) |
| 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. (pqac-00000001, pqac-00000004) |
| 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. (pqac-00000001, pqac-00000004) |
| 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. (pqac-00000002, pqac-00000009, pqac-00000010) |
| 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. (pqac-00000019, pqac-00000024) |
| 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. (pqac-00000016) |
| 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. (pqac-00000002, pqac-00000019) |
| 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. (pqac-00000008, pqac-00000009, pqac-00000012) |


*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.*