| Knowledge-base field | Evidence-based summary | Evidence level |
|---|---|---|
| Disease identity | Rare inherited metabolic myopathy characterized by acute, often recurrent skeletal-muscle breakdown with myoglobinuria; commonly termed **LPIN1-related recurrent rhabdomyolysis**, **lipin-1 deficiency**, or **LPIN1-related recurrent acute myoglobinuria**. (pqac-00000000, pqac-00000004) | Aggregated human cohorts |
| Inheritance | Classically **autosomal recessive**, caused by biallelic loss-of-function LPIN1 variants. Parents are generally asymptomatic heterozygotes, although cramps or myalgia have occasionally been reported in carriers; isolated heterozygous adult cases remain insufficient to establish a dominant disorder. (pqac-00000003, pqac-00000004) | Human cohorts; isolated case reports |
| Typical onset and course | Usually begins before age 6; one foundational cohort reported median onset at **21 months**. Patients are often clinically normal between attacks, with normal or near-normal baseline CK, although adolescent- and adult-onset disease occurs rarely. (pqac-00000000, pqac-00000004) | Human cohorts |
| Principal triggers | Febrile illness and infection are most common; fasting, prolonged or strenuous exercise, anesthesia, and other catabolic stressors also precipitate attacks. These exposures trigger episodes rather than cause the underlying genetic disease. (pqac-00000001, pqac-00000004) | Human cohorts and case series |
| Hallmark phenotypes and laboratory findings | Acute myalgia, weakness, muscle tenderness, fatigue, hypotonia, dark/cola- or rose-colored urine, myoglobinuria, and extreme CK elevation. Peak CK is commonly **>10,000 U/L** and may exceed **100,000 U/L**; one three-child series reported mean episode CK **147,660.7 ± 28,144.5 U/L** versus baseline **438.0 ± 215.9 U/L**, with marked AST elevation. Between episodes, examination, EMG, MRI, and CK can be normal. (pqac-00000001, pqac-00000002, pqac-00000018) | Human cohorts and case series |
| Major complications and mortality | Hyperkalemia and other electrolyte disturbances, circulatory collapse, arrhythmia/cardiac arrest, acute kidney injury from myoglobin-associated tubular injury, and multiorgan failure may occur. Published historical series reported **11/35 affected patients** dying during attacks; another report cited mortality up to **14%**, but modern population-level survival estimates are unavailable. (pqac-00000002, pqac-00000017) | Historical human cohorts/reviewed cases |
| Gene/protein mechanism | LPIN1 encodes lipin-1, a phosphatidate phosphatase that converts phosphatidic acid to diacylglycerol and also acts as a transcriptional coregulator. Loss of phosphatidate-phosphatase activity disrupts glycerolipid and membrane-lipid homeostasis, promotes phosphatidic-acid accumulation, abnormal lipid droplets, defective autophagy/mitophagy, mitochondrial dysfunction, and sarcoplasmic-reticulum stress; inflammatory cytokines may amplify this constitutive metabolic vulnerability during infection. (pqac-00000007, pqac-00000013, pqac-00000015, pqac-00000016) | Human cells; yeast functional assays; mouse models |
| Diagnosis | Suspect in severe or recurrent early-childhood rhabdomyolysis, particularly when attacks are infection/fasting-associated and CK normalizes between episodes. Confirm with sequencing plus deletion/duplication analysis of LPIN1 or a rhabdomyolysis/metabolic-myopathy panel; WES/WGS may be used when panel testing is unrevealing. RNA analysis can identify large deletions missed by routine DNA sequencing. Biochemical testing helps exclude fatty-acid oxidation disorders, glycogenoses, mitochondrial disease, RYR1-related susceptibility, TANGO2-related disease, and phosphoglycerate-kinase deficiency. (pqac-00000002, pqac-00000003, pqac-00000005) | Human diagnostic cohorts and case reports |
| Acute management | Medical emergency management is supportive: stop exertion, reverse fasting/catabolism, provide prompt carbohydrate/nutritional support and intravenous fluids, closely monitor urine output, CK, renal function, glucose, electrolytes, acid–base status, and ECG, and treat hyperkalemia, arrhythmia, shock, or acute kidney injury; renal-replacement therapy is reserved for standard indications. No disease-specific regimen has been validated in randomized trials. (pqac-00000001, pqac-00000010) | Case series; general rhabdomyolysis practice |
| Prevention | Maintain hydration and regular carbohydrate intake during illness, avoid prolonged fasting and unaccustomed strenuous exercise, and use an individualized emergency letter/sick-day plan for early hospital assessment and anti-catabolic treatment. Cascade testing and genetic counseling permit identification of affected siblings and reproductive-risk assessment. (pqac-00000003, pqac-00000005) | Expert recommendations and case-based evidence |
| Experimental therapies and trials | Systemic corticosteroids have been evaluated retrospectively for acute episodes, but available evidence is nonrandomized and does not establish universal dosing or efficacy. Hydroxychloroquine was used compassionately in eight genetically confirmed pediatric patients with planned assessment of attacks, pain, and arrhythmias; registry **NCT04007562** was subsequently withdrawn with enrollment recorded as zero, so efficacy remains unproven. Chemical chaperones and fatty-acid-oxidation activation improved disease features only in mice. (pqac-00000009, pqac-00000011, pqac-00000012, pqac-00000015) | Retrospective human evidence; trial registry; mouse experiments |
| Models | LPIN1-deficient human myoblasts model starvation responses, autophagic flux, mitophagy, mitochondrial ROS and inflammatory signaling. Muscle-specific Lpin1-deficient mice develop lipid accumulation, chronic necrosis/regeneration, abnormal mitochondria, stress-sensitive CK release, and chaperone-responsive myopathy. Zebrafish lpin1 loss disrupts motor-neuron projections, myelination, and neuromuscular junctions; partial rescue by Notch inhibitor DAPT supports a developmental Notch contribution, although this atypical neurologic phenotype is not the canonical recurrent-myoglobinuria presentation. (pqac-00000013, pqac-00000014, pqac-00000015) | Human cells; mouse; zebrafish |


*Table: Compact evidence-calibrated summary of LPIN1-related recurrent myoglobinuria, spanning clinical presentation, mechanism, diagnosis, management, investigational therapies, and experimental models.*