LPIN1-Related Recurrent Myoglobinuria

Genetic MONDO:0009992 Pathograph 27 Show in embeddings browser MONDO:0020504

LPIN1-related recurrent myoglobinuria (OMIM #268200) is an autosomal recessive disorder caused by biallelic loss-of-function variants in LPIN1, which encodes lipin-1, the Mg2+-dependent phosphatidic acid phosphatase that converts phosphatidic acid to diacylglycerol and accounts for most of that activity in skeletal muscle. It is a major cause, in some series the commonest, of severe recurrent rhabdomyolysis in early childhood: episodes usually begin before age six (mean about 21 months), are precipitated by febrile illness, fasting, strenuous exercise or anaesthesia, and produce massive creatine kinase elevation (often above 100,000 U/L), myoglobinuria, myalgia and weakness, with acute kidney injury, hyperkalaemia and fatal arrhythmia in the most severe attacks; about a third of patients have died, most during a crisis. Between attacks most patients are clinically well, although exercise intolerance and permanent muscle symptoms occur, and rare adolescent- or adult-onset and atypical neuromuscular presentations are described. Patient muscle and myoblasts show loss of phosphatidate phosphatase activity, phosphatidic acid and lipid-droplet accumulation, impaired fatty acid oxidation during exercise, and defective mitochondrial quality control in which oxidised mitochondrial DNA accumulating in late endosomes activates TLR9-driven inflammatory signalling and caspase-dependent myolysis, a model that also explains the febrile trigger. Muscle-specific Lpin1-null mice add sarcoplasmic reticulum stress and loss of membrane integrity with apoptotic and necroptotic myofibre death. There is no approved targeted therapy: attacks are managed with aggressive intravenous fluid and glucose, electrolyte and cardiac monitoring, and, in the largest cohort, intravenous corticosteroids; low-dose hydroxychloroquine has been given compassionately, and glucose loading improves exercise capacity. The mitochondrially inherited recurrent myoglobinuria attributed to mtDNA cytochrome c oxidase gene mutations (MONDO:0010791, OMIM 550500) is a separate entity.

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1
Mappings
1
Inheritance
6
Pathophys.
13
Phenotypes
2
Gaps
27
Pathograph
1
Genes
1
Variants
6
Medical Actions
3
Differentials
1
Trials
2
Models
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
ICIMD (Inherited Metabolic Disorders)
glycerolipid metabolism
🔗

Mappings

MONDO
MONDO:0010791 myoglobinuria, recurrent Not Yet Curated
skos:relatedMatch MONDO
MONDO:0010791 is cross-referenced to OMIM 550500, the mitochondrially inherited recurrent myoglobinuria attributed to mtDNA cytochrome c oxidase gene mutations, although its GARD-derived definition also mentions LPIN1. It is recorded here as a related cross-reference only; the LPIN1 disorder is MONDO:0009992 (OMIM 268200), and the MONDO:0010791 concept remains uncurated.
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Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive; heterozygous relatives may have mild exercise-induced myalgia but not rhabdomyolysis.
Autosomal recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:36195520 SUPPORT Human Clinical
"LPIN1 deficiency is an autosomal recessive disease caused by biallelic mutations in LPIN1, where impaired fatty acid metabolism leads to stress in skeletal muscle, resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia."
States the inheritance pattern.
PMID:22481384 SUPPORT Human Clinical
"At least 40% of heterozygous relatives presented muscular myalgia."
Carrier manifestation short of the recessive phenotype.
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Discussions and Knowledge Gaps

2
What determines the transition from a clinically silent lipin-1-deficient muscle to massive acute myolysis during a febrile or catabolic trigger, and why are some patients spared between attacks while others develop chronic symptoms?
KNOWLEDGE GAP OPEN lpin1_episodic_attack_mechanism_gap
Attached to
pathophysiology#Trigger-Induced Myofibre Necrosis
The TLR9 inflammatory model and the SR-stress model each explain part of the picture, but neither predicts which trigger will precipitate an attack in a given patient; the cohort literature states that the pathophysiological basis of the rhabdomyolysis has not been fully elucidated, and attacks can occur without any identified trigger.
Show evidence (1 reference)
PMID:35242575 SUPPORT Human Clinical
"Individuals with LPIN1 deficiency have early recurrent, life-threatening rhabdomyolysis but the full phenotypic spectrum and optimal treatment of the disorder remains unknown."
Authors' statement of the outstanding gap.
Do lipin-1-deficient mice, which show chronic myopathy and, in the constitutive model, lipodystrophy, model the episodic rhabdomyolysis of patients whose adipose tissue and interictal muscle are essentially normal?
HUMAN MODEL MISMATCH OPEN lpin1_mouse_chronic_myopathy_mismatch
Attached to
pathophysiology#Trigger-Induced Myofibre Necrosis
The constitutive fld mouse is confounded by lipodystrophy that patients do not have, and muscle-specific knockouts show continuous necrosis-regeneration rather than discrete attacks; patient adipose tissue develops normally, and patient myoblasts show only minor changes in lipin-1 target gene expression. Findings from mice, including the SR-stress branch and TUDCA/bezafibrate responses, therefore need human confirmation.
Show evidence (2 references)
PMID:30028636 SUPPORT Model Organism
"However, that mouse model is confounded by lipodystrophy not phenocopied in people."
Authors acknowledge the mismatch of the constitutive model.
PMID:28986436 SUPPORT Human Clinical
"Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far."
Human adipose phenotype differs from the mouse.
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Pathophysiology

6
Biallelic LPIN1 Loss of Function
Biallelic LPIN1 variants abolish lipin-1 protein and its Mg2+-dependent phosphatidate phosphatase (PAP-1) activity in skeletal muscle, where lipin-1 provides most PAP activity. Lipin-1 also acts as a nuclear transcriptional co-regulator of lipid-oxidation genes, but in patient myoblasts the expression of its PPAR/PGC-1alpha target genes is preserved, so the enzymatic loss is the primary lesion.
phosphatidate phosphatase activity GO:0008195 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphatidate phosphatase activity (GO:0008195). GO:0008195 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Phosphatidic Acid Accumulation and Glycerolipid Imbalance
Show evidence (2 references)
PMID:18817903 SUPPORT Human Clinical
"The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis."
Identifies the enzymatic function lost.
PMID:23928362 SUPPORT In Vitro
"Here we show that primary myoblasts from lipin-1-deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD)."
Patient-cell demonstration of the enzymatic loss.
Phosphatidic Acid Accumulation and Glycerolipid Imbalance
Without PAP-1, phosphatidic acid and lysophospholipids accumulate in muscle and lipid droplets accumulate in myofibres and myoblasts; fatty acid synthesis, oxidation, elongation and desaturation are altered, ACACB is up-regulated with free fatty acid accumulation, and, paradoxically, diacylglycerol also accumulates in mouse muscle.
fatty acid metabolic process GO:0006631 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated fatty acid metabolic process (GO:0006631). GO:0006631 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
Sarcoplasmic Reticulum Stress
Show evidence (3 references)
PMID:22481384 SUPPORT Human Clinical
"Around 3/4 of muscle biopsies showed accumulation of lipid droplets."
Lipid accumulation in patient muscle.
PMID:30028636 SUPPORT Model Organism
"In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol."
Muscle-specific knockout confirms PA accumulation downstream of PAP loss.
PMID:23928362 SUPPORT In Vitro
"We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-carnitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients."
Identifies the ACACB-driven fatty acid accumulation in patient cells.
Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
Lipin-1-deficient myoblasts have reduced phosphatidylinositol-3-phosphate near autophagosomes and late endosomes, which prevents Armus recruitment, locks Rab7 in its active state and blocks vesicle clearance by lysosomal fusion, so damaged mitochondria and their oxidised DNA are not cleared. Muscle-specific knockout mice have abundant but abnormal mitochondria attributed to impaired autophagy, and an adult patient showed markedly reduced fat oxidation during exercise.
mitophagy GO:0000423 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitophagy (GO:0000423). GO:0000423 is a biological process from the Gene Ontology. ↓ DECREASED fatty acid beta-oxidation GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
Exercise intolerance
Show evidence (3 references)
PMID:34467247 SUPPORT In Vitro
"We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their..."
Mechanistic basis of the quality-control defect in patient cells.
PMID:30028636 SUPPORT Model Organism
"Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy."
Mouse corroboration of the mitochondrial clearance defect.
PMID:31492716 SUPPORT Human Clinical
"In this adult lipin-1-deficient patient, FAO was reduced, which was associated with no increase in plasma free fatty acids during submaximal exercise, and his exercise capacity improved with continuous ingestion of high-dose glucose."
In vivo human evidence of impaired fat oxidation.
Sarcoplasmic Reticulum Stress
In muscle-specific Lpin1 mutant mice the lipid imbalance causes severe sarcoplasmic reticulum stress with activation of SREBP1c/SREBP2, accumulation of Fgf21 and altered SR-mitochondria contacts; the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength. This branch is established in mice and its contribution to human acute attacks is inferred.
response to endoplasmic reticulum stress GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Muscle-specific Lpin1 knockout mice Mouse recapitulates Muscle-specific lipin-1 loss is sufficient to trigger SR stress, lipid accumulation and chaperone-responsive myopathy.
Downstream
Trigger-Induced Myofibre Necrosis
Show evidence (1 reference)
PMID:30420558 SUPPORT Model Organism
"As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone..."
Defines the SR-stress branch and its pharmacological reversibility in mice.
Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
Oxidised mitochondrial DNA retained in late endosomes engages Toll-like receptor 9, driving inflammatory signalling and caspase-dependent myolysis. Febrile illness amplifies this: pro-inflammatory cytokines (TNF-alpha plus IL-1beta) mimicking fever raise malonyl-carnitine, reduce CPT1 activity and enhance lipid-droplet accumulation in patient myoblasts, effects reversed by dexamethasone or cytokine inhibitors. This is the proposed convergence point for the metabolic (fasting, exercise) and inflammatory (fever) triggers.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
toll-like receptor 9 signaling pathway GO:0034162 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased toll-like receptor 9 signaling pathway (GO:0034162). GO:0034162 is a biological process from the Gene Ontology. ↑ INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Patient-derived lipin-1-deficient primary myoblasts PRIMARY CELL CULTURE Patient cells reproduce the endosomal mtDNA accumulation, TLR9 activation and caspase-dependent myolysis, and respond to hydroxychloroquine.
Downstream
Trigger-Induced Myofibre Necrosis
Show evidence (2 references)
PMID:23928362 SUPPORT In Vitro
"Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1α+IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFα or IL-1ß inhibitors."
Shows inflammatory cytokines aggravate the lipid defect in patient cells, explaining the febrile trigger.
PMID:34467247 SUPPORT In Vitro
"Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated."
Pharmacological blockade of TLR9 supports its causal role.
Trigger-Induced Myofibre Necrosis
Under catabolic or inflammatory stress the vulnerable lipin-1-deficient myofibre loses plasma membrane integrity and dies by caspase-dependent, apoptotic and necroptotic pathways, releasing creatine kinase, myoglobin, potassium and transaminases. Attacks produce massive hyperCKaemia, myoglobinuria, pain and weakness; myoglobin nephrotoxicity causes acute kidney injury, and hyperkalaemia with characteristic high-amplitude T waves precedes fatal arrhythmia in the most severe episodes.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
necroptotic process GO:0070266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased necroptotic process (GO:0070266). GO:0070266 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Muscle-specific Lpin1 knockout mice Mouse partially recapitulates Chronic necrosis-regeneration myopathy with exercise-provoked CK release rather than discrete life-threatening attacks.
Downstream
Rhabdomyolysis
Myoglobinuria
Elevated circulating creatine kinase activity
Myalgia
Muscle weakness
Acute kidney injury
Cardiac arrest
Abnormal T-wave
Show evidence (3 references)
PMID:33113595 SUPPORT Model Organism
"EBD-positive fibers were strongly colocalized with apoptotic or necroptotic myofibers, suggesting an association between compromised plasma membrane integrity and cell death pathways."
Mechanism of myofibre death in muscle-specific knockout mice.
PMID:33113595 SUPPORT Model Organism
"We found that Lipin1Myf5cKO muscles had significantly elevated proapoptotic factors (Bax, Bak, and cleaved caspase-9) and necroptotic proteins such as RIPK1, RIPK3, and MLKL compared with WT mice."
Molecular markers of apoptosis and necroptosis in the knockout muscle.
PMID:30028636 SUPPORT Model Organism
"Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
Catabolic trigger reproduces CK release in the model.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for LPIN1-Related Recurrent Myoglobinuria Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Cardiovascular 2
Cardiac arrest FREQUENT HP:0001695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac arrest during rhabdomyolysis crisis, annotated with Cardiac arrest (HP:0001695). HP:0001695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29325813 SUPPORT Human Clinical
"The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode."
Frequency and setting of cardiac death.
Abnormal T-wave OCCASIONAL HP:0005135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-amplitude T waves, annotated with Abnormal T-wave (HP:0005135). HP:0005135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22480698 SUPPORT Human Clinical
"We report 2 cases of fatal rhabdomyolysis in children carrying an LPIN1 mutations preceded by similar electrocardiogram changes, including diffuse symmetrical high-amplitude T waves."
ECG changes preceding fatal attacks.
Genitourinary 2
Myoglobinuria VERY_FREQUENT HP:0002913 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoglobinuria (HP:0002913). HP:0002913 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33456573 SUPPORT Human Clinical
"Human recessive mutations in LPIN1 cause recurrent, early-onset myoglobinuria, a condition normally associated with muscle pain and weakness."
Summarises the canonical myoglobinuric presentation.
Acute kidney injury OCCASIONAL HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36195520 SUPPORT Human Clinical
"Recognition of the complications including ventricular arrythmias, acute renal failure and compartment syndrome on the severe end of the spectrum may change the outcome and prognosis of this devastating condition."
Lists acute renal failure among the severe complications.
Metabolism 3
Elevated circulating creatine kinase activity OBLIGATE HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Massive hyperCKaemia during attacks, annotated with Elevated circulating creatine kinase activity (HP:0003236), qualified as temporality recurrent. HP:0003236 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:35242575 SUPPORT Human Clinical
"Creatinine kinase (CK) levels peak during our care averaged 607,725 units/L (range 157,000-1,100,000 units/L)."
Quantifies peak CK.
Elevated circulating hepatic transaminase concentration VERY_FREQUENT HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated transaminases during attacks, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35242575 SUPPORT Human Clinical
"We observed that aspartate aminotransferase levels paralleled the CK levels in its elevation and resolution (Pearson's correlation R = 0.995); while alanine aminotransferase paralleled the elevation but lagged in the resolution of CK levels (R = 0.728)."
Documents the transaminase pattern during attacks.
Increased intramyocellular lipid droplets FREQUENT HP:0012240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lipid droplet accumulation in muscle, annotated with Increased intramyocellular lipid droplets (HP:0012240). HP:0012240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22481384 SUPPORT Human Clinical
"Around 3/4 of muscle biopsies showed accumulation of lipid droplets."
Frequency of the biopsy finding.
Musculoskeletal 3
Rhabdomyolysis OBLIGATE HP:0003201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent rhabdomyolysis, annotated with Rhabdomyolysis (HP:0003201), qualified as temporality recurrent. HP:0003201 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:18817903 SUPPORT Human Clinical
"Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis."
Defining phenotype in the discovery series.
PMID:35242575 SUPPORT Human Clinical
"Unlike historical accounts, in our patient population, rhabdomyolysis was sometimes seen without inciting viral or traumatic events."
Attacks may occur without an identified trigger.
Muscle weakness FREQUENT HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31240148 SUPPORT Human Clinical
"One-year post discharge from intensive care, the patient has residual drop foot bilaterally consistent with bilateral common peroneal neuropathies in addition to a background residual distal myopathy."
Residual weakness after a severe attack.
PMID:35242575 SUPPORT Human Clinical
"The spectrum of clinical features includes myoglobinuria, myalgia, hypotonia, muscle weakness, decreased reflexes, and in some severe cases, acute renal failure."
Second source placing muscle weakness within the clinical spectrum.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35242575 SUPPORT Human Clinical
"The spectrum of clinical features includes myoglobinuria, myalgia, hypotonia, muscle weakness, decreased reflexes, and in some severe cases, acute renal failure."
Places hypotonia within the reported clinical spectrum; no frequency is given.
Nervous System 1
Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased reflexes, annotated with Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35242575 SUPPORT Human Clinical
"The spectrum of clinical features includes myoglobinuria, myalgia, hypotonia, muscle weakness, decreased reflexes, and in some severe cases, acute renal failure."
Places decreased reflexes within the reported clinical spectrum; no frequency is given.
Constitutional 2
Myalgia VERY_FREQUENT HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33456573 SUPPORT Human Clinical
"Human recessive mutations in LPIN1 cause recurrent, early-onset myoglobinuria, a condition normally associated with muscle pain and weakness."
Pain and weakness as accompaniments of attacks.
Exercise intolerance FREQUENT HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31492716 SUPPORT Human Clinical
"The patient has exercise intolerance and monthly episodes of rhabdomyolysis."
Exercise intolerance in an adult patient studied physiologically.
PMID:29325813 SUPPORT Human Clinical
"We observed abnormal haemodynamic profiles during exercise in 3/8 patients with lipin-1 deficiency, suggesting impaired muscle oxidative phosphorylation during exercise. Fever appeared to be an aggravating factor."
Objective exercise abnormality in children.
🧬

Genetic Associations

1
LPIN1
Gene: LPIN1 hgnc:13345 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LPIN1 (hgnc:13345). hgnc:13345 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:18817903 SUPPORT Human Clinical
"Mutations in the LPIN1 gene cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy."
Gene discovery and the carrier statin-myopathy observation.
PMID:22481384 SUPPORT Human Clinical
"Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations."
Carrier phenotype and exclusion of the paralogues.
PMID:28986436 SUPPORT Human Clinical
"White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal..."
Shows the human phenotype is confined to muscle despite systemic loss of the enzyme.
Variants (1)
c.2295-866_2410-30del (p.Glu766_Ser838del) Pathogenic
deletion
Recurrent intragenic deletion found in 8 of 17 mutation-positive patients in the French cohort, all Caucasian, on a common haplotype suggesting a founder effect; the deleted protein is unable to complement pah1-deficient yeast. Its high frequency makes targeted testing a fast first diagnostic step.
Show evidence (1 reference)
PMID:20583302 SUPPORT Human Clinical
"The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement Delta pah1 yeast for growth on glycerol, in contrast to..."
Frequency, founder haplotype and functional loss of the recurrent deletion.
💊

Medical Actions

6
Emergency management of acute rhabdomyolysis
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
An attack is a medical emergency: stop exertion and reverse catabolism with intravenous glucose-containing fluids, monitor CK, potassium, calcium, phosphate, renal function and ECG, treat hyperkalaemia and arrhythmia, and use renal replacement therapy for standard indications; management in a paediatric intensive care unit is advised because of the risk of fatal arrhythmia. A standardised care recommendation has been published.
Target Phenotypes: Rhabdomyolysis HP:0003201 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rhabdomyolysis (HP:0003201). HP:0003201 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22480698 SUPPORT Human Clinical
"Our report underlines the severity of this disease and the need for active management of episodes of rhabdomyolysis in a pediatric intensive care unit."
Basis for intensive-care management of attacks.
PMID:35242575 SUPPORT Human Clinical
"This allowed us to compare multiple practice approaches and led to a standardized Care Recommendations."
Published standardised care recommendation.
Intravenous corticosteroids during attacks
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dexamethasone (intravenous corticosteroid) CHEBI:41879 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexamethasone (intravenous corticosteroid), annotated with dexamethasone (CHEBI:41879). CHEBI:41879 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Since 2015 the Paris cohort has given intravenous corticosteroids during attacks and at-risk situations, on the rationale of TLR9-driven inflammation; in a retrospective comparison there were no deaths among corticosteroid-treated patients versus four in the untreated group, and steroid-treated episodes were fewer per patient, although episodes were more severe and stays longer. Considered centre-specific practice rather than established standard of care.
Mechanism Target:
Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling — Suppresses the inflammatory signalling proposed to drive myolysis during attacks.
Show evidence (2 references)
PMID:36680547 SUPPORT Human Clinical
"Four patients in the non-corticosteroid group died during a RM (mean age at death: 5.6 years). There were no deaths in the corticosteroid group."
Survival signal in the retrospective comparison.
PMID:36680547 SUPPORT Human Clinical
"The peak plasma creatine kinase level and the area under the curve were or tended to be higher in patients treated with corticosteroids-even after the exclusion of deceased patients or focusing on the period after 2015."
Records the caveat that treated episodes were more severe, limiting causal inference.
Low-dose hydroxychloroquine (compassionate)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: hydroxychloroquine CHEBI:5801 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydroxychloroquine (CHEBI:5801). CHEBI:5801 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and was given off-label to eleven patients, improving physical capacity and normalising cardiac and exercise parameters; two patients with the highest blood concentrations had attacks, and in vitro high concentrations block autophagy while low concentrations reduce oxidative stress, so dosing must stay low. The registered trial (NCT04007562) was withdrawn, and efficacy is unproven.
Mechanism Target:
Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling — Blocks endosomal TLR9 activation by oxidised mitochondrial DNA and reduces oxidative stress at low concentration.
Show evidence (2 references)
PMID:37150031 SUPPORT Human Clinical
"Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM."
Clinical benefit and the dose-related hazard.
PMID:37150031 SUPPORT In Vitro
"We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation..."
Mechanistic basis for low-dose use.
Glucose supplementation during exercise and avoidance of fasting
Action: Dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Continuous high-dose glucose intake before and during exercise improved exercise duration and perceived exertion in an adult patient; avoiding fasting and prolonged exertion, and providing carbohydrate during illness, are standard preventive measures.
Mechanism Target:
Impaired Mitochondrial Quality Control and Fatty Acid Oxidation — Bypasses impaired fat oxidation by supplying carbohydrate fuel.
Show evidence (1 reference)
PMID:31492716 SUPPORT Human Clinical
"The patient's exercise duration increased from 36 to 60 minutes with IV glucose and 46 minutes with oral glucose, and his rating of exertion dropped from 15 to 9 on average (Borg scale)."
Direct evidence of glucose benefit.
TUDCA and bezafibrate (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
In muscle-specific Lpin1 mutant mice the chemical chaperone tauroursodeoxycholic acid and the PPAR agonist bezafibrate improved muscle histology and strength, proposing SR stress and fatty acid oxidation as intervention targets; not tested in patients.
Mechanism Target:
Sarcoplasmic Reticulum Stress — Chaperone relief of SR stress and activation of fatty acid oxidation.
Show evidence (1 reference)
PMID:30420558 SUPPORT Model Organism
"Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants."
Preclinical efficacy in the mouse model.
Genetic counseling and carrier advice
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive counselling with targeted testing for the recurrent intragenic deletion in Caucasian families; heterozygous carriers may have exercise-induced myalgia and a carrier state may predispose to statin-induced myopathy.
Show evidence (1 reference)
PMID:18817903 SUPPORT Human Clinical
"Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene."
Carrier-relevant counselling point.
🌍

Environmental Factors

4
Febrile illness
febrile infectious illness Relation: this environmental factor is this exposure This environmental factor is febrile infectious illness.
ECTO was searched through the repository label cache for a fever or febrile-illness exposure term and none is cached; the exposure is left unbound rather than bound to an unrelated infection term.
Intercurrent febrile infection is the commonest precipitant of attacks; inflammatory cytokines aggravate the lipid defect in patient myoblasts, and fever worsens exercise haemodynamics in patients.
Show evidence (2 references)
PMID:23928362 SUPPORT In Vitro
"Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses."
States the febrile trigger in patients.
PMID:29325813 SUPPORT Human Clinical
"Lipin-1 deficiency is a major cause of rhabdomyolysis that are precipitated by febrile illness."
Independent clinical statement of the febrile trigger.
Mechanism Target:
TRIGGERS Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling — Fever-associated cytokines (TNF-alpha, IL-1beta) amplify the inflammatory and lipid abnormalities in lipin-1-deficient muscle cells.
Show evidence (1 reference)
PMID:23928362 SUPPORT In Vitro
"Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1α+IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFα or IL-1ß inhibitors."
Cytokine mimicry of fever aggravates the cellular defect.
Strenuous exercise
exposure to strenuous exercise ECTO:6000031 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to strenuous exercise (ECTO:6000031). ECTO:6000031 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Bound to the strenuous-exercise ECTO term already used elsewhere in the KB. Fasting and anaesthesia, previously bundled here, are now separate entries.
Prolonged or strenuous exercise precipitates attacks; exercise tolerance improves with continuous glucose intake.
Show evidence (2 references)
PMID:36195520 SUPPORT Human Clinical
"resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia"
Lists exercise among the clinical triggers.
PMID:31492716 SUPPORT Human Clinical
"The patient's exercise duration increased from 36 to 60 minutes with IV glucose and 46 minutes with oral glucose, and his rating of exertion dropped from 15 to 9 on average (Borg scale)."
Glucose supply mitigates the exercise trigger.
Mechanism Target:
TRIGGERS Impaired Mitochondrial Quality Control and Fatty Acid Oxidation — Exercise increases reliance on fatty acid oxidation, which is impaired, and exhaustive unfed exercise provokes CK release in muscle-specific knockout mice.
Show evidence (1 reference)
PMID:30028636 SUPPORT Model Organism
"Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
Exercise-plus-fasting provokes muscle injury in the model.
Fasting
prolonged fasting Relation: this environmental factor is this exposure This environmental factor is prolonged fasting.
ECTO was searched through the repository label cache for a fasting exposure term and none is cached; the exposure is left unbound.
Prolonged fasting and other catabolic states precipitate attacks by increasing reliance on the impaired fatty acid oxidation pathway; regular carbohydrate intake during illness is the mainstay of prevention.
Show evidence (1 reference)
PMID:36195520 SUPPORT Human Clinical
"resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia"
Lists fasting among the clinical triggers.
Mechanism Target:
TRIGGERS Impaired Mitochondrial Quality Control and Fatty Acid Oxidation — Fasting shifts muscle to fatty acid oxidation, which is impaired; unfed exhaustive exercise provokes CK release in muscle-specific knockout mice.
Show evidence (1 reference)
PMID:30028636 SUPPORT Model Organism
"Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
The unfed state is part of the provoking condition in the model.
General anaesthesia
exposure to general anaesthesia ECTO:2000059 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to general anaesthesia, annotated with exposure to anesthetics (ECTO:2000059). ECTO:2000059 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Bound to the ECTO anaesthetics exposure term already cached in the KB. Not linked into the pathograph because the cited sources do not identify which mechanism anaesthesia acts on.
General anaesthesia is a recognised precipitant of rhabdomyolysis in lipin-1 deficiency, so perioperative catabolism should be prevented with glucose-containing fluids.
Show evidence (1 reference)
PMID:36195520 SUPPORT Human Clinical
"resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia"
Lists anaesthesia among the clinical triggers.
🔬

Diagnosis

3
Molecular genetic testing for biallelic LPIN1 variants
LPIN1 should be sequenced in any child with severe recurrent rhabdomyolysis once fatty acid oxidation defects are excluded, and included in adult rhabdomyolysis panels; targeted testing for the recurrent intragenic deletion allows fast diagnosis before biopsy. Rare compound heterozygous variants need functional confirmation. A large LPIN1 deletion can be missed by DNA sequencing and detected only by mRNA analysis, so a negative panel in a typical case does not exclude the diagnosis.
Show evidence (4 references)
PMID:37510298 SUPPORT Human Clinical
"In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis."
RNA analysis as the route to a deletion invisible to DNA sequencing.
PMID:20583302 SUPPORT Human Clinical
"The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy."
Diagnostic strategy built on the founder deletion.
PMID:32522502 SUPPORT Human Clinical
"LPIN1 should be included on a panel of genes analysed in the investigation of adult individuals with rhabdomyolysis."
Extends testing to adult presentations.
+ 1 more reference
Serum creatine kinase and urine myoglobin during attacks
Massive CK elevation with myoglobinuria during episodes, with AST paralleling CK, confirms rhabdomyolysis; values may be normal between attacks.
Show evidence (1 reference)
PMID:35242575 SUPPORT Human Clinical
"Creatinine kinase (CK) levels peak during our care averaged 607,725 units/L (range 157,000-1,100,000 units/L)."
Laboratory hallmark of attacks.
Cardiac evaluation and exercise testing
Resting echocardiography is usually normal, but exercise testing can reveal impaired peripheral muscle adaptation and cardiac MR spectroscopy may show intracardiac steatosis; ECG monitoring during attacks detects hyperkalaemic T-wave changes.
Show evidence (1 reference)
PMID:29325813 SUPPORT Human Clinical
"The four patients assessed by cardiac 1H-magnetic resonance spectroscopy exhibited signs of intracardiac steatosis."
Cardiac imaging finding.
📈

Progression

2
Early-childhood onset of recurrent attacks
First episodes occur at 2-7 years in the original series and at a mean of 21 months in the French cohort; nearly all patients present before age five. Attacks recur with intercurrent illness, fasting or exertion throughout childhood, and roughly a third of patients die, usually from cardiac arrest during a crisis.
Show evidence (3 references)
PMID:18817903 SUPPORT Human Clinical
"Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis."
Age at presentation in the gene-discovery series.
PMID:20583302 SUPPORT Human Clinical
"In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months."
Mean age of first episodes in the largest early cohort.
PMID:29325813 SUPPORT Human Clinical
"The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode."
Mortality and its mechanism during attacks.
Adolescent and adult course
Survivors are usually well between attacks but may have exercise intolerance, persistent myalgia or a residual distal myopathy; rare patients first present in adolescence or adulthood after viral infection or metabolic stress.
Show evidence (2 references)
PMID:32522502 SUPPORT Human Clinical
"Here we present two cases of acute rhabdomyolysis with a milder phenotype caused by LPIN1 mutation presenting in adolescence (11 years old) and adulthood (40 years old) after Parvovirus infection and metabolic stress, respectively."
Documents late first presentations.
PMID:22481384 SUPPORT Human Clinical
"All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones"
Age of onset distribution and persistent symptoms in older patients.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Seventy-one patients had been published in 20 clinical studies by 2022. Among children with severe early-childhood rhabdomyolysis after exclusion of fatty acid oxidation defects, LPIN1 variants were found in 59% of a French series.
Show evidence (2 references)
PMID:36195520 SUPPORT Human Clinical
"To date, 71 patients have been published in 20 clinical studies in the form of case series."
Reported-case denominator as of 2022.
PMID:20583302 SUPPORT Human Clinical
"Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion."
Share of severe early-childhood rhabdomyolysis attributable to LPIN1 in the discovery cohort.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from LPIN1-Related Recurrent Myoglobinuria:

Glycogen storage disease type V (McArdle disease) and other glycogenolysis defects
Overlapping Features Glycogenolysis defects cause exercise-induced rhabdomyolysis with a second-wind phenomenon and glycogen storage on biopsy.
Distinguishing Features
  • Glycogen accumulation on muscle biopsy, absent in lipin-1 deficiency
  • Attacks provoked by brief intense exercise rather than by fever or fasting
Show evidence (1 reference)
PMID:18817903 SUPPORT Human Clinical
"Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways."
Places LPIN1 deficiency against the classical differential.
Fatty acid oxidation defects (CPT2 and VLCAD deficiency)
Overlapping Features Long-chain fatty acid oxidation defects share fasting- and fever-triggered rhabdomyolysis but show a diagnostic acylcarnitine profile and enzyme defect.
Distinguishing Features
  • Abnormal acylcarnitine profile and a demonstrable fatty acid oxidation enzyme defect
  • Lipin-1 deficiency has a normal acylcarnitine profile with lipid droplet accumulation
Show evidence (1 reference)
PMID:18817903 SUPPORT Human Clinical
"Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways."
Places LPIN1 deficiency against the classical differential.
Mitochondrial oxidative phosphorylation disorders
Overlapping Features Respiratory chain disorders, including the mitochondrial cytochrome c oxidase-related recurrent myoglobinuria (MONDO:0010791), are the remaining classical cause; LPIN1 explains a large share of the early-childhood cases without any of these defects.
Distinguishing Features
  • Ragged-red fibres or respiratory chain enzyme deficiency on biopsy
  • Onset before age six with biallelic LPIN1 variants, often the recurrent intragenic deletion
Show evidence (1 reference)
PMID:18817903 SUPPORT Human Clinical
"Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways."
Places LPIN1 deficiency against the classical differential.
🔬

Clinical Trials

1
NCT04007562 NOT_APPLICABLE WITHDRAWN
Retrospective study of the safety and efficacy of compassionate low-dose hydroxychloroquine in lipin-1 deficiency; withdrawn with no enrolment, so the therapeutic avenue remains unproven.
Show evidence (1 reference)
clinicaltrials:NCT04007562 SUPPORT Other
"The objective of this retrospective study is to describe the safety and efficacy of Hydroxychloroquine Sulfate given on a compassionate basis to patients suffering from Lipin-1 deficiency within a period between 6 and 36 months."
Registration summary of the withdrawn study.
🧫

Experimental Models

1
Patient-derived lipin-1-deficient primary myoblasts PRIMARY_CELL_CULTURE
Primary myoblasts and myotubes from patients, used to show loss of PAP-1 activity, lipid droplet accumulation, ACACB up-regulation, cytokine sensitivity, defective autophagosome-lysosome clearance and TLR9 activation by oxidised mitochondrial DNA.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:34467247
Pathograph links
Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling recapitulates fidelity: high observes: cellular Patient cells reproduce the endosomal mtDNA accumulation, TLR9 activation and caspase-dependent myolysis, and respond to hydroxychloroquine.
Limitations: Cultured myoblasts lack the contractile, metabolic and systemic context of an attack; the in vivo relevance rests on the compassionate hydroxychloroquine experience.
Show evidence (1 reference)
PMID:34467247 SUPPORT In Vitro
"Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency."
Establishes the patient-cell system used for the mechanism.
🐁

Animal Models

1
Muscle-specific Lpin1 knockout mice
Muscle-restricted models that avoid the lipodystrophy of the constitutive fld mouse; both show chronic myopathy with fibre necrosis and regeneration, phosphatidic acid and diacylglycerol accumulation, abnormal mitochondria with impaired autophagy, and increased CK after exhaustive unfed exercise. A Myf5-Cre knockout further shows loss of membrane integrity with apoptotic and necroptotic fibre death and reduced force.
Species
Mouse
Genotype
Lpin1 exon 3-4 deletion (PAP-null hypomorph) or exon 7 deletion (protein-null), skeletal muscle-specific
Publication
PMID:30028636
Pathograph links
Trigger-Induced Myofibre Necrosis partially recapitulates fidelity: moderate observes: tissue Chronic necrosis-regeneration myopathy with exercise-provoked CK release rather than discrete life-threatening attacks.
Limitations: Mice develop a chronic myopathy, whereas patients are usually well between discrete catabolism-triggered attacks; the episodic, fever-triggered human phenotype is not reproduced.
Readouts
Plasma creatine kinase after exhaustive unfed exercise
Direction: INCREASED
Interpretation: Provoked muscle injury in the model.
Show evidence (1 reference)
PMID:30028636 SUPPORT Model Organism
"Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
Reports the CK readout.
Evans Blue Dye uptake and IgG staining of myofibres
Direction: INCREASED
Interpretation: Loss of sarcolemmal integrity in dying fibres.
Show evidence (1 reference)
PMID:33113595 SUPPORT Model Organism
"Moreover, Lipin1Myf5cKO muscle had significantly higher membrane disruptions, as evidenced by increased IgG staining and elevated uptake of Evans Blue Dye (EBD) and increased serum creatine kinase activity in Lipin1Myf5cKO muscle fibers."
Reports the membrane-integrity readout.
Show evidence (1 reference)
PMID:30028636 SUPPORT Model Organism
"These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches."
Authors' assessment of the model's relevance.
Sarcoplasmic Reticulum Stress recapitulates fidelity: moderate observes: cellular Muscle-specific lipin-1 loss is sufficient to trigger SR stress, lipid accumulation and chaperone-responsive myopathy.
Limitations: The SR-stress branch has not been demonstrated in patient muscle, so its role in human attacks is inferred from the mouse.
Show evidence (1 reference)
PMID:30420558 SUPPORT Model Organism
"Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids."
Establishes the model and its lipid phenotype.
{ }

Source YAML

click to show 
name: LPIN1-Related Recurrent Myoglobinuria
category: Genetic
creation_date: "2026-09-05T16:30:00Z"
synonyms:
- Myoglobinuria, acute recurrent, autosomal recessive
- Lipin-1 deficiency
- LPIN1 deficiency
- LPIN1-related rhabdomyolysis
- Acute recurrent myoglobinuria of childhood due to LPIN1 deficiency
description: >
  LPIN1-related recurrent myoglobinuria (OMIM #268200) is an autosomal recessive disorder
  caused by biallelic loss-of-function variants in LPIN1, which encodes lipin-1, the
  Mg2+-dependent phosphatidic acid phosphatase that converts phosphatidic acid to
  diacylglycerol and accounts for most of that activity in skeletal muscle. It is a major
  cause, in some series the commonest, of severe recurrent rhabdomyolysis in early
  childhood: episodes usually begin before age six (mean about 21 months), are precipitated
  by febrile illness, fasting, strenuous exercise or anaesthesia, and produce massive
  creatine kinase elevation (often above 100,000 U/L), myoglobinuria, myalgia and weakness,
  with acute kidney injury, hyperkalaemia and fatal arrhythmia in the most severe attacks;
  about a third of patients have died, most during a crisis. Between attacks most patients
  are clinically well, although exercise intolerance and permanent muscle symptoms occur,
  and rare adolescent- or adult-onset and atypical neuromuscular presentations are
  described. Patient muscle and myoblasts show loss of phosphatidate phosphatase activity,
  phosphatidic acid and lipid-droplet accumulation, impaired fatty acid oxidation during
  exercise, and defective mitochondrial quality control in which oxidised mitochondrial DNA
  accumulating in late endosomes activates TLR9-driven inflammatory signalling and
  caspase-dependent myolysis, a model that also explains the febrile trigger. Muscle-specific
  Lpin1-null mice add sarcoplasmic reticulum stress and loss of membrane integrity with
  apoptotic and necroptotic myofibre death. There is no approved targeted therapy: attacks
  are managed with aggressive intravenous fluid and glucose, electrolyte and cardiac
  monitoring, and, in the largest cohort, intravenous corticosteroids; low-dose
  hydroxychloroquine has been given compassionately, and glucose loading improves exercise
  capacity. The mitochondrially inherited recurrent myoglobinuria attributed to mtDNA
  cytochrome c oxidase gene mutations (MONDO:0010791, OMIM 550500) is a separate entity.
disease_term:
  preferred_term: LPIN1-related acute recurrent myoglobinuria
  term:
    id: MONDO:0009992
    label: myoglobinuria, acute recurrent, autosomal recessive
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010791
      label: myoglobinuria, recurrent
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0010791 is cross-referenced to OMIM 550500, the mitochondrially inherited
      recurrent myoglobinuria attributed to mtDNA cytochrome c oxidase gene mutations, although
      its GARD-derived definition also mentions LPIN1. It is recorded here as a related
      cross-reference only; the LPIN1 disorder is MONDO:0009992 (OMIM 268200), and the
      MONDO:0010791 concept remains uncurated.
parents:
- MONDO:0020504
classifications:
  icimd_category:
  - classification_value: glycerolipid_metabolism
    notes: >-
      Lipin-1 is the phosphatidate phosphatase of the glycerolipid (Kennedy) pathway,
      converting phosphatidic acid to diacylglycerol for triglyceride and phospholipid
      synthesis; placed with the ICIMD disorders of glycerolipid metabolism (category 14).
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Seventy-one patients had been published in 20 clinical studies by 2022. Among children
    with severe early-childhood rhabdomyolysis after exclusion of fatty acid oxidation
    defects, LPIN1 variants were found in 59% of a French series.
  evidence:
  - reference: PMID:36195520
    reference_title: "Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 71 patients have been published in 20 clinical studies in the form of case series."
    explanation: Reported-case denominator as of 2022.
  - reference: PMID:20583302
    reference_title: "LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion."
    explanation: Share of severe early-childhood rhabdomyolysis attributable to LPIN1 in the discovery cohort.
progression:
- phase: Early-childhood onset of recurrent attacks
  notes: >-
    First episodes occur at 2-7 years in the original series and at a mean of 21 months in
    the French cohort; nearly all patients present before age five. Attacks recur with
    intercurrent illness, fasting or exertion throughout childhood, and roughly a third of
    patients die, usually from cardiac arrest during a crisis.
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis."
    explanation: Age at presentation in the gene-discovery series.
  - reference: PMID:20583302
    reference_title: "LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months."
    explanation: Mean age of first episodes in the largest early cohort.
  - reference: PMID:29325813
    reference_title: "Cardiac function and exercise adaptation in 8 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode."
    explanation: Mortality and its mechanism during attacks.
- phase: Adolescent and adult course
  notes: >-
    Survivors are usually well between attacks but may have exercise intolerance, persistent
    myalgia or a residual distal myopathy; rare patients first present in adolescence or
    adulthood after viral infection or metabolic stress.
  evidence:
  - reference: PMID:32522502
    reference_title: "First presentation of LPIN1 acute rhabdomyolysis in adolescence and adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present two cases of acute rhabdomyolysis with a milder phenotype caused by LPIN1 mutation presenting in adolescence (11 years old) and adulthood (40 years old) after Parvovirus infection and metabolic stress, respectively."
    explanation: Documents late first presentations.
  - reference: PMID:22481384
    reference_title: "Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones"
    explanation: Age of onset distribution and persistent symptoms in older patients.
genetic:
- name: LPIN1
  gene_term:
    preferred_term: LPIN1
    term:
      id: hgnc:13345
      label: LPIN1
  relationship_type: CAUSATIVE
  notes: >
    Biallelic LPIN1 (2p25.1) variants cause the disease; most are nonsense, frameshift or
    splice variants or intragenic deletions, with a minority of missense and in-frame
    changes that need functional support. A recurrent intragenic deletion,
    c.2295-866_2410-30del (p.Glu766_Ser838del), on a shared haplotype accounted for 47% of
    mutated alleles in Caucasian patients and fails to complement pah1-deficient yeast.
    Heterozygous carriers may have exercise-induced myalgia and one carrier of a pathogenic
    allele developed statin-induced myopathy. Adipose tissue develops normally despite loss
    of lipin-1, unlike the lipodystrophy of Lpin1-null mice.
  variants:
  - name: c.2295-866_2410-30del (p.Glu766_Ser838del)
    description: >
      Recurrent intragenic deletion found in 8 of 17 mutation-positive patients in the French
      cohort, all Caucasian, on a common haplotype suggesting a founder effect; the deleted
      protein is unable to complement pah1-deficient yeast. Its high frequency makes targeted
      testing a fast first diagnostic step.
    type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:20583302
      reference_title: "LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement Delta pah1 yeast for growth on glycerol, in contrast to normal LPIN1."
      explanation: Frequency, founder haplotype and functional loss of the recurrent deletion.
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the LPIN1 gene cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy."
    explanation: Gene discovery and the carrier statin-myopathy observation.
  - reference: PMID:22481384
    reference_title: "Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations."
    explanation: Carrier phenotype and exclusion of the paralogues.
  - reference: PMID:28986436
    reference_title: "Normal human adipose tissue functions and differentiation in patients with biallelic LPIN1 inactivating mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids."
    explanation: Shows the human phenotype is confined to muscle despite systemic loss of the enzyme.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >
    Autosomal recessive; heterozygous relatives may have mild exercise-induced myalgia but
    not rhabdomyolysis.
  evidence:
  - reference: PMID:36195520
    reference_title: "Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPIN1 deficiency is an autosomal recessive disease caused by biallelic mutations in LPIN1, where impaired fatty acid metabolism leads to stress in skeletal muscle, resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia."
    explanation: States the inheritance pattern.
  - reference: PMID:22481384
    reference_title: "Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least 40% of heterozygous relatives presented muscular myalgia."
    explanation: Carrier manifestation short of the recessive phenotype.
pathophysiology:
- name: Biallelic LPIN1 Loss of Function
  description: >
    Biallelic LPIN1 variants abolish lipin-1 protein and its Mg2+-dependent phosphatidate
    phosphatase (PAP-1) activity in skeletal muscle, where lipin-1 provides most PAP activity.
    Lipin-1 also acts as a nuclear transcriptional co-regulator of lipid-oxidation genes, but
    in patient myoblasts the expression of its PPAR/PGC-1alpha target genes is preserved,
    so the enzymatic loss is the primary lesion.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: phosphatidate phosphatase activity
    term:
      id: GO:0008195
      label: phosphatidate phosphatase activity
    modifier: DECREASED
  downstream:
  - target: Phosphatidic Acid Accumulation and Glycerolipid Imbalance
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18817903
      reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of phospholipid content disclosed accumulation of phosphatidic acid and lysophospholipids in muscle tissue of the more severe genotype."
      explanation: Substrate accumulation in patient muscle links enzyme loss to the lipid imbalance.
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis."
    explanation: Identifies the enzymatic function lost.
  - reference: PMID:23928362
    reference_title: "Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that primary myoblasts from lipin-1-deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD)."
    explanation: Patient-cell demonstration of the enzymatic loss.
- name: Phosphatidic Acid Accumulation and Glycerolipid Imbalance
  description: >
    Without PAP-1, phosphatidic acid and lysophospholipids accumulate in muscle and lipid
    droplets accumulate in myofibres and myoblasts; fatty acid synthesis, oxidation,
    elongation and desaturation are altered, ACACB is up-regulated with free fatty acid
    accumulation, and, paradoxically, diacylglycerol also accumulates in mouse muscle.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: fatty acid metabolic process
    term:
      id: GO:0006631
      label: fatty acid metabolic process
    modifier: DYSREGULATED
  downstream:
  - target: Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Sarcoplasmic Reticulum Stress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30420558
      reference_title: "Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress"
      explanation: Links the lipid imbalance to SR stress in the mouse model.
  evidence:
  - reference: PMID:22481384
    reference_title: "Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Around 3/4 of muscle biopsies showed accumulation of lipid droplets."
    explanation: Lipid accumulation in patient muscle.
  - reference: PMID:30028636
    reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol."
    explanation: Muscle-specific knockout confirms PA accumulation downstream of PAP loss.
  - reference: PMID:23928362
    reference_title: "Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-carnitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients."
    explanation: Identifies the ACACB-driven fatty acid accumulation in patient cells.
- name: Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
  description: >
    Lipin-1-deficient myoblasts have reduced phosphatidylinositol-3-phosphate near
    autophagosomes and late endosomes, which prevents Armus recruitment, locks Rab7 in its
    active state and blocks vesicle clearance by lysosomal fusion, so damaged mitochondria and
    their oxidised DNA are not cleared. Muscle-specific knockout mice have abundant but
    abnormal mitochondria attributed to impaired autophagy, and an adult patient showed
    markedly reduced fat oxidation during exercise.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mitophagy
    term:
      id: GO:0000423
      label: mitophagy
    modifier: DECREASED
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  downstream:
  - target: Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34467247
      reference_title: "Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis."
      explanation: Defective clearance leads directly to endosomal mtDNA accumulation and TLR9 activation.
  - target: Exercise intolerance
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34467247
    reference_title: "Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function."
    explanation: Mechanistic basis of the quality-control defect in patient cells.
  - reference: PMID:30028636
    reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy."
    explanation: Mouse corroboration of the mitochondrial clearance defect.
  - reference: PMID:31492716
    reference_title: "Fat oxidation is impaired during exercise in lipin-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this adult lipin-1-deficient patient, FAO was reduced, which was associated with no increase in plasma free fatty acids during submaximal exercise, and his exercise capacity improved with continuous ingestion of high-dose glucose."
    explanation: In vivo human evidence of impaired fat oxidation.
- name: Sarcoplasmic Reticulum Stress
  description: >
    In muscle-specific Lpin1 mutant mice the lipid imbalance causes severe sarcoplasmic
    reticulum stress with activation of SREBP1c/SREBP2, accumulation of Fgf21 and altered
    SR-mitochondria contacts; the chaperone TUDCA and the fatty acid oxidation activator
    bezafibrate improve muscle histology and strength. This branch is established in mice
    and its contribution to human acute attacks is inferred.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  downstream:
  - target: Trigger-Induced Myofibre Necrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:30420558
    reference_title: "Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants."
    explanation: Defines the SR-stress branch and its pharmacological reversibility in mice.
- name: Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
  description: >
    Oxidised mitochondrial DNA retained in late endosomes engages Toll-like receptor 9,
    driving inflammatory signalling and caspase-dependent myolysis. Febrile illness amplifies
    this: pro-inflammatory cytokines (TNF-alpha plus IL-1beta) mimicking fever raise
    malonyl-carnitine, reduce CPT1 activity and enhance lipid-droplet accumulation in patient
    myoblasts, effects reversed by dexamethasone or cytokine inhibitors. This is the proposed
    convergence point for the metabolic (fasting, exercise) and inflammatory (fever) triggers.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: toll-like receptor 9 signaling pathway
    term:
      id: GO:0034162
      label: toll-like receptor 9 signaling pathway
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  triggers:
  - preferred_term: Febrile illness
  - preferred_term: Fasting
  - preferred_term: Strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  downstream:
  - target: Trigger-Induced Myofibre Necrosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34467247
      reference_title: "Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis."
      explanation: Authors' causal model linking TLR9 inflammation to myolysis.
  evidence:
  - reference: PMID:23928362
    reference_title: "Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1α+IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFα or IL-1ß inhibitors."
    explanation: Shows inflammatory cytokines aggravate the lipid defect in patient cells, explaining the febrile trigger.
  - reference: PMID:34467247
    reference_title: "Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated."
    explanation: Pharmacological blockade of TLR9 supports its causal role.
- name: Trigger-Induced Myofibre Necrosis
  description: >
    Under catabolic or inflammatory stress the vulnerable lipin-1-deficient myofibre loses
    plasma membrane integrity and dies by caspase-dependent, apoptotic and necroptotic
    pathways, releasing creatine kinase, myoglobin, potassium and transaminases. Attacks
    produce massive hyperCKaemia, myoglobinuria, pain and weakness; myoglobin nephrotoxicity
    causes acute kidney injury, and hyperkalaemia with characteristic high-amplitude T waves
    precedes fatal arrhythmia in the most severe episodes.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: necroptotic process
    term:
      id: GO:0070266
      label: necroptotic process
    modifier: INCREASED
  downstream:
  - target: Rhabdomyolysis
    causal_link_type: DIRECT
  - target: Myoglobinuria
    causal_link_type: DIRECT
  - target: Elevated circulating creatine kinase activity
    causal_link_type: DIRECT
  - target: Myalgia
    causal_link_type: DIRECT
  - target: Muscle weakness
    causal_link_type: DIRECT
  - target: Acute kidney injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cardiac arrest
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Abnormal T-wave
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33113595
    reference_title: "Loss of membrane integrity drives myofiber death in lipin1-deficient skeletal muscle."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "EBD-positive fibers were strongly colocalized with apoptotic or necroptotic myofibers, suggesting an association between compromised plasma membrane integrity and cell death pathways."
    explanation: Mechanism of myofibre death in muscle-specific knockout mice.
  - reference: PMID:33113595
    reference_title: "Loss of membrane integrity drives myofiber death in lipin1-deficient skeletal muscle."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that Lipin1Myf5cKO muscles had significantly elevated proapoptotic factors (Bax, Bak, and cleaved caspase-9) and necroptotic proteins such as RIPK1, RIPK3, and MLKL compared with WT mice."
    explanation: Molecular markers of apoptosis and necroptosis in the knockout muscle.
  - reference: PMID:30028636
    reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
    explanation: Catabolic trigger reproduces CK release in the model.
phenotypes:
- name: Rhabdomyolysis
  category: Musculoskeletal
  frequency: OBLIGATE
  description: >
    Recurrent, massive, life-threatening rhabdomyolysis precipitated by febrile illness,
    fasting, exercise or anaesthesia is the defining feature; episodes can also occur without
    an identifiable trigger.
  phenotype_term:
    preferred_term: Recurrent rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
    temporality: RECURRENT
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis."
    explanation: Defining phenotype in the discovery series.
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike historical accounts, in our patient population, rhabdomyolysis was sometimes seen without inciting viral or traumatic events."
    explanation: Attacks may occur without an identified trigger.
- name: Myoglobinuria
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Dark urine from myoglobin release accompanies attacks and is the historical name of the disorder.
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  evidence:
  - reference: PMID:33456573
    reference_title: "Lipin 1 deficiency causes adult-onset myasthenia with motor neuron dysfunction in humans and neuromuscular junction defects in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human recessive mutations in LPIN1 cause recurrent, early-onset myoglobinuria, a condition normally associated with muscle pain and weakness."
    explanation: Summarises the canonical myoglobinuric presentation.
- name: Elevated circulating creatine kinase activity
  category: Laboratory
  frequency: OBLIGATE
  description: >
    Peak CK during attacks averaged over 600,000 U/L (range 157,000-1,100,000 U/L) in one
    cohort; AST rises in parallel with CK.
  phenotype_term:
    preferred_term: Massive hyperCKaemia during attacks
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
    temporality: RECURRENT
  evidence:
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatinine kinase (CK) levels peak during our care averaged 607,725 units/L (range 157,000-1,100,000 units/L)."
    explanation: Quantifies peak CK.
- name: Elevated circulating hepatic transaminase concentration
  category: Laboratory
  frequency: VERY_FREQUENT
  description: >
    AST and ALT rise with CK during attacks and are muscle-derived; AST tracks CK closely
    while ALT lags in resolution.
  phenotype_term:
    preferred_term: Elevated transaminases during attacks
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed that aspartate aminotransferase levels paralleled the CK levels in its elevation and resolution (Pearson's correlation R = 0.995); while alanine aminotransferase paralleled the elevation but lagged in the resolution of CK levels (R = 0.728)."
    explanation: Documents the transaminase pattern during attacks.
- name: Myalgia
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Muscle pain accompanies attacks, and exercise-induced myalgia may persist between them, including in heterozygous relatives.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:33456573
    reference_title: "Lipin 1 deficiency causes adult-onset myasthenia with motor neuron dysfunction in humans and neuromuscular junction defects in zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human recessive mutations in LPIN1 cause recurrent, early-onset myoglobinuria, a condition normally associated with muscle pain and weakness."
    explanation: Pain and weakness as accompaniments of attacks.
- name: Muscle weakness
  category: Musculoskeletal
  frequency: FREQUENT
  description: Acute weakness during attacks; survivors of severe episodes may retain a distal myopathy or foot drop.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:31240148
    reference_title: "Long-term outcomes in a 25-year-old female affected with lipin-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One-year post discharge from intensive care, the patient has residual drop foot bilaterally consistent with bilateral common peroneal neuropathies in addition to a background residual distal myopathy."
    explanation: Residual weakness after a severe attack.
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of clinical features includes myoglobinuria, myalgia, hypotonia, muscle weakness, decreased reflexes, and in some severe cases, acute renal failure."
    explanation: Second source placing muscle weakness within the clinical spectrum.
- name: Exercise intolerance
  category: Musculoskeletal
  frequency: FREQUENT
  description: Exercise intolerance with impaired fat oxidation and abnormal haemodynamic adaptation to exercise; improved by glucose loading.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:31492716
    reference_title: "Fat oxidation is impaired during exercise in lipin-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient has exercise intolerance and monthly episodes of rhabdomyolysis."
    explanation: Exercise intolerance in an adult patient studied physiologically.
  - reference: PMID:29325813
    reference_title: "Cardiac function and exercise adaptation in 8 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed abnormal haemodynamic profiles during exercise in 3/8 patients with lipin-1 deficiency, suggesting impaired muscle oxidative phosphorylation during exercise. Fever appeared to be an aggravating factor."
    explanation: Objective exercise abnormality in children.
- name: Increased intramyocellular lipid droplets
  category: Histopathology
  frequency: FREQUENT
  description: Lipid droplet accumulation in about three-quarters of muscle biopsies; biopsy is no longer needed for diagnosis.
  phenotype_term:
    preferred_term: Lipid droplet accumulation in muscle
    term:
      id: HP:0012240
      label: Increased intramyocellular lipid droplets
  evidence:
  - reference: PMID:22481384
    reference_title: "Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Around 3/4 of muscle biopsies showed accumulation of lipid droplets."
    explanation: Frequency of the biopsy finding.
- name: Acute kidney injury
  category: Renal
  frequency: OCCASIONAL
  description: Pigment nephropathy from myoglobinuria in severe attacks; compartment syndrome is a further complication.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:36195520
    reference_title: "Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of the complications including ventricular arrythmias, acute renal failure and compartment syndrome on the severe end of the spectrum may change the outcome and prognosis of this devastating condition."
    explanation: Lists acute renal failure among the severe complications.
- name: Cardiac arrest
  category: Cardiovascular
  frequency: FREQUENT
  description: About a third of patients die of cardiac arrest during a crisis, attributed to hyperkalaemia-related arrhythmia.
  phenotype_term:
    preferred_term: Cardiac arrest during rhabdomyolysis crisis
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:29325813
    reference_title: "Cardiac function and exercise adaptation in 8 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode."
    explanation: Frequency and setting of cardiac death.
- name: Abnormal T-wave
  category: Cardiovascular
  frequency: OCCASIONAL
  description: Diffuse symmetrical high-amplitude T waves preceded fatal arrhythmia in two children, consistent with hyperkalaemia.
  phenotype_term:
    preferred_term: High-amplitude T waves
    term:
      id: HP:0005135
      label: Abnormal T-wave
  evidence:
  - reference: PMID:22480698
    reference_title: "Fatal rhabdomyolysis in 2 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 2 cases of fatal rhabdomyolysis in children carrying an LPIN1 mutations preceded by similar electrocardiogram changes, including diffuse symmetrical high-amplitude T waves."
    explanation: ECG changes preceding fatal attacks.
- name: Hypotonia
  category: Neurological
  description: Hypotonia is listed within the clinical spectrum, mainly during or after attacks.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of clinical features includes myoglobinuria, myalgia, hypotonia, muscle weakness, decreased reflexes, and in some severe cases, acute renal failure."
    explanation: Places hypotonia within the reported clinical spectrum; no frequency is given.
- name: Hyporeflexia
  category: Neurological
  description: Decreased tendon reflexes are reported within the clinical spectrum.
  phenotype_term:
    preferred_term: Decreased reflexes
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of clinical features includes myoglobinuria, myalgia, hypotonia, muscle weakness, decreased reflexes, and in some severe cases, acute renal failure."
    explanation: Places decreased reflexes within the reported clinical spectrum; no frequency is given.
environmental:
- name: Febrile illness
  description: >
    Intercurrent febrile infection is the commonest precipitant of attacks; inflammatory
    cytokines aggravate the lipid defect in patient myoblasts, and fever worsens exercise
    haemodynamics in patients.
  exposure_term:
    preferred_term: febrile infectious illness
  influences_mechanisms:
  - target: Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Fever-associated cytokines (TNF-alpha, IL-1beta) amplify the inflammatory and lipid
      abnormalities in lipin-1-deficient muscle cells.
    evidence:
    - reference: PMID:23928362
      reference_title: "Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1α+IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFα or IL-1ß inhibitors."
      explanation: Cytokine mimicry of fever aggravates the cellular defect.
  evidence:
  - reference: PMID:23928362
    reference_title: "Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses."
    explanation: States the febrile trigger in patients.
  - reference: PMID:29325813
    reference_title: "Cardiac function and exercise adaptation in 8 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lipin-1 deficiency is a major cause of rhabdomyolysis that are precipitated by febrile illness."
    explanation: Independent clinical statement of the febrile trigger.
  notes: >-
    ECTO was searched through the repository label cache for a fever or febrile-illness
    exposure term and none is cached; the exposure is left unbound rather than bound to an
    unrelated infection term.
- name: Strenuous exercise
  description: >
    Prolonged or strenuous exercise precipitates attacks; exercise tolerance improves with
    continuous glucose intake.
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  influences_mechanisms:
  - target: Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Exercise increases reliance on fatty acid oxidation, which is impaired, and exhaustive
      unfed exercise provokes CK release in muscle-specific knockout mice.
    evidence:
    - reference: PMID:30028636
      reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
      explanation: Exercise-plus-fasting provokes muscle injury in the model.
  evidence:
  - reference: PMID:36195520
    reference_title: "Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia"
    explanation: Lists exercise among the clinical triggers.
  - reference: PMID:31492716
    reference_title: "Fat oxidation is impaired during exercise in lipin-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's exercise duration increased from 36 to 60 minutes with IV glucose and 46 minutes with oral glucose, and his rating of exertion dropped from 15 to 9 on average (Borg scale)."
    explanation: Glucose supply mitigates the exercise trigger.
  notes: >-
    Bound to the strenuous-exercise ECTO term already used elsewhere in the KB. Fasting and
    anaesthesia, previously bundled here, are now separate entries.
- name: Fasting
  description: >
    Prolonged fasting and other catabolic states precipitate attacks by increasing reliance
    on the impaired fatty acid oxidation pathway; regular carbohydrate intake during illness
    is the mainstay of prevention.
  exposure_term:
    preferred_term: prolonged fasting
  influences_mechanisms:
  - target: Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Fasting shifts muscle to fatty acid oxidation, which is impaired; unfed exhaustive
      exercise provokes CK release in muscle-specific knockout mice.
    evidence:
    - reference: PMID:30028636
      reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
      explanation: The unfed state is part of the provoking condition in the model.
  evidence:
  - reference: PMID:36195520
    reference_title: "Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia"
    explanation: Lists fasting among the clinical triggers.
  notes: >-
    ECTO was searched through the repository label cache for a fasting exposure term and none
    is cached; the exposure is left unbound.
- name: General anaesthesia
  description: >
    General anaesthesia is a recognised precipitant of rhabdomyolysis in lipin-1 deficiency,
    so perioperative catabolism should be prevented with glucose-containing fluids.
  exposure_term:
    preferred_term: exposure to general anaesthesia
    term:
      id: ECTO:2000059
      label: exposure to anesthetics
  evidence:
  - reference: PMID:36195520
    reference_title: "Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia"
    explanation: Lists anaesthesia among the clinical triggers.
  notes: >-
    Bound to the ECTO anaesthetics exposure term already cached in the KB. Not linked into the
    pathograph because the cited sources do not identify which mechanism anaesthesia acts on.
treatments:
- name: Emergency management of acute rhabdomyolysis
  description: >
    An attack is a medical emergency: stop exertion and reverse catabolism with intravenous
    glucose-containing fluids, monitor CK, potassium, calcium, phosphate, renal function and
    ECG, treat hyperkalaemia and arrhythmia, and use renal replacement therapy for standard
    indications; management in a paediatric intensive care unit is advised because of the
    risk of fatal arrhythmia. A standardised care recommendation has been published.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:22480698
    reference_title: "Fatal rhabdomyolysis in 2 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report underlines the severity of this disease and the need for active management of episodes of rhabdomyolysis in a pediatric intensive care unit."
    explanation: Basis for intensive-care management of attacks.
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This allowed us to compare multiple practice approaches and led to a standardized Care Recommendations."
    explanation: Published standardised care recommendation.
- name: Intravenous corticosteroids during attacks
  description: >
    Since 2015 the Paris cohort has given intravenous corticosteroids during attacks and
    at-risk situations, on the rationale of TLR9-driven inflammation; in a retrospective
    comparison there were no deaths among corticosteroid-treated patients versus four in the
    untreated group, and steroid-treated episodes were fewer per patient, although episodes
    were more severe and stays longer. Considered centre-specific practice rather than
    established standard of care.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone (intravenous corticosteroid)
      term:
        id: CHEBI:41879
        label: dexamethasone
  target_mechanisms:
  - target: Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
    description: Suppresses the inflammatory signalling proposed to drive myolysis during attacks.
  evidence:
  - reference: PMID:36680547
    reference_title: "Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients in the non-corticosteroid group died during a RM (mean age at death: 5.6 years). There were no deaths in the corticosteroid group."
    explanation: Survival signal in the retrospective comparison.
  - reference: PMID:36680547
    reference_title: "Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The peak plasma creatine kinase level and the area under the curve were or tended to be higher in patients treated with corticosteroids-even after the exclusion of deceased patients or focusing on the period after 2015."
    explanation: Records the caveat that treated episodes were more severe, limiting causal inference.
- name: Low-dose hydroxychloroquine (compassionate)
  description: >
    Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and was given
    off-label to eleven patients, improving physical capacity and normalising cardiac and
    exercise parameters; two patients with the highest blood concentrations had attacks,
    and in vitro high concentrations block autophagy while low concentrations reduce
    oxidative stress, so dosing must stay low. The registered trial (NCT04007562) was
    withdrawn, and efficacy is unproven.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxychloroquine
      term:
        id: CHEBI:5801
        label: hydroxychloroquine
  target_mechanisms:
  - target: Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
    description: Blocks endosomal TLR9 activation by oxidised mitochondrial DNA and reduces oxidative stress at low concentration.
  evidence:
  - reference: PMID:37150031
    reference_title: "Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM."
    explanation: Clinical benefit and the dose-related hazard.
  - reference: PMID:37150031
    reference_title: "Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation."
    explanation: Mechanistic basis for low-dose use.
- name: Glucose supplementation during exercise and avoidance of fasting
  description: >
    Continuous high-dose glucose intake before and during exercise improved exercise duration
    and perceived exertion in an adult patient; avoiding fasting and prolonged exertion, and
    providing carbohydrate during illness, are standard preventive measures.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Impaired Mitochondrial Quality Control and Fatty Acid Oxidation
    description: Bypasses impaired fat oxidation by supplying carbohydrate fuel.
  evidence:
  - reference: PMID:31492716
    reference_title: "Fat oxidation is impaired during exercise in lipin-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's exercise duration increased from 36 to 60 minutes with IV glucose and 46 minutes with oral glucose, and his rating of exertion dropped from 15 to 9 on average (Borg scale)."
    explanation: Direct evidence of glucose benefit.
- name: TUDCA and bezafibrate (preclinical)
  description: >
    In muscle-specific Lpin1 mutant mice the chemical chaperone tauroursodeoxycholic acid and
    the PPAR agonist bezafibrate improved muscle histology and strength, proposing SR stress
    and fatty acid oxidation as intervention targets; not tested in patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Sarcoplasmic Reticulum Stress
    description: Chaperone relief of SR stress and activation of fatty acid oxidation.
  evidence:
  - reference: PMID:30420558
    reference_title: "Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants."
    explanation: Preclinical efficacy in the mouse model.
- name: Genetic counseling and carrier advice
  description: >
    Autosomal recessive counselling with targeted testing for the recurrent intragenic
    deletion in Caucasian families; heterozygous carriers may have exercise-induced myalgia and
    a carrier state may predispose to statin-induced myopathy.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene."
    explanation: Carrier-relevant counselling point.
clinical_trials:
- name: NCT04007562
  phase: NOT_APPLICABLE
  status: WITHDRAWN
  description: >
    Retrospective study of the safety and efficacy of compassionate low-dose
    hydroxychloroquine in lipin-1 deficiency; withdrawn with no enrolment, so the
    therapeutic avenue remains unproven.
  evidence:
  - reference: clinicaltrials:NCT04007562
    reference_title: "Acute Rhabdomyolysis and Muscle Pain Associated With Mutations in the LPIN1 Gene - A Retrospective Study Describing the Safety and Efficacy of Hydroxychloroquine Sulfate Given on a Compassionate Basis to Patients Suffering From Lipin-1 Deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The objective of this retrospective study is to describe the safety and efficacy of Hydroxychloroquine Sulfate given on a compassionate basis to patients suffering from Lipin-1 deficiency within a period between 6 and 36 months."
    explanation: Registration summary of the withdrawn study.
diagnosis:
- name: Molecular genetic testing for biallelic LPIN1 variants
  description: >
    LPIN1 should be sequenced in any child with severe recurrent rhabdomyolysis once fatty
    acid oxidation defects are excluded, and included in adult rhabdomyolysis panels; targeted
    testing for the recurrent intragenic deletion allows fast diagnosis before biopsy. Rare
    compound heterozygous variants need functional confirmation. A large LPIN1 deletion can
    be missed by DNA sequencing and detected only by mRNA analysis, so a negative panel in a
    typical case does not exclude the diagnosis.
  evidence:
  - reference: PMID:37510298
    reference_title: "NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis."
    explanation: RNA analysis as the route to a deletion invisible to DNA sequencing.
  - reference: PMID:20583302
    reference_title: "LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy."
    explanation: Diagnostic strategy built on the founder deletion.
  - reference: PMID:32522502
    reference_title: "First presentation of LPIN1 acute rhabdomyolysis in adolescence and adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPIN1 should be included on a panel of genes analysed in the investigation of adult individuals with rhabdomyolysis."
    explanation: Extends testing to adult presentations.
  - reference: PMID:32913636
    reference_title: "Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Functional and biochemical tests should be carried out to confirm or exclude pathogenicity of the LPIN1 variants."
    explanation: Caution on variant interpretation.
- name: Serum creatine kinase and urine myoglobin during attacks
  description: Massive CK elevation with myoglobinuria during episodes, with AST paralleling CK, confirms rhabdomyolysis; values may be normal between attacks.
  evidence:
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatinine kinase (CK) levels peak during our care averaged 607,725 units/L (range 157,000-1,100,000 units/L)."
    explanation: Laboratory hallmark of attacks.
- name: Cardiac evaluation and exercise testing
  description: >
    Resting echocardiography is usually normal, but exercise testing can reveal impaired
    peripheral muscle adaptation and cardiac MR spectroscopy may show intracardiac steatosis;
    ECG monitoring during attacks detects hyperkalaemic T-wave changes.
  evidence:
  - reference: PMID:29325813
    reference_title: "Cardiac function and exercise adaptation in 8 children with LPIN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The four patients assessed by cardiac 1H-magnetic resonance spectroscopy exhibited signs of intracardiac steatosis."
    explanation: Cardiac imaging finding.
differential_diagnoses:
- name: Glycogen storage disease type V (McArdle disease) and other glycogenolysis defects
  description: >
    Glycogenolysis defects cause exercise-induced rhabdomyolysis with a second-wind
    phenomenon and glycogen storage on biopsy.
  distinguishing_features:
  - Glycogen accumulation on muscle biopsy, absent in lipin-1 deficiency
  - Attacks provoked by brief intense exercise rather than by fever or fasting
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways."
    explanation: Places LPIN1 deficiency against the classical differential.
- name: Fatty acid oxidation defects (CPT2 and VLCAD deficiency)
  description: >
    Long-chain fatty acid oxidation defects share fasting- and fever-triggered rhabdomyolysis
    but show a diagnostic acylcarnitine profile and enzyme defect.
  distinguishing_features:
  - Abnormal acylcarnitine profile and a demonstrable fatty acid oxidation enzyme defect
  - Lipin-1 deficiency has a normal acylcarnitine profile with lipid droplet accumulation
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways."
    explanation: Places LPIN1 deficiency against the classical differential.
- name: Mitochondrial oxidative phosphorylation disorders
  description: >
    Respiratory chain disorders, including the mitochondrial cytochrome c oxidase-related
    recurrent myoglobinuria (MONDO:0010791), are the remaining classical cause; LPIN1
    explains a large share of the early-childhood cases without any of these defects.
  distinguishing_features:
  - Ragged-red fibres or respiratory chain enzyme deficiency on biopsy
  - Onset before age six with biallelic LPIN1 variants, often the recurrent intragenic deletion
  evidence:
  - reference: PMID:18817903
    reference_title: "Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways."
    explanation: Places LPIN1 deficiency against the classical differential.
animal_models:
- name: Muscle-specific Lpin1 knockout mice
  species: Mouse
  genotype: Lpin1 exon 3-4 deletion (PAP-null hypomorph) or exon 7 deletion (protein-null), skeletal muscle-specific
  publication: PMID:30028636
  description: >
    Muscle-restricted models that avoid the lipodystrophy of the constitutive fld mouse; both
    show chronic myopathy with fibre necrosis and regeneration, phosphatidic acid and
    diacylglycerol accumulation, abnormal mitochondria with impaired autophagy, and increased
    CK after exhaustive unfed exercise. A Myf5-Cre knockout further shows loss of membrane
    integrity with apoptotic and necroptotic fibre death and reduced force.
  modeled_mechanisms:
  - target: Trigger-Induced Myofibre Necrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Chronic necrosis-regeneration myopathy with exercise-provoked CK release rather than discrete life-threatening attacks.
    limitations: >-
      Mice develop a chronic myopathy, whereas patients are usually well between discrete
      catabolism-triggered attacks; the episodic, fever-triggered human phenotype is not
      reproduced.
    readouts:
    - name: Plasma creatine kinase after exhaustive unfed exercise
      target: Trigger-Induced Myofibre Necrosis
      direction: INCREASED
      interpretation: Provoked muscle injury in the model.
      evidence:
      - reference: PMID:30028636
        reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed."
        explanation: Reports the CK readout.
    - name: Evans Blue Dye uptake and IgG staining of myofibres
      target: Trigger-Induced Myofibre Necrosis
      direction: INCREASED
      interpretation: Loss of sarcolemmal integrity in dying fibres.
      evidence:
      - reference: PMID:33113595
        reference_title: "Loss of membrane integrity drives myofiber death in lipin1-deficient skeletal muscle."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Moreover, Lipin1Myf5cKO muscle had significantly higher membrane disruptions, as evidenced by increased IgG staining and elevated uptake of Evans Blue Dye (EBD) and increased serum creatine kinase activity in Lipin1Myf5cKO muscle fibers."
        explanation: Reports the membrane-integrity readout.
    evidence:
    - reference: PMID:30028636
      reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches."
      explanation: Authors' assessment of the model's relevance.
  - target: Sarcoplasmic Reticulum Stress
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Muscle-specific lipin-1 loss is sufficient to trigger SR stress, lipid accumulation and chaperone-responsive myopathy.
    limitations: >-
      The SR-stress branch has not been demonstrated in patient muscle, so its role in human
      attacks is inferred from the mouse.
    evidence:
    - reference: PMID:30420558
      reference_title: "Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids."
      explanation: Establishes the model and its lipid phenotype.
experimental_models:
- name: Patient-derived lipin-1-deficient primary myoblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Primary myoblasts and myotubes from patients, used to show loss of PAP-1 activity, lipid
    droplet accumulation, ACACB up-regulation, cytokine sensitivity, defective
    autophagosome-lysosome clearance and TLR9 activation by oxidised mitochondrial DNA.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:34467247
  modeled_mechanisms:
  - target: Oxidized Mitochondrial DNA-TLR9 Inflammatory Signaling
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Patient cells reproduce the endosomal mtDNA accumulation, TLR9 activation and caspase-dependent myolysis, and respond to hydroxychloroquine.
    limitations: >-
      Cultured myoblasts lack the contractile, metabolic and systemic context of an attack;
      the in vivo relevance rests on the compassionate hydroxychloroquine experience.
    evidence:
    - reference: PMID:34467247
      reference_title: "Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency."
      explanation: Establishes the patient-cell system used for the mechanism.
discussions:
- discussion_id: lpin1_episodic_attack_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Trigger-Induced Myofibre Necrosis
  prompt: >
    What determines the transition from a clinically silent lipin-1-deficient muscle to
    massive acute myolysis during a febrile or catabolic trigger, and why are some patients
    spared between attacks while others develop chronic symptoms?
  rationale: >
    The TLR9 inflammatory model and the SR-stress model each explain part of the picture, but
    neither predicts which trigger will precipitate an attack in a given patient; the cohort
    literature states that the pathophysiological basis of the rhabdomyolysis has not been
    fully elucidated, and attacks can occur without any identified trigger.
  evidence:
  - reference: PMID:35242575
    reference_title: "LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with LPIN1 deficiency have early recurrent, life-threatening rhabdomyolysis but the full phenotypic spectrum and optimal treatment of the disorder remains unknown."
    explanation: Authors' statement of the outstanding gap.
- discussion_id: lpin1_mouse_chronic_myopathy_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Trigger-Induced Myofibre Necrosis
  prompt: >
    Do lipin-1-deficient mice, which show chronic myopathy and, in the constitutive model,
    lipodystrophy, model the episodic rhabdomyolysis of patients whose adipose tissue and
    interictal muscle are essentially normal?
  rationale: >
    The constitutive fld mouse is confounded by lipodystrophy that patients do not have, and
    muscle-specific knockouts show continuous necrosis-regeneration rather than discrete
    attacks; patient adipose tissue develops normally, and patient myoblasts show only minor
    changes in lipin-1 target gene expression. Findings from mice, including the SR-stress
    branch and TUDCA/bezafibrate responses, therefore need human confirmation.
  evidence:
  - reference: PMID:30028636
    reference_title: "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, that mouse model is confounded by lipodystrophy not phenocopied in people."
    explanation: Authors acknowledge the mismatch of the constitutive model.
  - reference: PMID:28986436
    reference_title: "Normal human adipose tissue functions and differentiation in patients with biallelic LPIN1 inactivating mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far."
    explanation: Human adipose phenotype differs from the mouse.
notes: >
  Curated as a single Disease entry under MONDO:0009992 (OMIM 268200). The claim was first
  filed against the stub for MONDO:0010791 ("myoglobinuria, recurrent"), whose OMIM
  cross-reference (550500) is the mitochondrially inherited cytochrome c oxidase-related form;
  that stub was annotated and left in the queue, and the concept is recorded here only as a
  skos:relatedMatch. Sources: the 2008 gene-discovery paper, the 2010-2012 French cohort
  papers, the 2021 mechanism paper on mitochondrial quality control and TLR9, mouse
  muscle-specific knockout studies, the 2022 US cohort care recommendations, and the 2023
  corticosteroid and hydroxychloroquine reports. Deep research: Edison/falcon report
  research/LPIN1-Related_Recurrent_Myoglobinuria-deep-research-falcon.md (14/14 references
  verified; preflight-dr SKIP because MONDO records no causal gene for the originally targeted
  term, resolved manually via OMIM). Atypical presentations (adult-onset myasthenia with motor
  neuron dysfunction, PMID:33456573) are noted but not modelled as separate nodes. No
  GeneReviews chapter exists for this disorder.
📚

References & Deep Research

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Evaluations and curation notes (2)

Record notes

Curated as a single Disease entry under MONDO:0009992 (OMIM 268200). The claim was first filed against the stub for MONDO:0010791 ("myoglobinuria, recurrent"), whose OMIM cross-reference (550500) is the mitochondrially inherited cytochrome c oxidase-related form; that stub was annotated and left in the queue, and the concept is recorded here only as a skos:relatedMatch. Sources: the 2008 gene-discovery paper, the 2010-2012 French cohort papers, the 2021 mechanism paper on mitochondrial quality control and TLR9, mouse muscle-specific knockout studies, the 2022 US cohort care recommendations, and the 2023 corticosteroid and hydroxychloroquine reports. Deep research: Edison/falcon report research/LPIN1-Related_Recurrent_Myoglobinuria-deep-research-falcon.md (14/14 references verified; preflight-dr SKIP because MONDO records no causal gene for the originally targeted term, resolved manually via OMIM). Atypical presentations (adult-onset myasthenia with motor neuron dysfunction, PMID:33456573) are noted but not modelled as separate nodes. No GeneReviews chapter exists for this disorder.

Create: LPIN1-Related_Recurrent_Myoglobinuria (LPIN1, MONDO:0009992) · 2026-09-05T22:08:27Z · View source

Created the LPIN1 acute recurrent myoglobinuria entry as a single Disease. Identity correction: the claim (#11146) was filed against stubs/Myoglobinuria_Recurrent.yaml (MONDO:0010791). just preflight-dr returned SKIP (no causal gene in MONDO) and runoak inspection showed MONDO:0010791 xrefs OMIM:550500, the mitochondrially inherited cytochrome c oxidase-related recurrent myoglobinuria; the LPIN1 disorder is MONDO:0009992 (OMIM:268200), which had no KB entry, stub or claim. The entry therefore uses MONDO:0009992 as disease_term, records MONDO:0010791 as a skos:relatedMatch, the claim issue was retitled, and the MONDO:0010791 stub was annotated (notes) and left in the queue rather than deleted. Sources: PMID:18817903 (gene discovery), PMID:20583302 and PMID:22481384 and PMID:22480698 (French cohorts, founder deletion, fatal ECG changes), PMID:23928362 and PMID:34467247 (patient myoblast mechanism: lipid droplets, cytokine sensitivity, mitochondrial quality control and TLR9), PMID:30028636, PMID:33113595 and PMID:30420558 (muscle-specific mouse models), PMID:31492716 and PMID:29325813 (exercise physiology and cardiac studies), PMID:28986436 (normal adipose tissue), PMID:35242575 (US cohort and care recommendations), PMID:36680547 (corticosteroids), PMID:37150031 (hydroxychloroquine), PMID:36195520, PMID:32522502, PMID:31240148, PMID:32913636, PMID:33456573. Deep research: Edison/falcon report research/LPIN1-Related_Recurrent_Myoglobinuria-deep-research-falcon.md (14/14 references verified, 11/11 terms verified), read for the mechanism chain, phenotype list and treatment sections; its causal chain matches the entry. NCIT:C2322 (Corticosteroid) was tried as a therapeutic_agent and rejected by the ChemicalEntityTerm dynamic enum, so dexamethasone (CHEBI:41879) is bound instead. Environmental triggers: febrile illness left unbound (no fever/febrile ECTO term in the label cache), strenuous exercise bound to ECTO:6000031. Validation: just validate pass, just validate-terms pass, count-verified-snippets 73/73, check-causal-targets and check-entity-refs clean, check-environmental-evidence clean, check-stubs and validate-stubs clean after the stub annotation. No GeneReviews chapter exists for this disorder.

Falcon ▸
LPIN1-Related Recurrent Myoglobinuria: Disease-Characteristics Report
Edison Scientific Literature 24 citations 2026-09-05T19:11:04.818160

LPIN1-Related Recurrent Myoglobinuria: Disease-Characteristics Report

Executive summary

LPIN1-related recurrent myoglobinuria is a rare, usually childhood-onset metabolic myopathy caused by biallelic loss-of-function variants in LPIN1. Its defining manifestation is episodic, potentially catastrophic rhabdomyolysis—typically precipitated by fever, infection, fasting, strenuous exercise, or another catabolic stress—with myalgia, weakness, dark urine/myoglobinuria, and extremely high serum creatine kinase (CK). Patients are often clinically well between attacks. Historical series reported substantial acute mortality, but contemporary prevalence, incidence, long-term survival, and validated quality-of-life data are unavailable. Current care is preventive and supportive; neither corticosteroids nor hydroxychloroquine has been established by randomized trials. Mechanistic work implicates disrupted phosphatidic-acid metabolism, abnormal membrane lipids, defective autophagy/mitophagy, mitochondrial and sarcoplasmic-reticulum stress, and amplification by inflammatory signals. (michot2012studyoflpin1 pages 1-2, tong2021acuterecurrentrhabdomyolysis pages 7-8, michot2010lpin1genemutations pages 5-7, hamel2021compromisedmitochondrialquality pages 25-26)

The following table provides a compact evidence-calibrated overview.

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. (michot2012studyoflpin1 pages 1-2, michot2010lpin1genemutations pages 5-7) 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. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5, michot2010lpin1genemutations pages 5-7) 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. (michot2012studyoflpin1 pages 1-2, michot2010lpin1genemutations pages 5-7) 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. (abdallah2025lpin1genevariant pages 1-2, michot2010lpin1genemutations pages 5-7) 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. (abdallah2025lpin1genevariant pages 1-2, tong2021acuterecurrentrhabdomyolysis pages 7-8, michot2012studyoflpin1 pages 6-8) 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. (tong2021acuterecurrentrhabdomyolysis pages 7-8, michot2012studyoflpin1 pages 8-10) 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. (tong2021acuterecurrentrhabdomyolysis pages 9-9, hamel2021compromisedmitochondrialquality pages 25-26, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6, michot2010lpin1genemutations pages 5-7) 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. (tong2021acuterecurrentrhabdomyolysis pages 7-8, bareja2025adultonsetepisodicrhabdomyolysis pages 3-5, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6) 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. (abdallah2025lpin1genevariant pages 1-2, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6) 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. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6) 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. (hamel2021compromisedmitochondrialquality pages 26-26, NCT04007562 chunk 2, tarr2025emergencymanagementof pages 13-13, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6) 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. (hamel2021compromisedmitochondrialquality pages 25-26, lu2021lipin1deficiency pages 16-17, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6) 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.

1. Disease information

Definition and nomenclature

The disorder is an inherited metabolic myopathy in which LPIN1 deficiency predisposes skeletal muscle to acute necrosis and release of CK, myoglobin, potassium, phosphate, purines, and other intracellular constituents. “Myoglobinuria” describes urinary myoglobin and dark urine; “rhabdomyolysis” describes the underlying skeletal-muscle destruction. The latter is therefore the more complete clinical name.

Common names include:

  • LPIN1-related recurrent myoglobinuria
  • LPIN1-related recurrent rhabdomyolysis
  • Lipin-1 deficiency
  • Recurrent acute myoglobinuria, autosomal recessive
  • Acute recurrent myoglobinuria of childhood

Key identifiers are MONDO:0010791 and OMIM #268200. The gene is LPIN1. No disease-specific ICD-10-CM code is established; coding generally uses rhabdomyolysis (M62.82) plus an appropriate genetic/metabolic diagnosis. Likewise, MeSH indexes the manifestations and molecular entity rather than providing a uniquely specific disease heading. Orphanet and ICD-11 identifiers should be locally verified before database ingestion because nomenclature mappings can change.

This report primarily aggregates disease-level resources, published cohorts, case series, case reports, trial-registry records, and experimental studies. It is not derived from an individual EHR. Some quantitative observations nevertheless originate from individual patients or small cohorts and are labeled accordingly.

The foundational publications include Zeharia et al. (2008/2009), American Journal of Human Genetics, “Mutations in LPIN1 Cause Recurrent Acute Myoglobinuria in Childhood,” DOI: https://doi.org/10.1016/j.ajhg.2008.12.003; Michot et al. (2010), Human Mutation, DOI: https://doi.org/10.1002/humu.21282; and Michot et al. (2012), Journal of Inherited Metabolic Disease, DOI: https://doi.org/10.1007/s10545-012-9461-6. (michot2012studyoflpin1 pages 1-2, michot2010lpin1genemutations pages 5-7)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The canonical disease is caused by germline biallelic pathogenic LPIN1 variants and follows autosomal-recessive inheritance. Most established alleles abolish or markedly reduce lipin-1 phosphatidate-phosphatase function. A yeast complementation experiment showed that a recurrent deletion construct did not rescue the relevant metabolic defect, directly supporting loss of function. (michot2010lpin1genemutations pages 5-7)

Genetic risk factors

Severe disease is associated especially with two null or severe hypomorphic alleles—nonsense, frameshift, splice-altering, exon-level deletion, or damaging missense/in-frame variants. A recurrent approximately 1.76-kb deletion, reported as c.2295-866_2410-30del; p.Glu766_Ser838del and affecting exons 18–19/C-LIP-region sequence, occurred in 8/17 Caucasian patients in one foundational series. Shared breakpoints and haplotype supported a founder event. (michot2010lpin1genemutations pages 5-7)

Occasional cramps or myalgia have been reported among heterozygous relatives, and at least 40% of heterozygous relatives in one study had myalgia. Rare reports also describe adult rhabdomyolysis with a single detected allele. These findings may indicate mild carrier susceptibility, an undetected second variant, or coincidental disease; they do not yet establish routine dominant inheritance or high carrier penetrance. (michot2012studyoflpin1 pages 1-2, bareja2025adultonsetepisodicrhabdomyolysis pages 3-5)

No reproducible modifier gene, protective allele, polygenic score, or disease-specific epigenetic modifier has been validated. Large chromosomal abnormalities are not the usual mechanism, although copy-number variants and unusual mechanisms such as uniparental isodisomy are possible.

Environmental and lifestyle triggers

Fever and infection are the best documented triggers. Fasting, calorie deprivation, strenuous or prolonged exercise, and anesthesia are also reported. A Chinese case linked prolonged weight training plus calorie deprivation to attacks. These factors precipitate episodes in genetically susceptible muscle; they do not cause the inherited disorder. (abdallah2025lpin1genevariant pages 1-2, tong2021acuterecurrentrhabdomyolysis pages 7-8, michot2010lpin1genemutations pages 5-7)

Possible medication associations are anecdotal. One adult reported temporal relationships with theophylline, mefenamic acid, co-trimoxazole, and combined oral contraceptives, but the authors found no convincing causal evidence. Statins warrant caution in susceptible patients, but disease-specific risk estimates are unavailable. (michot2012studyoflpin1 pages 6-8)

Protective factors

No proven genetic protective factor exists. Practical environmental protection consists of avoiding prolonged fasting and unaccustomed exhaustive exercise, maintaining hydration and carbohydrate intake during illness, treating fever/infection promptly, and implementing an individualized emergency regimen before catabolism and CK escalation become severe. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)

3. Phenotypes

The canonical course is episodic, not steadily progressive. Typical onset is infancy or early childhood, generally before age six; one series reported a median of 21 months. Rare adolescent and adult presentations—including onset at 42 years—have occurred. (michot2012studyoflpin1 pages 1-2, michot2010lpin1genemutations pages 5-7)

Suggested phenotype annotations include:

  • Recurrent rhabdomyolysis — acute, severe, episodic; core phenotype. Suggested HPO: Rhabdomyolysis (HP:0003201), Recurrent rhabdomyolysis where supported by the current HPO release.
  • Myoglobinuria/dark urine — rose, red-brown, or cola-colored urine during attacks. HPO: Myoglobinuria (HP:0002913).
  • Marked hyperCKemia — frequently >10,000 U/L and often >100,000 U/L. In a 2025 three-child Egyptian series, episode CK was 147,660.7 ± 28,144.5 U/L versus baseline 438.0 ± 215.9 U/L; AST was 2,034.2 ± 1,770.0 U/L versus baseline 110.66 ± 105.13 U/L. HPO: Elevated circulating creatine kinase concentration (HP:0003236). (abdallah2025lpin1genevariant pages 1-2, tong2021acuterecurrentrhabdomyolysis pages 7-8)
  • Myalgia and muscle tenderness — acute and trigger-associated; exercise-induced myalgia can persist in adults. HPO: Myalgia (HP:0003326).
  • Acute muscle weakness, fatigue, hypotonia, and reduced reflexes — variable and often reversible between episodes. Suggested HPO: Muscle weakness (HP:0001324), Fatigue (HP:0012378), Muscular hypotonia (HP:0001252), Hyporeflexia (HP:0001265). (abdallah2025lpin1genevariant pages 1-2)
  • Exercise intolerance — variable, especially in later-onset or surviving adults. HPO: Exercise intolerance (HP:0003546).
  • Elevated transaminases — AST can be extreme and primarily muscle-derived; this should not automatically be interpreted as primary hepatic disease.
  • Acute kidney injury — secondary to pigment nephropathy, hypovolemia, acidemia, and tubular obstruction; not obligatory. HPO: Acute kidney injury (HP:0001919). (abdallah2025lpin1genevariant pages 1-2, tong2021acuterecurrentrhabdomyolysis pages 7-8)
  • Electrolyte disturbance, hyperuricemia, arrhythmia, circulatory failure, or cardiac arrest — severe downstream complications rather than invariant primary features. (tong2021acuterecurrentrhabdomyolysis pages 7-8, NCT04007562 chunk 2)

Muscle examination, CK, electromyography, and calf MRI may be normal or nearly normal between episodes. Baseline mild hyperCKemia and exercise-related symptoms nevertheless occur in some patients. (tong2021acuterecurrentrhabdomyolysis pages 7-8, michot2010lpin1genemutations pages 5-7)

A muscle-biopsy survey found lipid-droplet accumulation in approximately three-quarters of examined biopsies. Other findings included type-I fiber predominance, type-II atrophy, occasional mitochondrial aggregates, weak cytochrome-c oxidase staining, or a nonspecific necrotizing/regenerating metabolic myopathy. A normal or nonspecific biopsy does not exclude disease. (michot2012studyoflpin1 pages 1-2, michot2012studyoflpin1 pages 6-8)

No LPIN1-specific EQ-5D, SF-36, PROMIS, or validated quality-of-life study was identified. Expected burdens include recurrent emergency admission, exercise restriction, school/work interruption, fear of febrile illness, and potential intensive-care morbidity, but these have not been quantified with disease-specific instruments.

4. Genetic and molecular information

Causal gene: LPIN1, encoding lipin-1, on chromosome 2. Disease-causing variants are germline. Somatic mutation is not the recognized mechanism.

Pathogenic classes include nonsense and frameshift variants, splice variants, exon-level or intragenic deletions, and functionally damaging missense/in-frame alleles. In one early series, 12 of 13 coding-region mutations were nonsense/frameshift variants, with the remaining lesion an in-frame deletion affecting the C-LIP domain. (michot2010lpin1genemutations pages 5-7)

Reported examples include:

  • Recurrent p.Glu766_Ser838del deletion: founder-associated loss of function.
  • c.1684G>T; p.Glu562Ter: homozygous likely pathogenic null allele in an adult survivor.
  • p.Arg388Ter plus p.Arg810Cys: compound heterozygosity in a Chinese child; the second was novel and computationally damaging.
  • c.1696G>C; p.Asp566His: reported homozygously in severe childhood rhabdomyolysis, but the original report relied partly on prediction; current ClinVar/ACMG classification should be independently checked before clinical use.
  • Novel or atypical missense/in-frame combinations require segregation, population-frequency, RNA, enzymatic, and functional evidence because not every rare LPIN1 variant is pathogenic. (tong2021acuterecurrentrhabdomyolysis pages 7-8, bareja2025adultonsetepisodicrhabdomyolysis pages 3-5)

Exact gnomAD frequencies and ClinVar classifications are transcript- and genome-build-dependent and should be populated by live variant-level queries. Established severe alleles are individually rare; aggregate carrier frequency and penetrance have not been robustly estimated.

No validated modifier gene or disease-specific methylation signature is known. No recurrent aneuploidy, translocation, or inversion defines the disorder.

5. Environmental information

No toxin, radiation, pollution, smoking exposure, alcohol exposure, occupational exposure, or infectious organism is independently causal. Viral and bacterial febrile illnesses act as nonspecific inflammatory/catabolic triggers. Exercise is beneficial in ordinary health but can precipitate attacks when unusually intense or combined with fasting. No pathogen-specific prophylaxis exists.

The gene–environment interaction is biologically plausible and experimentally supported: constitutive lipid-metabolic vulnerability in LPIN1-deficient myoblasts is exacerbated by inflammatory cytokines, while inflammatory inducers can repress LPIN1 expression. Thus infection likely combines increased energy demand, fasting/catabolism, fever, and cytokine signaling to cross the threshold for myofiber necrosis. (michot2010lpin1genemutations pages 5-7, michot2012studyoflpin1 pages 8-10)

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic LPIN1 loss-of-function variants lead to deficient lipin-1 protein or phosphatidate-phosphatase activity in skeletal myofibers.
  2. Reduced phosphatidate-phosphatase activity leads to disturbed conversion of phosphatidic acid (PA) to diacylglycerol (DAG), abnormal glycerolipid/membrane-lipid composition, and lipid-droplet accumulation.
  3. Lipid disequilibrium leads to altered fatty-acid synthesis, oxidation, elongation and desaturation, and perturbed PA/DAG-dependent signaling.
  4. These abnormalities lead to defective autophagy and mitochondrial quality control, damaged-mitochondrial accumulation, impaired oxidative capacity, reactive-oxygen stress, and abnormal sarcoplasmic-reticulum–mitochondrial contacts.
  5. They also lead to sarcoplasmic-reticulum stress and activation of SREBP1c/SREBP2 and FGF21 responses in mouse muscle; extrapolation of the complete branch to human attacks remains partly inferential.
  6. Fever, infection, fasting, or exhaustive exercise leads to increased energy demand, catabolism, and inflammatory signaling in already vulnerable muscle.
  7. Inflammatory and metabolic stress leads to failure of myofiber membrane/organelle homeostasis and acute myocyte necrosis.
  8. Myocyte necrosis leads to release of CK, myoglobin, potassium, phosphate, purines, and transaminases, producing pain, weakness, hyperCKemia, and dark urine.
  9. Systemic release and volume depletion lead to arrhythmia, circulatory collapse, pigment-associated acute kidney injury, and—during the most severe attacks—multiorgan failure or death.

Lipin-1 has two broad functions: a cytoplasmic phosphatidic-acid phosphatase role generating DAG and a nuclear transcriptional-coregulatory role affecting lipid/energy programs. The recurrent deletion’s failure to complement yeast pah1 deficiency supports loss of biochemical function. (michot2012studyoflpin1 pages 1-2, michot2010lpin1genemutations pages 5-7)

Muscle-specific mouse models separate PAP deficiency from whole-body lipodystrophy. They show PA and DAG accumulation, chronic fiber necrosis/regeneration, abnormal mitochondria, impaired autophagy, and increased CK after exhaustive exercise while unfed. Chemical chaperone TUDCA and the PPAR agonist/FAO activator bezafibrate improved histology and strength in mice; these are mechanistic proofs of concept, not validated human treatments. (bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)

Hamel et al. examined autophagic flux, mitophagy, mitochondrial membrane potential, ROS, respiration, mtDNA damage, calcium mobilization, and Toll-like-receptor signaling in patient-derived myoblasts. This supports a model in which defective mitochondrial disposal and inflammatory sensing participate in acute injury. Publication: August 2021, Cell Reports Medicine 2:100370; PMID 34467247; DOI: https://doi.org/10.1016/j.xcrm.2021.100370. (NCT04007562 chunk 2, hamel2021compromisedmitochondrialquality pages 25-26)

An atypical adult neuromuscular LPIN1 phenotype and zebrafish work implicated excessive Notch signaling and AGRIN–LRP4–MuSK-related neuromuscular-junction abnormalities; DAPT partly rescued zebrafish defects. This branch is relevant to LPIN1 biology but should not be assumed to drive canonical childhood rhabdomyolysis. (lu2021lipin1deficiency pages 16-17)

Suggested GO terms include phosphatidate phosphatase activity (molecular function), glycerolipid biosynthetic process, triglyceride biosynthetic process, fatty-acid oxidation, autophagy, mitophagy, mitochondrial organization, response to endoplasmic-reticulum stress, muscle-cell homeostasis, and necrotic cell death. Suggested cell terms include skeletal-muscle fiber/myocyte and myoblast; kidney proximal-tubule epithelial cells are secondary targets of filtered myoglobin.

No disease-specific single-cell atlas, spatial-transcriptomic study, organoid model, validated circulating proteomic signature, or clinical multi-omics classifier was identified. Existing lipidomic, respiratory, and imaging assays are predominantly research tools.

7. Anatomical structures affected

The primary site is skeletal muscle, especially skeletal myofibers. Suggested anatomy terms are UBERON skeletal muscle tissue and musculoskeletal system; the phenotype is generally systemic rather than unilateral or anatomically focal. The sarcolemma, sarcoplasmic reticulum, mitochondria, autophagosome/lysosome system, lipid droplets, and nucleus/transcriptional machinery are relevant subcellular structures.

Secondary organs include:

  • Kidney, especially proximal tubules, through myoglobin-associated pigment nephropathy and hemodynamic injury.
  • Heart/conduction system, through hyperkalemia, metabolic disturbance, and possibly intrinsic stress susceptibility; arrhythmia is a critical acute complication.
  • Circulatory and respiratory systems, during shock, respiratory muscle weakness, or multiorgan failure.

Suggested GO cellular components include mitochondrion, mitochondrial membrane, sarcoplasmic reticulum, endoplasmic-reticulum membrane, lipid droplet, autophagosome, lysosome, nuclear envelope, and sarcolemma.

8. Temporal development

The typical pattern is abrupt onset during a trigger, rapid CK escalation over hours to days, and recovery after supportive treatment. In early reports, onset was before age five with a median of 21 months and 1–10 attacks per patient. Other cohorts characterize onset before age six; rare cases begin in adolescence or adulthood. (michot2010lpin1genemutations pages 5-7, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)

Between attacks there may be complete clinical remission and normal CK. The disorder remains lifelong because the genotype persists, but attack frequency is variable and may decline with age in some survivors. There is no validated staging system. Critical intervention windows are the first signs of febrile illness, reduced intake, muscle pain, weakness, or dark urine—before severe catabolism, electrolyte disturbance, and renal injury develop.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed carrier parents, each pregnancy conventionally has a 25% probability of an affected child, 50% probability of a heterozygous carrier, and 25% probability of inheriting neither familial allele. Penetrance of severe biallelic loss-of-function genotypes appears high but has not been measured population-wide; expressivity is variable in age at onset, triggers, number of attacks, and survival. Anticipation is not expected. Germline mosaicism has not emerged as a characteristic mechanism.

In one selected cohort of patients with onset before six years and CK >10,000 U/L, LPIN1 variants accounted for 46%, demonstrating high diagnostic yield in that narrowly defined severe subgroup—not population prevalence. Another early series found biallelic mutations in 17/29 severely affected young patients. (michot2010lpin1genemutations pages 5-7, michot2012studyoflpin1 pages 6-8)

Population incidence and prevalence per 100,000, carrier frequency, and sex ratio are unknown. Reports span European, Middle Eastern, South Asian, East Asian, and African populations, arguing against geographic exclusivity. Founder enrichment of the recurrent exon 18–19 deletion was reported among Caucasian patients. Consanguinity increases the probability of homozygous rare alleles but is not required. (michot2012studyoflpin1 pages 1-2, michot2010lpin1genemutations pages 5-7)

10. Diagnostics

Acute evaluation

Immediate tests should include CK, plasma/serum myoglobin if available, urinalysis with microscopy, creatinine, urea, electrolytes (especially potassium, calcium, phosphate and bicarbonate), glucose, venous/arterial acid–base assessment when severe, AST/ALT, urate, complete blood count, and ECG. A heme-positive urine dipstick with few or no erythrocytes supports myoglobinuria, but absence does not exclude rhabdomyolysis.

Genetic confirmation

Preferred testing is an inherited-rhabdomyolysis/metabolic-myopathy panel containing LPIN1 with sequence and deletion/duplication analysis. Single-gene testing is reasonable when the phenotype and familial alleles are clear. WES or WGS is appropriate for atypical or panel-negative disease, but laboratories must demonstrate reliable copy-number and difficult-region coverage. In a 2023 54-gene hyperCKemia panel cohort of 139 patients, definite diagnoses were obtained in 15.1%; importantly, RNA analysis identified a large LPIN1 deletion missed by DNA sequencing, illustrating the value of transcript studies when only one allele is found. DOI: https://doi.org/10.3390/genes14071393. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5)

CMA, karyotyping, FISH, mitochondrial-genome testing, and repeat-expansion analysis are not first-line LPIN1 tests unless broader clinical findings indicate them. Muscle RNA sequencing, enzymatic PAP assays, lipidomics, or patient-myoblast studies may resolve selected uncertain cases but are not routine diagnostics.

Differential diagnosis

Important alternatives include fatty-acid oxidation disorders—especially CPT II deficiency—glycogenoses such as McArdle disease, mitochondrial myopathies, RYR1/CACNA1S-related exertional or malignant-hyperthermia susceptibility, TANGO2-related metabolic crises, FLAD1/ETFDH-related lipid-storage myopathy, dystrophinopathy, ANO5-related disease, phosphoglycerate-kinase deficiency, viral myositis, autoimmune myositis, trauma, seizures, heat injury, toxins, and drug-associated rhabdomyolysis. PGK deficiency is particularly relevant when hemolytic anemia and hyperbilirubinemia accompany myoglobinuria. (tong2021acuterecurrentrhabdomyolysis pages 7-8)

No universally adopted LPIN1-specific clinical diagnostic criteria exist. Molecular confirmation requires pathogenic/likely pathogenic variants in trans, with phenotype and segregation consistency.

Screening

LPIN1 disease is not part of standard population newborn screening. Following diagnosis, cascade testing of siblings and relatives is important because a presymptomatic affected sibling may benefit from an emergency plan. Carrier testing, prenatal diagnosis, and preimplantation genetic testing are possible after familial variants are established.

11. Outcome and prognosis

Historical outcomes were severe: one combined series reported 11/35 affected patients and 10 unstudied siblings dying during attacks; another early report documented five patient deaths plus three sibling deaths. A later review cited mortality up to 14%. These estimates come from selected historical cases and should not be interpreted as current population mortality. (tong2021acuterecurrentrhabdomyolysis pages 7-8, michot2010lpin1genemutations pages 5-7, michot2012studyoflpin1 pages 8-10)

Acute prognostic threats include very young age, delayed carbohydrate/fluid treatment, extreme CK rise, hyperkalemia, arrhythmia, shock, oliguria/AKI, and multiorgan involvement. Survivors can recover normal strength and CK between episodes, although some develop exercise intolerance, persistent myalgia, mild hyperCKemia, chronic weakness, or renal sequelae. No validated prognostic biomarker beyond attack severity and organ-injury measures exists. Five- and ten-year survival, life expectancy, disability-adjusted life-years, and treatment-stratified outcome rates are unavailable.

12. Treatment

Acute strategy

An attack is a medical emergency. Management generally comprises:

  1. Stop exertion and reverse fasting/catabolism with carbohydrate and nutritional support.
  2. Give prompt isotonic intravenous fluid, individualized to age, cardiac status, urine output, and renal function.
  3. Monitor CK trajectory, fluid balance, creatinine, potassium, calcium, phosphate, bicarbonate, glucose, urate, and ECG.
  4. Treat hyperkalemia, arrhythmia, shock, acid–base disturbance, and hypoglycemia by standard emergency protocols.
  5. Use dialysis/continuous renal-replacement therapy for conventional indications such as refractory hyperkalemia, acidosis, fluid overload, or severe renal failure—not merely for a high CK value.
  6. Involve metabolic medicine, neurology, nephrology, intensive care, and cardiology as severity requires.

There is no approved LPIN1-specific drug, enzyme replacement, gene therapy, RNA therapy, cell therapy, or surgery. Suggested NCIT intervention concepts include intravenous fluid therapy, glucose administration, electrolyte replacement, cardiac monitoring, renal dialysis, nutritional support, and genetic counseling.

Corticosteroids

A 2023 retrospective study evaluated systemic corticosteroids during acute LPIN1 attacks: Tuchmann-Durand et al., Journal of Inherited Metabolic Disease 46:649–661, DOI: https://doi.org/10.1002/jimd.12592. A separate 2023 report described dexamethasone use, DOI: https://doi.org/10.1016/j.ymgmr.2023.100961. These reports are clinically important recent developments, but the retrieved evidence did not provide a randomized comparator or universally validated dose. Steroids should therefore be considered center-specific/experimental rather than routine standard of care. (tarr2025emergencymanagementof pages 13-13)

Hydroxychloroquine

Hydroxychloroquine was used compassionately in a small Paris cohort, motivated by mitochondrial-DNA/inflammatory signaling biology. Registry NCT04007562 specified genetically confirmed pediatric LPIN1 deficiency, at least six months of treatment, and outcomes including attacks, pain, and arrhythmia over 36 months. The registry now records the study as withdrawn with zero enrollment, while the associated publication describes an eight-patient clinical experience; this discrepancy and the nonrandomized design preclude a firm efficacy conclusion. ECG/ophthalmologic and other standard hydroxychloroquine safety monitoring would be necessary if used experimentally. (hamel2021compromisedmitochondrialquality pages 26-26, NCT04007562 chunk 2)

Preclinical approaches

TUDCA and bezafibrate improved muscle histology/strength in LPIN1-deficient mice. Notch inhibition rescued aspects of an atypical zebrafish neuromuscular phenotype. AAV-lipin-1 restoration has shown benefit in a Duchenne model, not LPIN1-deficient human disease. None is established therapy for recurrent myoglobinuria. (lu2021lipin1deficiency pages 16-17, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)

No LPIN1-specific pharmacogenomic guideline, response rate, or comparative adverse-event dataset is available. Rehabilitation should be individualized after recovery, avoiding sudden exhaustive or fasting-state exercise.

13. Prevention

  • Primary prevention of genotype: not possible after conception; reproductive options include carrier testing, genetic counseling, prenatal diagnosis, and preimplantation genetic testing.
  • Secondary prevention: molecular diagnosis and cascade screening before a first catastrophic episode; no population or newborn screening program is established.
  • Tertiary prevention: emergency letter, sick-day carbohydrate/hydration plan, prompt evaluation during fever or poor intake, avoidance of prolonged fasting and unaccustomed exhaustive exercise, perioperative planning, and education about dark urine, muscle pain, weakness, and reduced urine output. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5, bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)

Routine immunization is appropriate because preventing febrile infections may indirectly prevent attacks, but no LPIN1-specific vaccine exists. Vaccination itself should be managed with ordinary fever/hydration precautions rather than withheld without a separate contraindication.

14. Other species and natural disease

No well-established, naturally occurring veterinary LPIN1 recurrent-myoglobinuria syndrome with a validated breed association was identified. Consequently, no VBO breed term or zoonotic concern applies. The disorder is not infectious and has no cross-species transmission.

Orthologous Lpin1/lpin1 genes are conserved in mouse and zebrafish, enabling mechanistic comparison. Whole-body Lpin1-deficient fatty-liver-dystrophy mice develop lipodystrophy not characteristic of affected humans, limiting direct phenotypic translation. Muscle-specific models better isolate the myopathy.

15. Model organisms

Mouse

Muscle-specific deletion models remove PAP activity while retaining some transcriptional function or eliminate lipin-1 protein. They reproduce lipid accumulation, PA/DAG dysregulation, chronic fiber necrosis/regeneration, abnormal mitochondria, impaired autophagy, and stress-sensitive CK release. They do not perfectly reproduce the abrupt, infection-dominated human course and may exhibit chronic pathology absent between human attacks. (bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)

Human cellular models

Primary patient myoblasts/myotubes permit analysis of lipid metabolism, cytokine sensitivity, starvation-induced autophagic flux, CCCP-induced mitophagy, mitochondrial respiration, membrane potential, ROS, mtDNA injury, calcium signaling, and innate immune pathways. They provide the most disease-proximal mechanistic system but lack whole-body renal, cardiac, endocrine, and immune interactions. (hamel2021compromisedmitochondrialquality pages 25-26, michot2010lpin1genemutations pages 5-7)

Zebrafish

Morpholino knockdown or mutant-mRNA expression produces myotome defects, reduced motor-neuron projections, myelination and neuromuscular-junction abnormalities, impaired touch responses, and altered swimming. Partial rescue by DAPT supports Notch involvement. These developmental neural phenotypes model an atypical LPIN1 presentation more than classic recurrent rhabdomyolysis. (lu2021lipin1deficiency pages 16-17)

No validated LPIN1 organoid, humanized large-animal model, or CRISPR-corrected clinical platform was identified.

Recent developments and evidence gaps

Research published in 2023 emphasized two developments: NGS-based metabolic-myopathy diagnostics augmented by RNA analysis for cryptic LPIN1 deletions, and retrospective systemic-corticosteroid treatment of acute attacks. Neither changed the fundamental evidence hierarchy: diagnosis is increasingly genomic, while treatment remains largely supportive and preventive. Disease-specific 2024 primary clinical research was sparse; recent work involving lipin-1 in other muscular disorders should not be conflated with treatment evidence for LPIN1 deficiency. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5, tarr2025emergencymanagementof pages 13-13)

Major unresolved needs are a multinational natural-history registry; contemporary incidence and survival estimates; standardized attack definitions and core outcomes; prospective comparison of anti-catabolic protocols; controlled evaluation of corticosteroids and hydroxychloroquine; variant-specific functional assays; and clinically translatable strategies to restore PAP activity, mitochondrial quality control, or muscle LPIN1 expression.

Selected exact abstract quotations

  • Michot et al. (2012) concluded that LPIN1 myolysis is a major cause of severe early-onset rhabdomyolysis and documented adult disease; the study evaluated 171 symptomatic patients and found two LPIN1 mutations in 18. DOI: https://doi.org/10.1007/s10545-012-9461-6. (michot2012studyoflpin1 pages 1-2)
  • Che et al. (2020): “Lipin-1, encoded by LPIN1 gene, serves as an enzyme and a transcriptional co-regulator to regulate lipid metabolism and mitochondrial respiratory chain.” DOI: https://doi.org/10.1186/s12887-020-02134-5.
  • Rashid et al. (2019): “Our data reveal that SR stress and alterations in SR–mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.” DOI: https://doi.org/10.15252/embj.201899576. (bareja2025adultonsetepisodicrhabdomyolysis pages 5-6)
  • Invernizzi et al. (2023): “In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis.” DOI: https://doi.org/10.3390/genes14071393. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5)

Evidence-quality note

The strongest disease-specific evidence consists of retrospective cohorts, molecular case series, patient-derived-cell studies, and genetically engineered models. Frequencies from referral cohorts are subject to ascertainment bias; treatment reports are uncontrolled; adult heterozygous cases require caution; and several ontology and clinical-code mappings should be verified against the current release before production ingestion.

References

  1. (michot2012studyoflpin1 pages 1-2): Caroline Michot, Laurence Hubert, Norma B. Romero, Amr Gouda, Asmaa Mamoune, Suja Mathew, Edwin Kirk, Louis Viollet, Shamima Rahman, Soumeya Bekri, Heidi Peters, James McGill, Emma Glamuzina, Michelle Farrar, Maya der von Hagen, Ian E. Alexander, Brian Kirmse, Magalie Barth, Pascal Laforet, Pascale Benlian, Arnold Munnich, Marc JeanPierre, Orly Elpeleg, Ophry Pines, Agnès Delahodde, Yves de Keyzer, and Pascale de Lonlay. Study of lpin1, lpin2 and lpin3 in rhabdomyolysis and exercise-induced myalgia. Journal of Inherited Metabolic Disease, 35:1119-1128, Apr 2012. URL: https://doi.org/10.1007/s10545-012-9461-6, doi:10.1007/s10545-012-9461-6. This article has 125 citations and is from a peer-reviewed journal.

  2. (tong2021acuterecurrentrhabdomyolysis pages 7-8): Ke Tong and Geng-Sheng Yu. Acute recurrent rhabdomyolysis in a chinese boy associated with a novel compound heterozygous lpin1 variant: a case report. BMC Neurology, Jan 2021. URL: https://doi.org/10.1186/s12883-021-02050-w, doi:10.1186/s12883-021-02050-w. This article has 12 citations and is from a peer-reviewed journal.

  3. (michot2010lpin1genemutations pages 5-7): Caroline Michot, Laurence Hubert, Michèle Brivet, Linda De Meirleir, Vassili Valayannopoulos, Wolfgang Müller-Felber, Ramesh Venkateswaran, Hélène Ogier, Isabelle Desguerre, Cécilia Altuzarra, Elizabeth Thompson, Martin Smitka, Angela Huebner, Marie Husson, Rita Horvath, Patrick Chinnery, Frederic M. Vaz, Arnold Munnich, Orly Elpeleg, Agnès Delahodde, Yves de Keyzer, and Pascale de Lonlay. Lpin1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Human Mutation, 31:E1564-E1573, Jul 2010. URL: https://doi.org/10.1002/humu.21282, doi:10.1002/humu.21282. This article has 175 citations and is from a domain leading peer-reviewed journal.

  4. (hamel2021compromisedmitochondrialquality pages 25-26): Yamina Hamel, François-Xavier Mauvais, Marine Madrange, Perrine Renard, Corinne Lebreton, Ivan Nemazanyy, Olivier Pellé, Nicolas Goudin, Xiaoyun Tang, Mathieu P. Rodero, Caroline Tuchmann-Durand, Patrick Nusbaum, David N. Brindley, Peter van Endert, and Pascale de Lonlay. Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis. Cell Reports Medicine, 2:100370, Aug 2021. URL: https://doi.org/10.1016/j.xcrm.2021.100370, doi:10.1016/j.xcrm.2021.100370. This article has 23 citations and is from a peer-reviewed journal.

  5. (bareja2025adultonsetepisodicrhabdomyolysis pages 3-5): Naman Bareja, Rafail A Chionatos, Camelia Valhuerdi Porto, Nikita Srinivasan, and Mehdi Ghasemi. Adult-onset episodic rhabdomyolysis in a patient with a heterozygous lipin 1 (lpin1) mutation: a case report. Cureus, Jan 2025. URL: https://doi.org/10.7759/cureus.76772, doi:10.7759/cureus.76772. This article has 4 citations.

  6. (abdallah2025lpin1genevariant pages 1-2): Tarek M. A. Abdallah, Said S. El-Feky, Nourhan A. A. Salem, Ghada M. Mashaal, and Zaghloul E. Gouda. Lpin-1 gene variant in egyptian children: acute recurrent myoglobinuria. Jul 2025. URL: https://doi.org/10.1007/s44162-025-00106-w, doi:10.1007/s44162-025-00106-w. This article has 1 citations.

  7. (michot2012studyoflpin1 pages 6-8): Caroline Michot, Laurence Hubert, Norma B. Romero, Amr Gouda, Asmaa Mamoune, Suja Mathew, Edwin Kirk, Louis Viollet, Shamima Rahman, Soumeya Bekri, Heidi Peters, James McGill, Emma Glamuzina, Michelle Farrar, Maya der von Hagen, Ian E. Alexander, Brian Kirmse, Magalie Barth, Pascal Laforet, Pascale Benlian, Arnold Munnich, Marc JeanPierre, Orly Elpeleg, Ophry Pines, Agnès Delahodde, Yves de Keyzer, and Pascale de Lonlay. Study of lpin1, lpin2 and lpin3 in rhabdomyolysis and exercise-induced myalgia. Journal of Inherited Metabolic Disease, 35:1119-1128, Apr 2012. URL: https://doi.org/10.1007/s10545-012-9461-6, doi:10.1007/s10545-012-9461-6. This article has 125 citations and is from a peer-reviewed journal.

  8. (michot2012studyoflpin1 pages 8-10): Caroline Michot, Laurence Hubert, Norma B. Romero, Amr Gouda, Asmaa Mamoune, Suja Mathew, Edwin Kirk, Louis Viollet, Shamima Rahman, Soumeya Bekri, Heidi Peters, James McGill, Emma Glamuzina, Michelle Farrar, Maya der von Hagen, Ian E. Alexander, Brian Kirmse, Magalie Barth, Pascal Laforet, Pascale Benlian, Arnold Munnich, Marc JeanPierre, Orly Elpeleg, Ophry Pines, Agnès Delahodde, Yves de Keyzer, and Pascale de Lonlay. Study of lpin1, lpin2 and lpin3 in rhabdomyolysis and exercise-induced myalgia. Journal of Inherited Metabolic Disease, 35:1119-1128, Apr 2012. URL: https://doi.org/10.1007/s10545-012-9461-6, doi:10.1007/s10545-012-9461-6. This article has 125 citations and is from a peer-reviewed journal.

  9. (tong2021acuterecurrentrhabdomyolysis pages 9-9): Ke Tong and Geng-Sheng Yu. Acute recurrent rhabdomyolysis in a chinese boy associated with a novel compound heterozygous lpin1 variant: a case report. BMC Neurology, Jan 2021. URL: https://doi.org/10.1186/s12883-021-02050-w, doi:10.1186/s12883-021-02050-w. This article has 12 citations and is from a peer-reviewed journal.

  10. (bareja2025adultonsetepisodicrhabdomyolysis pages 5-6): Naman Bareja, Rafail A Chionatos, Camelia Valhuerdi Porto, Nikita Srinivasan, and Mehdi Ghasemi. Adult-onset episodic rhabdomyolysis in a patient with a heterozygous lipin 1 (lpin1) mutation: a case report. Cureus, Jan 2025. URL: https://doi.org/10.7759/cureus.76772, doi:10.7759/cureus.76772. This article has 4 citations.

  11. (hamel2021compromisedmitochondrialquality pages 26-26): Yamina Hamel, François-Xavier Mauvais, Marine Madrange, Perrine Renard, Corinne Lebreton, Ivan Nemazanyy, Olivier Pellé, Nicolas Goudin, Xiaoyun Tang, Mathieu P. Rodero, Caroline Tuchmann-Durand, Patrick Nusbaum, David N. Brindley, Peter van Endert, and Pascale de Lonlay. Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis. Cell Reports Medicine, 2:100370, Aug 2021. URL: https://doi.org/10.1016/j.xcrm.2021.100370, doi:10.1016/j.xcrm.2021.100370. This article has 23 citations and is from a peer-reviewed journal.

  12. (NCT04007562 chunk 2): Acute Rhabdomyolysis and Muscle Pain Associated With Mutations in the LPIN1 Gene - A Retrospective Study Describing the Safety and Efficacy of Hydroxychloroquine Sulfate Given on a Compassionate Basis to Patients Suffering From Lipin-1 Deficiency. Assistance Publique - Hôpitaux de Paris. 2019. ClinicalTrials.gov Identifier: NCT04007562

  13. (tarr2025emergencymanagementof pages 13-13): J. Dexter Tarr and Andrew A. M. Morris. Emergency management of intoxication‐type inherited metabolic disorders. Journal of Inherited Metabolic Disease, Feb 2025. URL: https://doi.org/10.1002/jimd.70007, doi:10.1002/jimd.70007. This article has 3 citations and is from a peer-reviewed journal.

  14. (lu2021lipin1deficiency pages 16-17): Shuxian Lu, Zhaojie Lyu, Zhihao Wang, Yao Kou, Cong Liu, Shengyue Li, Mengyan Hu, Hongjie Zhu, Wenxing Wang, Ce Zhang, Yung-Shu Kuan, Yi-Wen Liu, Jianming Chen, and Jing Tian. Lipin 1 deficiency causes adult-onset myasthenia with motor neuron dysfunction in humans and neuromuscular junction defects in zebrafish. Theranostics, 11:2788-2805, Jan 2021. URL: https://doi.org/10.7150/thno.53330, doi:10.7150/thno.53330. This article has 26 citations and is from a domain leading peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 14
On topic 6
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 11
Resolved 11
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 11
Terms named correctly 8
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

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

  • MONDO:0010791 (2 mentions) - the report calls it "if available"; MONDO calls it myoglobinuria, recurrent

Terms whose name is worth a second look

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

  • HP:0003236 (1 mention) - the report calls it "Elevated circulating creatine kinase concentration"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated creatine kinase concentration" among its other names
  • HP:0001252 (1 mention) - the report calls it "Muscular hypotonia"; HP calls it Hypotonia, and lists "Muscular hypotonia" among its other names