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Classifications

Harrison's Part

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Subtypes

3

Myopathic (adult) form MONDO:0009704

The most common and least severe form, and the most common inherited disorder of muscle fatty acid metabolism. Onset from childhood to adulthood with recurrent, trigger-provoked attacks of myalgia, muscle weakness and rhabdomyolysis with myoglobinuria; patients are typically asymptomatic between episodes. Fixed weakness is uncommon. The thermolabile S113L variant predominates, explaining fever- and exercise-triggered crises. Diagnostic pitfall: the acylcarnitine profile can be entirely normal between episodes.

Show evidence (1 reference)

ORPHA:228302 SUPPORT Other

"is the most common and the least severe form of CPT II deficiency"

Orphanet defines the myopathic form as the most common and least severe.

Severe infantile hepatocardiomuscular form MONDO:0010914

The early-onset form, presenting in infancy or early childhood with hypoketotic hypoglycemia, liver failure, cardiomyopathy and arrhythmia, frequently precipitated by fasting or intercurrent illness. Multiorgan involvement distinguishes it from the muscle-restricted myopathic form.

Show evidence (1 reference)

ORPHA:228305 SUPPORT Other

"is the early-onset form of the disease"

Orphanet defines the severe infantile form as the early-onset form.

Lethal neonatal form MONDO:0012136

The lethal form, presenting within days of birth with multisystem failure. Uniquely among the three forms it includes dysmorphic and malformative features that arise before birth - neuronal migration defects and cystic kidneys - implying a developmental consequence of fetal long-chain fatty acid oxidation failure rather than a purely postnatal energy crisis.

Show evidence (1 reference)

ORPHA:228308 SUPPORT Other

"is the lethal form of the disease which presents with multisystem failure"

Orphanet defines the neonatal form as the lethal, multisystem-failure form.

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Pathophysiology

5

Impaired mitochondrial long-chain fatty acid oxidation

Loss of CPT-II function impairs mitochondrial beta-oxidation of long-chain fatty acids, resulting in accumulation of long-chain acylcarnitines and disruption of energy homeostasis, especially during fasting, illness, fever, or prolonged exercise when reliance on fatty acid oxidation increases.

skeletal muscle fiber CL:0008002 hepatocyte CL:0000182

CPT2 hgnc:2330

fatty acid beta-oxidation GO:0006635 long-chain fatty acid metabolic process GO:0001676

mitochondrion GO:0005739

Downstream

Long-chain acylcarnitines (C16, C18:1) CPT2 impairment blocks reconversion of long-chain acylcarnitines to long-chain acyl-CoA, producing the characteristic plasma long-chain acylcarnitine signature.

Free carnitine (C0) Long-chain acyl group trapping as acylcarnitine esters can reduce the free carnitine pool in symptomatic patients.

Palmitoyl-carnitine in muscle CPT2-deficient oxidative skeletal muscle accumulates palmitoyl-carnitine, providing the upstream substrate for LCAC-mediated calcium handling injury.

LCAC-mediated calcium dyshomeostasis in skeletal muscle Accumulated LCACs, including palmitoyl-carnitine, inhibit sarcoplasmic reticulum calcium uptake in CPT2-deficient muscle.

Hypoketotic hypoglycemia Severe hepatic long-chain FAO impairment reduces fasting energy and ketone production, producing hypoketotic hypoglycemia in neonatal and infantile forms.

Cardiomyopathy Cardiac long-chain FAO dependence makes severe CPT2 deficiency manifest as cardiomyopathy and heart failure.

Liver dysfunction Hepatic long-chain FAO failure contributes to liver dysfunction or failure in severe neonatal and infantile CPT2 deficiency.

Myopathy Skeletal-muscle energy failure in infantile CPT2 deficiency manifests as myopathy.

Abnormality of neuronal migration Severe neonatal CPT2 deficiency includes neuronal migration defects; the precise developmental intermediates are not resolved.

Renal cyst Severe neonatal CPT2 deficiency includes cystic kidneys; the direct renal-development mechanism remains uncertain.

Metabolic myofiber injury and rhabdomyolysis In skeletal muscle, long-chain FAO failure creates ATP stress and toxic lipid intermediate accumulation that lead to episodic myofiber breakdown.

Exercise intolerance During exertion, skeletal muscle reliance on fatty acid oxidation unmasks the CPT2 block, producing exercise intolerance and precipitating rhabdomyolysis attacks.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders."

Directly supports impaired fatty acid oxidation as the core defect in CPT II deficiency.

Thermolability of mutant CPT-II enzyme

The common myopathic variant p.Ser113Leu produces an enzyme with near-normal baseline activity but marked thermolability at elevated temperatures (40-45 degrees C) and abnormal sensitivity to inhibition by malonyl-CoA. This provides a mechanistic rationale for fever- and exertion-triggered metabolic crises, as the mutant enzyme loses activity precisely when fatty acid oxidation demand is greatest.

protein folding GO:0006457

carnitine O-palmitoyltransferase activity GO:0004095 ↓ DECREASED

Downstream

Impaired mitochondrial long-chain fatty acid oxidation Heat- and inhibitor-sensitive CPT2 variants lose functional activity during stress, reducing cellular beta-oxidation and ATP generation.

Show evidence (2 references)

PMID:28054946 SUPPORT In Vitro

"the wild-type and the S113L variants showed the same enzymatic activity. However, the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C and an abnormal sensitivity to inhibition by malony-CoA."

Demonstrates thermolability of S113L variant and abnormal malonyl-CoA sensitivity using recombinant enzymes.

PMID:28054946 SUPPORT Other

"The thermolability of the mutant enzyme might explain why symptoms in muscle CPT II deficiency mainly occur during prolonged exercise, infections and exposure to cold."

Links thermolability mechanism to clinical trigger factors.

LCAC-mediated calcium dyshomeostasis in skeletal muscle

In CPT2-deficient muscle, accumulation of long-chain acylcarnitines (LCACs), particularly palmitoyl-carnitine, directly inhibits sarcoplasmic reticulum calcium uptake, disrupts excitation-contraction coupling structures, and increases mitochondrial calcium stress and permeability transition pore susceptibility. This leads to contractile dysfunction and myofiber injury beyond simple energy failure.

skeletal muscle fiber CL:0008002

calcium ion homeostasis GO:0055074

sarcoplasmic reticulum GO:0016529

Downstream

Metabolic myofiber injury and rhabdomyolysis LCAC-driven calcium uptake impairment and contractile proteome disruption compromise muscle structure and function.

Show evidence (1 reference)

PMID:39182841 SUPPORT In Vitro

"Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake."

Directly demonstrates LCAC-mediated inhibition of SR calcium uptake in CPT2-deficient muscle model.

Metabolic myofiber injury and rhabdomyolysis

During metabolic stress, CPT2-deficient skeletal muscle cannot meet energy demands from long-chain fatty acid oxidation and accumulates lipid intermediates. The resulting ATP stress, calcium dyshomeostasis, and contractile structure disruption lead to episodic myofiber injury, rhabdomyolysis, leakage of creatine kinase and myoglobin, and secondary renal risk.

skeletal muscle fiber CL:0008002

muscle contraction GO:0006936 ↓ DECREASED

Downstream

Rhabdomyolysis Metabolic myofiber injury manifests clinically as recurrent rhabdomyolysis.

Myalgia Recurrent myofiber metabolic injury produces attacks of muscle pain.

Muscle weakness Acute myofiber dysfunction during attacks manifests as episodic muscle weakness.

Episodic muscle stiffness Attack-related contractile dysfunction manifests as stiffness and cramps during exercise or febrile illness.

Myoglobinuria Rhabdomyolysis releases myoglobin from damaged myofibers into urine.

Creatine kinase Serum CK rises as a biochemical marker of attack-related myofiber injury.

Acute kidney injury Massive rhabdomyolysis can cause AKI through myoglobin-mediated renal injury.

Show evidence (2 references)

PMID:29502916 SUPPORT Other

"Partial deficiency of CPT2 activity typically leads to episodes of recurrent rhabdomyolysis in adolescence or adulthood, the most common phenotype in this disorder."

Review-level CPT2 deficiency summary supports recurrent rhabdomyolysis as the main skeletal-muscle outcome of partial CPT2 activity.

PMID:39182841 SUPPORT Model Organism

"Our data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis."

Cpt2-deficient mouse muscle data provide mechanistic support for muscle structural and contractile injury.

Carnitine shuttle disruption

CPT-II is the final enzyme of the three-component carnitine shuttle that transports long-chain fatty acids into the mitochondrial matrix. CPT-I on the outer mitochondrial membrane converts acyl-CoA to acylcarnitine, CACT translocates acylcarnitine across the inner membrane, and CPT-II regenerates acyl-CoA inside the mitochondrion. Loss of CPT-II activity blocks this shuttle at its terminal step.

carnitine shuttle GO:0006853

mitochondrial inner membrane GO:0005743

Downstream

Impaired mitochondrial long-chain fatty acid oxidation Loss of the terminal CPT2 step prevents long-chain acylcarnitines from being regenerated as mitochondrial acyl-CoA substrates for beta-oxidation.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"The carnitine palmitoyltransferase (CPT) system consists of two enzymes, CPT I and CPT II, and is involved in the transport of long-chain fatty acids into the mitochondrial compartment. The enzymes are located in the outer (CPT I) and inner mitochondrial membrane (CPT II)."

Describes the carnitine shuttle system and localization of CPT-I and CPT-II.

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Pathograph

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

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Phenotypes

14

Cardiovascular 1

Cardiomyopathy HP:0001638

Characteristic of the two severe forms, where GeneReviews lists it among the defining features, and additionally reported as a complication of the myopathic form - hence all three subtypes. No frequency band is asserted: the previous OCCASIONAL rested on a single case report of reduced ejection fraction in a myopathic patient, which cannot support a disease-level band, and cardiomyopathy is characteristic rather than occasional in the severe forms, so a single band would misdescribe both ends. Omitted per docs/frequency-evidence-guidelines.md.

Show evidence (3 references)

PMID:20301431 SUPPORT Human Clinical

"Lethal neonatal and severe infantile hepatocardiomuscular phenotypes are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death."

GeneReviews lists cardiomyopathy among the defining features of both severe forms, supporting the subtype assignment.

PMID:37933340 SUPPORT Human Clinical

"Echocardiogram showed a left ventricle ejection fraction (LVEF) of 40%."

Documents cardiomyopathy with reduced ejection fraction in a myopathic CPT II patient.

PMID:37933340 SUPPORT Human Clinical

"The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction."

Identifies cardiomyopathy as a feature of severe early-onset CPT II deficiency.

Digestive 1

Liver dysfunction Decreased liver function HP:0001410

Show evidence (3 references)

PMID:20301431 SUPPORT Human Clinical

"Lethal neonatal and severe infantile hepatocardiomuscular phenotypes are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death."

GeneReviews lists cardiomyopathy among the defining features of both severe forms, supporting the subtype assignment.

PMID:37933340 SUPPORT Human Clinical

"The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction."

Human clinical summary identifies liver dysfunction in severe early-onset CPT II deficiency.

PMID:29502916 SUPPORT Other

"Later-onset, infantile disease is characterized by liver failure, cardiomyopathy, myopathy, and ketotic hypoglycemia in the first year of life."

Review-level CPT2 deficiency summary supports liver failure in infantile disease.

Genitourinary 3

Myoglobinuria VERY_FREQUENT HP:0002913

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%)"

Quantifies myoglobinuria at 86% in myopathic CPT II deficiency cohort.

PMID:37933340 SUPPORT Human Clinical

"We report an otherwise healthy 38-year-old patient who presented with severe myalgia, cramps, fatigue, low-grade fever, and transient myoglobinuria, after intense physical training."

Case presentation showing transient myoglobinuria as a presenting feature.

Acute kidney injury HP:0001919

No frequency band is asserted. The previous OCCASIONAL (5-29%) sat against the cited source describing AKI as "one of the most common complications" of massive rhabdomyolysis, which points higher, but neither source quantifies it. Omitted rather than guessed.

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure."

Lists renal failure as a complication of rhabdomyolysis in CPT II deficiency.

PMID:37933340 SUPPORT Human Clinical

"One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy"

Directly identifies AKI as a common rhabdomyolysis complication in CPT II deficiency.

Renal cyst HP:0000107

Show evidence (1 reference)

PMID:29502916 SUPPORT Other

"A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys."

Review-level CPT2 deficiency summary lists cystic kidneys in severe neonatal disease.

Metabolism 2

Hypoketotic hypoglycemia HP:0001985

No frequency band is asserted - the sources establish hypoketotic hypoglycemia as a defining feature of both severe forms without quantifying it, and the previous disease-level FREQUENT band was scoped to the whole disease while the accompanying context string restricted it to the severe forms.

Show evidence (2 references)

PMID:37933340 SUPPORT Human Clinical

"The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction."

Confirms hypoketotic hypoglycemia as a hallmark of severe early-onset CPT II forms.

PMID:20301431 SUPPORT Human Clinical

"Lethal neonatal and severe infantile hepatocardiomuscular phenotypes are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death."

GeneReviews confirms hypoketotic hypoglycemia as a defining feature of both severe early-onset phenotypes.

Elevated creatine kinase Elevated circulating creatine kinase concentration HP:0003236

No frequency band is asserted. The available quantitative evidence (3 of 6 children with raised muscle enzymes, PMID:38650450) would indicate roughly 50%, i.e. FREQUENT rather than the VERY_FREQUENT previously recorded, but a denominator of six is too small to band reliably and the figure is not specific to CK. Per docs/frequency-evidence-guidelines.md, omitted rather than guessed.

Show evidence (1 reference)

PMID:38650450 SUPPORT Human Clinical

"3 cases presented with clinical manifestations of fever, muscle weakness, and increased muscle enzymes."

Documents increased muscle enzymes (including CK) as a clinical manifestation in CPT2-deficient children.

Musculoskeletal 4

Rhabdomyolysis VERY_FREQUENT HP:0003201

The VERY_FREQUENT band is carried by the myoglobinuria figure (86% of a 50-patient muscle CPT II cohort) used as a proxy, since no source reports a rhabdomyolysis percentage directly; myoglobinuria is the clinical marker of a rhabdomyolysis episode, so the proxy is close but not identical. GeneReviews additionally notes a sex bias in symptomatic expression: males are more likely to be symptomatic than females.

Show evidence (3 references)

PMID:20301431 SUPPORT Human Clinical

"Males are more likely to be symptomatic than females."

GeneReviews records a sex bias in symptomatic expression of CPT II deficiency, absent from this entry before review.

PMID:28054946 SUPPORT Other

"Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure."

Directly lists rhabdomyolysis as a clinical feature of muscle CPT II deficiency.

PMID:28054946 SUPPORT Other

"Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%)"

Quantifies myoglobinuria at 86% in a retrospective cohort of 50 patients with MUSCLE (myopathic) CPT II deficiency; the frequency band applies to the myopathic subtype.

Muscle weakness FREQUENT HP:0001324

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%)"

Quantifies muscle weakness at 76% in myopathic CPT II cohort.

Myopathy HP:0003198

Show evidence (1 reference)

PMID:29502916 SUPPORT Other

"Later-onset, infantile disease is characterized by liver failure, cardiomyopathy, myopathy, and ketotic hypoglycemia in the first year of life."

Review-level CPT2 deficiency summary identifies myopathy as a severe infantile phenotype.

Episodic muscle stiffness Exercise-induced muscle stiffness HP:0008967

No frequency band is asserted. The previous FREQUENT rested on a single case report; no source quantifies stiffness separately from the myalgia band.

Show evidence (1 reference)

PMID:37933340 SUPPORT Human Clinical

"The latter is characterized by muscle pain and weakness and stiffness, typically triggered by exercise or febrile illnesses"

Directly describes muscle stiffness as a characteristic feature of myopathic CPT II deficiency.

Constitutional 2

Myalgia VERY_FREQUENT HP:0003326

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"Almost all patients (94%) described attacks of myalgia."

Quantifies myalgia at 94% in a retrospective cohort of 50 patients with MUSCLE (myopathic) CPT II deficiency; the frequency band therefore applies to the myopathic subtype, not to CPT II deficiency as a whole.

PMID:37933340 SUPPORT Human Clinical

"We report an otherwise healthy 38-year-old patient who presented with severe myalgia, cramps, fatigue, low-grade fever, and transient myoglobinuria, after intense physical training."

Case report illustrating typical exercise-triggered myalgia presentation.

Exercise intolerance HP:0003546

Show evidence (1 reference)

PMID:29502916 SUPPORT Human Clinical

"Affected individuals present with exercise intolerance and recurrent attacks of rhabdomyolysis triggered by fasting, rigorous exercise, cold, and acute illness."

Review-level CPT2 deficiency summary directly documents exercise intolerance in affected individuals.

Other 1

Abnormality of neuronal migration HP:0002269

Show evidence (1 reference)

PMID:29502916 SUPPORT Other

"A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys."

Review-level CPT2 deficiency summary lists neuronal migration defects in severe neonatal disease.

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Genetic Associations

2

CPT2 gene variants

Gene: CPT2 hgnc:2330

Autosomal recessive

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"Three phenotypes of CPT II deficiency are known: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a mild myopathic form"

Describes the three clinical phenotypes of CPT II deficiency.

PMID:39429887 SUPPORT Human Clinical

"The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms."

Quantifies case distribution across the three clinical subtypes.

Variants (3)

CPT2 - p.Ser113Leu (S113L)

The most common pathogenic variant, found in approximately 90% of myopathic CPT II patients with an allele frequency of 60-70%. Produces a thermolabile enzyme with abnormal sensitivity to malonyl-CoA inhibition.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"In approximately 90% the molecular basis is a p. S113L mutation in homozygous or heterozygous state with an allele frequency of 60%–70%"

Quantifies S113L prevalence and allele frequency in myopathic CPT II cohort.

CPT2 - c.338C>T and c.482G>A compound heterozygote

Compound heterozygous CPT2 variants identified by whole-genome sequencing in a patient with recurrent rhabdomyolysis and normal inter-episode acylcarnitine profiles.

CPT2 - Various private mutations

More than 60 mostly private mutations have been described in CPT2 beyond the common S113L variant. Novel variants include p.F352L, p.R498L, p.F434S, p.A515P, and c.153-2A>G reported in a Chinese pediatric cohort.

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"In addition there are more than 60 mostly private mutations"

Documents the breadth of private CPT2 mutations beyond S113L.

PMID:38650450 SUPPORT Human Clinical

"including 3 known variants (p.R631C, p.T589M, and p.D255G) and 5 newly reported variants (p.F352L, p.R498L, p.F434S, p.A515P, and c.153-2A>G)."

Reports novel CPT2 variants identified in a Chinese pediatric cohort.

CPT2 (Pathogenic Variants)

Gene: CPT2 hgnc:2330

Show evidence (1 reference)

CGGV:assertion_1a57ea10-6ca0-4311-94f1-0ad036a38ca6-2018-03-27T160000.000Z SUPPORT Other

ClinGen classifies the CPT2-carnitine palmitoyltransferase II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

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Medical Actions

8

Avoidance of metabolic triggers

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Lifestyle modification to avoid prolonged exercise, fasting, cold exposure, and other metabolic stressors is the primary preventive strategy. Patients should modify daily activities to prevent recurrent rhabdomyolysis episodes. A distinct and easily overlooked hazard is general anaesthesia, which GeneReviews says should proceed with caution because of possible risk of malignant hyperthermia or rhabdomyolysis - to the point that genetic testing of at-risk asymptomatic siblings is advised BEFORE they undergo anaesthesia.

Mechanism Target:

MODULATES Impaired mitochondrial long-chain fatty acid oxidation — Avoiding fasting, sustained exercise, fever/illness, and cold exposure reduces stress-induced reliance on the impaired long-chain fatty acid oxidation pathway.

Show evidence (1 reference)

PMID:29502916 SUPPORT Human Clinical

"Individuals with CPT2 deficiency should be instructed to avoid prolonged fasting (>10 hours) and sustained, intensive exercise."

Review-level management guidance supports trigger avoidance to reduce metabolic stress on the CPT2-deficient pathway.

Target Phenotypes: Rhabdomyolysis HP:0003201 Myalgia HP:0003326 Muscle weakness HP:0001324 Myoglobinuria HP:0002913 Acute kidney injury HP:0001919 Exercise intolerance HP:0003546

Show evidence (5 references)

PMID:37933340 SUPPORT Human Clinical

"The patient was discharged upon the improvement of renal function with lifestyle modification recommendations."

Supports lifestyle modification as a key management strategy.

PMID:28054946 SUPPORT Other

"Trigger factors are prolonged exercise, fasting, fever and exposure to cold"

Identification of trigger factors directly supports avoidance strategy.

PMID:20301431 SUPPORT Human Clinical

"Agents/circumstances to avoid: Avoid extended fasting and prolonged exercise."

GeneReviews states the core avoidance set for CPT II deficiency.

+ 2 more references

High-carbohydrate, low-fat diet

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Dietary modification emphasizing high carbohydrate and low long-chain fat intake to reduce reliance on fatty acid oxidation. Medium-chain triglyceride (MCT) supplementation may be used as an alternative energy source since MCT can bypass the carnitine shuttle.

Mechanism Target:

BYPASSES Impaired mitochondrial long-chain fatty acid oxidation — Carbohydrate before and during exercise and MCT supplementation provide alternative energy substrate so muscle is less dependent on long-chain fatty acid oxidation.

Show evidence (2 references)

PMID:29502916 SUPPORT Human Clinical

"Carbohydrate intake before and during exercise may prevent attacks."

Review-level management guidance supports carbohydrate intake to prevent exertional attacks.

PMID:29502916 SUPPORT Human Clinical

"Dietary supplementation with MCT provides an alternative substrate for FAO."

Review-level management guidance supports MCT as an alternative substrate that can bypass the carnitine shuttle.

Target Phenotypes: Rhabdomyolysis HP:0003201 Exercise intolerance HP:0003546 Hypoketotic hypoglycemia HP:0001985

Show evidence (1 reference)

PMID:29502916 SUPPORT Human Clinical

"MCT oil (0.5 g/kg lean body weight) has been demonstrated to improve exercise tolerance in individuals with long-chain FAODs if administered 20 minutes before exercise"

Provides the dosing and demonstrated exercise-tolerance benefit of MCT supplementation in long-chain fatty-acid oxidation disorders.

Aggressive fluid resuscitation for rhabdomyolysis

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Emergency management of acute rhabdomyolysis episodes with aggressive intravenous fluid therapy using crystalloid solutions to prevent or treat myoglobin-induced acute kidney injury.

Target Phenotypes: Rhabdomyolysis HP:0003201 Myoglobinuria HP:0002913 Acute kidney injury HP:0001919

Show evidence (2 references)

PMID:37933340 SUPPORT Human Clinical

"One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy; crystalloid solutions are preferred."

Directly recommends aggressive fluid resuscitation with crystalloids for rhabdomyolysis-associated AKI.

PMID:37933340 SUPPORT Human Clinical

"Fluid resuscitation was started. Acute kidney injury was diagnosed and managed with plasmapheresis and five sessions of hemodialysis."

Documents clinical management of AKI with fluid resuscitation and renal replacement therapy.

Carnitine supplementation

Action: carnitine supplementation Ontology label: Nutritional Support NCIT:C15433

L-carnitine supplementation may be used to support conjugation and excretion of accumulated long-chain acyl groups, though its use remains debated in fatty acid oxidation disorders. Free carnitine is often decreased in CPT2 deficiency.

Mechanism Target:

MODULATES Impaired mitochondrial long-chain fatty acid oxidation — Carnitine supplementation is a conditional supportive strategy for persistently low free carnitine, but its clinical utility in CPT2 deficiency remains uncertain.

Show evidence (1 reference)

PMID:29502916 SUPPORT Human Clinical

"Carnitine supplementation is probably not useful but may be given if levels are persistently low."

Review-level guidance partially supports carnitine supplementation only when free carnitine is persistently low.

Show evidence (1 reference)

PMID:38650450 SUPPORT Human Clinical

"Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines."

Decreased free carnitine provides rationale for supplementation.

Bezafibrate

Action: Pharmacotherapy NCIT:C15986

Agent: bezafibrate NCIT:C87449

A fibrate investigated as pharmacotherapy for CPT II deficiency on the basis of in vitro evidence that fibrates upregulate CPT2 expression. A randomized, double-blind, crossover trial in patients with CPT II (n=5) and VLCAD (n=5) deficiency found NO effect: despite the expected lipid-lowering, there were no changes in palmitate oxidation, total fatty acid oxidation, or heart rate during exercise. The authors graded this Class I evidence that bezafibrate is ineffective, and concluded that the in vitro therapeutic promise does not translate in vivo. Bezafibrate is recorded here as a refuted therapeutic hypothesis, not a candidate treatment.

Mechanism Target:

MODULATES Impaired mitochondrial long-chain fatty acid oxidation — REFUTED MECHANISM, retained as a negative result. Bezafibrate was hypothesised to improve fat oxidation during exercise in CPT2 and VLCAD deficiency by upregulating CPT2 expression; randomized double-blind testing found no change in palmitate oxidation, total fatty acid oxidation, or heart rate. treatment_effect is MODULATES only because the enum offers no null value - the REFUTE evidence items are what carry the finding.

Show evidence (2 references)

clinicaltrials:NCT00983788 SUPPORT

"The main criteria for assessing the potential effect of this drug will be the fat oxidation rate studied during a moderate workload on cycle ergometer"

Trial record supports fat oxidation during exercise as the mechanistic endpoint for bezafibrate in CPT2/VLCAD deficiency.

PMID:24453079 REFUTE Human Clinical

"Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise."

Randomized crossover trial refutes the proposed mechanism - lipid-lowering occurred but fatty acid oxidation was unchanged.

Target Phenotypes: Exercise intolerance HP:0003546 Myalgia HP:0003326 Rhabdomyolysis HP:0003201

Show evidence (3 references)

clinicaltrials:NCT00983788 SUPPORT

"The investigators propose to evaluate the effect of bezafibrate on metabolism during exercise in 22 adult patients affected with carnitine palmitoyltransferase II (CPTII) or very-long chain acyl-CoA-dehydrogenase (VLCAD) deficiencies."

Directly supports bezafibrate as a studied intervention in adults with CPT II deficiency.

PMID:24453079 REFUTE Human Clinical

"Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies."

The trial's stated conclusion directly refutes clinical benefit of bezafibrate in CPT II deficiency.

PMID:24453079 REFUTE Human Clinical

"This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies."

Class I evidence grading establishes the strength of the negative result.

Triheptanoin (Dojolvi)

Action: nutritional supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: triheptanoin

An odd-chain (C7) triglyceride providing anaplerotic substrate to sustain the TCA cycle, gluconeogenesis and energy production - the rationale being that conventional even-chain MCT supplies acetyl-CoA but does not replenish depleted TCA-cycle intermediates. Unlike bezafibrate, triheptanoin is an approved therapy: it is licensed as a source of calories and fatty acids for long-chain fatty acid oxidation disorders, the class that includes CPT II deficiency. A double-blind randomized comparison against MCT showed a positive cardiac effect, with improvement in major clinical events in open-label extension studies.

Mechanism Target:

BYPASSES Impaired mitochondrial long-chain fatty acid oxidation — Triheptanoin is intended to provide alternative odd-chain substrate and anaplerotic support in long-chain fatty acid oxidation disorders.

Show evidence (2 references)

clinicaltrials:NCT01379625 SUPPORT

"This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders."

Trial record supports triheptanoin as an intervention aimed at muscle pain, cardiac function, and energy in LC-FAOD.

PMID:40633017 SUPPORT Human Clinical

"Triheptanoin is an anaplerotic source of calories for treatment of LC-FAODs, providing a source of substrates to sustain the TCA cycle, gluconeogenesis, and energy production."

States the anaplerotic mechanism that distinguishes triheptanoin from conventional even-chain MCT.

Target Phenotypes: Myalgia HP:0003326 Cardiomyopathy HP:0001638 Exercise intolerance HP:0003546 Rhabdomyolysis HP:0003201

Show evidence (5 references)

PMID:20301431 SUPPORT Human Clinical

"Targeted therapies: Low-fat/high-carbohydrate diet as prescribed by metabolic dietician; triheptanoin for one third of daily calories."

GeneReviews gives the triheptanoin dosing target, previously absent from the entry.

PMID:20301431 SUPPORT Human Clinical

"Medium-chain triglyceride (MCT) oil can be substituted in areas where triheptanoin is not available."

Records the substitution guidance where the approved agent is unavailable.

clinicaltrials:NCT01379625 SUPPORT

"This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders."

Supports triheptanoin as a clinical trial intervention for LC-FAOD populations that include CPT II deficiency.

+ 2 more references

Newborn screening

Action: disease screening Ontology label: Disease Screening NCIT:C15419

CPT II deficiency is detectable by newborn screening via tandem mass spectrometry using elevated long-chain acylcarnitines (C16, C18:1) as primary markers. Three of six children in one cohort were diagnosed through neonatal screening. However, biochemical abnormalities may only be detectable during metabolic stress.

Target Phenotypes: Hypoketotic hypoglycemia HP:0001985 Cardiomyopathy HP:0001638 Liver dysfunction HP:0001410 Rhabdomyolysis HP:0003201

Show evidence (2 references)

PMID:38650450 SUPPORT Human Clinical

"Three cases were diagnosed at neonatal screening"

Documents successful neonatal screening diagnosis in CPT2 deficiency.

PMID:38650450 SUPPORT Human Clinical

"An early diagnosis can be facilitated by neonatal blood tandem mass spectrometry screening and genetic testing, and most patients have good prognosis after a timely diagnosis and treatment."

Supports the value of newborn screening for early diagnosis and improved outcomes.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Counseling for affected families regarding autosomal recessive inheritance, carrier testing, recurrence risk, and reproductive options including prenatal genetic testing.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"The disease follows an autosomal recessive mode of inheritance."

Autosomal recessive inheritance directly supports the role of genetic counseling for carrier and recurrence risk assessment.

🌍

Environmental Factors

4

Prolonged exercise

Exercise is the most common trigger for rhabdomyolysis episodes, reported in 87% of patients. Sustained muscle activity increases reliance on fatty acid oxidation, unmasking the enzymatic defect.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"The most common trigger factors were exercise (87%) and infection (62%)."

Quantifies exercise as the most common trigger at 87%.

Mechanism Target:

TRIGGERS Impaired mitochondrial long-chain fatty acid oxidation — Sustained exercise shifts muscle onto fatty acid oxidation for fuel, so it loads the exact pathway this enzyme cannot service. The deficiency is silent until demand exceeds residual capacity, which is why attacks are exertional rather than constant.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"The most common trigger factors were exercise (87%) and infection (62%)."

Identifies exercise as the most common trigger factor, present in 87% of episodes, the demand state that unmasks the enzymatic block.

Fasting

Fasting increases dependency on fatty acid oxidation for energy, precipitating metabolic crises.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"Trigger factors are prolonged exercise, fasting, fever and exposure to cold"

Lists fasting as a recognized trigger factor.

Mechanism Target:

TRIGGERS Impaired mitochondrial long-chain fatty acid oxidation — Fasting withdraws glucose and forces reliance on fatty acid oxidation, imposing the same demand on the blocked pathway that exercise does by a different route.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"Trigger factors are prolonged exercise, fasting, fever and exposure to cold"

Lists fasting among the trigger factors, alongside prolonged exercise, fever and cold, all states that force reliance on fatty acid oxidation.

Fever and infection

Fever both increases energy demand and, in thermolabile variants, directly destabilizes the mutant CPT-II enzyme. Infections triggered episodes in 62% of patients.

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"The most common trigger factors were exercise (87%) and infection (62%)."

Infection is the second most common trigger at 62%.

PMID:28054946 SUPPORT In Vitro

"the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C"

Thermolability of S113L variant at fever-range temperatures explains fever as a trigger.

Mechanism Target:

TRIGGERS Thermolability of mutant CPT-II enzyme — Fever is mechanistically distinct from the other triggers in this entry. Rather than merely raising fatty acid oxidation demand, a febrile core temperature directly destabilises the mutant enzyme, so it targets the thermolability node rather than the shared demand node.

Show evidence (1 reference)

PMID:28054946 SUPPORT In Vitro

"the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C"

The mutant enzyme showed abnormal thermal destabilization at 40 and 45 degrees Celsius, the temperature range reached in fever. Support is PARTIAL because the demonstration is an in vitro enzyme assay rather than a clinical measurement.

Cold exposure

Exposure to cold is a recognized trigger for metabolic crises in CPT II deficiency.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"Trigger factors are prolonged exercise, fasting, fever and exposure to cold"

Lists cold exposure among recognized trigger factors.

Mechanism Target:

TRIGGERS Impaired mitochondrial long-chain fatty acid oxidation — Cold raises thermogenic demand, which is met by fatty acid oxidation, so it loads the blocked pathway through the known intermediate of shivering and non-shivering thermogenesis.

Show evidence (1 reference)

PMID:28054946 SUPPORT Other

"Trigger factors are prolonged exercise, fasting, fever and exposure to cold"

Lists exposure to cold among the trigger factors for metabolic decompensation in this disorder.

🔬

Biochemical Markers

4

Long-chain acylcarnitines (C16, C18:1) (INCREASED)

Context: Elevation of long-chain acylcarnitines, particularly palmitoylcarnitine (C16:0) and oleoylcarnitine (C18:1), is the hallmark biochemical signature detectable by tandem mass spectrometry. However, profiles may be normal between crises, and sampling during metabolic stress is critical.

Pathograph Readouts

Readout Of Impaired mitochondrial long-chain fatty acid oxidation Positive Diagnostic

Elevated long-chain acylcarnitine species are the diagnostic plasma readout of the CPT2 carnitine-shuttle block.

Show evidence (1 reference)

PMID:29502916 SUPPORT Human Clinical

"The plasma acylcarnitine profile shows elevated C16, C18:1, and C18:2 carnitine species."

Review-level CPT2 deficiency summary identifies elevated long-chain acylcarnitines as the diagnostic biochemical signature.

Show evidence (1 reference)

PMID:38650450 SUPPORT Human Clinical

"Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines."

Documents elevated C16 and C18:1 acylcarnitines in CPT2-deficient children.

Free carnitine (C0) (DECREASED)

Context: Free carnitine levels may be decreased or low-normal, reflecting sequestration as long-chain acylcarnitines that cannot be metabolized due to CPT-II dysfunction.

Pathograph Readouts

Readout Of Impaired mitochondrial long-chain fatty acid oxidation Negative Diagnostic

Decreased free carnitine can accompany the CPT2 block when long-chain acyl groups are trapped as acylcarnitine esters.

Show evidence (1 reference)

PMID:38650450 SUPPORT Human Clinical

"Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines."

Human pediatric CPT2 cases show decreased free carnitine with elevated long-chain acylcarnitines.

Show evidence (1 reference)

PMID:38650450 SUPPORT Human Clinical

"Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines."

Documents decreased free carnitine in CPT2-deficient children alongside elevated acylcarnitines.

Creatine kinase (INCREASED)

Context: Markedly elevated during rhabdomyolysis episodes, reflecting skeletal muscle damage. Returns to normal between episodes. Serves as an acute marker of metabolic crisis severity.

Pathograph Readouts

Readout Of Metabolic myofiber injury and rhabdomyolysis Positive Monitoring

CK elevation tracks acute metabolic myofiber injury during rhabdomyolysis episodes.

Show evidence (1 reference)

PMID:29502916 SUPPORT Human Clinical

"CK levels are high during rhabdomyolysis but may return to normal or be only mildly elevated when affected individuals are well."

Review-level CPT2 deficiency summary supports CK as an episodic monitoring readout of rhabdomyolysis.

Show evidence (1 reference)

PMID:38650450 SUPPORT Human Clinical

"3 cases presented with clinical manifestations of fever, muscle weakness, and increased muscle enzymes."

Increased muscle enzymes (CK) documented during symptomatic episodes in CPT2 deficiency.

Palmitoyl-carnitine in muscle (INCREASED)

Context: Palmitoyl-carnitine (C16:0) accumulates preferentially in oxidative muscle fibers in CPT2 deficiency and directly inhibits sarcoplasmic reticulum calcium uptake, linking it to the pathogenesis of muscle contractile dysfunction.

Show evidence (2 references)

PMID:39182841 SUPPORT Model Organism

"Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle."

Cpt2-deficient mouse soleus directly supports palmitoyl-carnitine accumulation in skeletal muscle.

PMID:39182841 SUPPORT In Vitro

"Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake."

Directly supports palmitoyl-carnitine-mediated inhibition of calcium handling in muscle.

📈

Progression

3

Neonatal multisystem failure

Lethal neonatal Age: First days of life

The lethal form presents within days of birth with multisystem failure. Malformative features present at birth - neuronal migration defects and cystic kidneys - indicate that fetal long-chain fatty acid oxidation failure has developmental as well as bioenergetic consequences, distinguishing this form from the purely postnatal energy crises of the other two.

Show evidence (2 references)

ORPHA:228308 SUPPORT Other

"is the lethal form of the disease which presents with multisystem failure"

Orphanet characterises the neonatal form as lethal multisystem failure.

PMID:29502916 SUPPORT Other

"A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys."

Details the neonatal-form presentation including the malformative features.

Infantile hepatocardiomuscular crises

Severe infantile Age: Infancy to early childhood

The early-onset form presents with fasting- or illness-precipitated hypoketotic hypoglycemia, liver failure, cardiomyopathy and arrhythmia. Course is one of recurrent multiorgan decompensation rather than the muscle-restricted, fully-recovering episodes of the myopathic form.

Show evidence (1 reference)

ORPHA:228305 SUPPORT Other

"is the early-onset form of the disease"

Orphanet characterises this as the early-onset form.

Episodic myopathic crises with symptom-free intervals

Myopathic Age: Childhood to adulthood

Crises are episodic and provoked by prolonged exercise, fasting, fever or cold exposure; between crises patients are typically asymptomatic and, importantly, biochemically normal. Onset is more often in childhood than in adulthood despite the label "adult form" - a retrospective cohort found 60% had early-childhood onset. Persistent fixed weakness is characteristically absent. Repeated rhabdomyolysis episodes carry cumulative renal risk through myoglobin nephrotoxicity.

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"Sixty percent of the patients had an early childhood onset compared to later adolescent or adulthood onsets."

Corrects the common assumption that the myopathic form is an adult-onset disease.

PMID:28054946 SUPPORT Other

"it is clinically characterized by attacks of myalgia and rhabdomyolysis without persistent muscle weakness and lipid accumulation in muscle fibers"

Establishes the episodic pattern with absence of fixed interictal weakness.

📊

Prevalence

2

Worldwide

Cases In Literature Ultra Rare

A 2024 review of 262 PubMed articles on CPT-2 deficiency detailed 245 reported cases spanning the lethal neonatal, severe infantile hepatocardiomuscular and myopathic forms. Case counts are a floor rather than a true prevalence: the myopathic form is under-ascertained because acylcarnitine profiles can be entirely normal between episodes.

Show evidence (1 reference)

PMID:39429887 SUPPORT Human Clinical

"The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms."

Provides the cumulative reported-case count across all three clinical forms.

Worldwide

Unknown Unknown Myopathic

The myopathic form is the most common of the three and is described as the most common inherited disorder of lipid metabolism affecting skeletal muscle. No reliable population rate is available; the disorder is under-ascertained because between-episode biochemistry can be normal.

Show evidence (2 references)

PMID:28054946 SUPPORT Other

"CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders."

Supports the relative predominance of the myopathic form among muscle fatty-acid-metabolism disorders.

PMID:20301431 SUPPORT Human Clinical

"The CPT2-related myopathic phenotype is the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria."

Two relative-frequency anchors from GeneReviews - most common lipid-metabolism disorder of skeletal muscle, and the single most frequent cause of hereditary myoglobinuria. These are the closest thing to a rate available for a disorder with no published population denominator.

🔬

Clinical Trials

3

NCT00983788 PHASE_II COMPLETED

Randomized, double-blind, placebo-controlled crossover trial evaluating bezafibrate effects on exercise metabolism in adults with CPT II or VLCAD deficiency.

Target Phenotypes: Exercise intolerance HP:0003546 Myopathy HP:0003198

Show evidence (1 reference)

clinicaltrials:NCT00983788 SUPPORT

"This study will be an 9-month, randomized, double-blind, placebo-controlled crossover trial."

Supports trial design and intervention context for bezafibrate in CPT II/LC-FAOD disease.

NCT01886378 PHASE_II COMPLETED

Open-label Phase 2 trial evaluating UX007 (triheptanoin) clinical effects and safety in LC-FAOD.

Target Phenotypes: Myopathy HP:0003198 Cardiomyopathy HP:0001638

Show evidence (1 reference)

clinicaltrials:NCT01886378 SUPPORT

"The primary objective of the study was to evaluate the impact of UX007 on acute clinical pathophysiology associated with LC-FAOD following 24 weeks of treatment."

Supports UX007/triheptanoin as an evaluated trial intervention in LC-FAOD.

NCT01379625 PHASE_II COMPLETED

Phase 2 trial of triheptanoin for long-chain fatty acid oxidation disorders, including outcomes relevant to muscle and cardiac function.

Target Phenotypes: Exercise intolerance HP:0003546 Cardiomyopathy HP:0001638

Show evidence (1 reference)

clinicaltrials:NCT01379625 SUPPORT

"This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders."

Supports triheptanoin trial targeting clinically relevant muscle and cardiac outcomes in LC-FAOD.

{ }

Source YAML

click to show

name: Carnitine Palmitoyltransferase II Deficiency
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
synonyms:
- CPT II deficiency
- CPT2 deficiency
- Carnitine palmitoyl transferase 2 deficiency
- CPT-II deficiency
description: 'Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessive inborn error of mitochondrial long-chain fatty acid oxidation caused by biallelic pathogenic variants in CPT2. CPT-II is an inner mitochondrial membrane enzyme that reconverts long-chain acylcarnitines back to long-chain acyl-CoA for entry into beta-oxidation, forming the final step of the carnitine shuttle. Three clinical phenotypes are recognized: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and the most common adult myopathic form characterized by recurrent exercise- or illness-triggered myalgia, rhabdomyolysis, and myoglobinuria. A 2024 comprehensive literature review across 262 PubMed articles detailed 245 reported cases spanning all three forms; the myopathic form predominates and is the most common inherited disorder of muscle fatty acid metabolism.

  '
disease_term:
  preferred_term: carnitine palmitoyltransferase II deficiency
  term:
    id: MONDO:0015515
    label: carnitine palmitoyltransferase II deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
has_subtypes:
- name: Myopathic
  display_name: Myopathic (adult) form
  classification: clinical_severity
  subtype_term:
    preferred_term: carnitine palmitoyl transferase II deficiency, myopathic form
    term:
      id: MONDO:0009704
      label: carnitine palmitoyl transferase II deficiency, myopathic form
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0009704
        label: carnitine palmitoyl transferase II deficiency, myopathic form
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:228302
      mapping_justification: >
        Orphanet ORPHA:228302 lists MONDO:0009704 as an exact cross-reference.
  description: >-
    The most common and least severe form, and the most common inherited disorder
    of muscle fatty acid metabolism. Onset from childhood to adulthood with
    recurrent, trigger-provoked attacks of myalgia, muscle weakness and
    rhabdomyolysis with myoglobinuria; patients are typically asymptomatic
    between episodes. Fixed weakness is uncommon. The thermolabile S113L variant
    predominates, explaining fever- and exercise-triggered crises. Diagnostic
    pitfall: the acylcarnitine profile can be entirely normal between episodes.
  evidence:
  - reference: ORPHA:228302
    reference_title: "Carnitine palmitoyl transferase II deficiency, myopathic form"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is the most common and the least severe form of CPT II deficiency
    explanation: Orphanet defines the myopathic form as the most common and least severe.
- name: Severe infantile
  display_name: Severe infantile hepatocardiomuscular form
  classification: clinical_severity
  subtype_term:
    preferred_term: carnitine palmitoyl transferase II deficiency, severe infantile form
    term:
      id: MONDO:0010914
      label: carnitine palmitoyl transferase II deficiency, severe infantile form
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0010914
        label: carnitine palmitoyl transferase II deficiency, severe infantile form
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:228305
      mapping_justification: >
        Orphanet ORPHA:228305 lists MONDO:0010914 as an exact cross-reference.
  description: >-
    The early-onset form, presenting in infancy or early childhood with
    hypoketotic hypoglycemia, liver failure, cardiomyopathy and arrhythmia,
    frequently precipitated by fasting or intercurrent illness. Multiorgan
    involvement distinguishes it from the muscle-restricted myopathic form.
  evidence:
  - reference: ORPHA:228305
    reference_title: "Carnitine palmitoyl transferase II deficiency, severe infantile form"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is the early-onset form of the disease
    explanation: Orphanet defines the severe infantile form as the early-onset form.
- name: Lethal neonatal
  display_name: Lethal neonatal form
  classification: clinical_severity
  subtype_term:
    preferred_term: carnitine palmitoyl transferase II deficiency, neonatal form
    term:
      id: MONDO:0012136
      label: carnitine palmitoyl transferase II deficiency, neonatal form
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0012136
        label: carnitine palmitoyl transferase II deficiency, neonatal form
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:228308
      mapping_justification: >
        Orphanet ORPHA:228308 lists MONDO:0012136 as an exact cross-reference.
  description: >-
    The lethal form, presenting within days of birth with multisystem failure.
    Uniquely among the three forms it includes dysmorphic and malformative
    features that arise before birth - neuronal migration defects and cystic
    kidneys - implying a developmental consequence of fetal long-chain fatty acid
    oxidation failure rather than a purely postnatal energy crisis.
  evidence:
  - reference: ORPHA:228308
    reference_title: "Carnitine palmitoyl transferase II deficiency, neonatal form"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is the lethal form of the disease which presents with multisystem failure
    explanation: Orphanet defines the neonatal form as the lethal, multisystem-failure form.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: 'A 2024 review of 262 PubMed articles on CPT-2 deficiency detailed 245 reported cases spanning the lethal neonatal, severe infantile hepatocardiomuscular and myopathic forms. Case counts are a floor rather than a true prevalence: the myopathic form is under-ascertained because acylcarnitine profiles can be entirely normal between episodes.

    '
  evidence:
  - reference: PMID:39429887
    reference_title: "Recurrent rhabdomyolysis caused by palmitoyltransferase II (CPT-2) deficiency but complete normal acylcarnitine profile: A patient presentation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms.
    explanation: Provides the cumulative reported-case count across all three clinical forms.
- subtype: Myopathic
  population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: 'The myopathic form is the most common of the three and is described as the most common inherited disorder of lipid metabolism affecting skeletal muscle. No reliable population rate is available; the disorder is under-ascertained because between-episode biochemistry can be normal.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders.
    explanation: Supports the relative predominance of the myopathic form among muscle fatty-acid-metabolism disorders.
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CPT2-related myopathic phenotype is the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria.
    explanation: Two relative-frequency anchors from GeneReviews - most common lipid-metabolism disorder of skeletal muscle, and the single most frequent cause of hereditary myoglobinuria. These are the closest thing to a rate available for a disorder with no published population denominator.
progression:
- subtype: Lethal neonatal
  phase: Neonatal multisystem failure
  age_range: First days of life
  notes: 'The lethal form presents within days of birth with multisystem failure. Malformative features present at birth - neuronal migration defects and cystic kidneys - indicate that fetal long-chain fatty acid oxidation failure has developmental as well as bioenergetic consequences, distinguishing this form from the purely postnatal energy crises of the other two.

    '
  evidence:
  - reference: ORPHA:228308
    reference_title: "Carnitine palmitoyl transferase II deficiency, neonatal form"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is the lethal form of the disease which presents with multisystem failure
    explanation: Orphanet characterises the neonatal form as lethal multisystem failure.
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
    explanation: Details the neonatal-form presentation including the malformative features.
- subtype: Severe infantile
  phase: Infantile hepatocardiomuscular crises
  age_range: Infancy to early childhood
  notes: 'The early-onset form presents with fasting- or illness-precipitated hypoketotic hypoglycemia, liver failure, cardiomyopathy and arrhythmia. Course is one of recurrent multiorgan decompensation rather than the muscle-restricted, fully-recovering episodes of the myopathic form.

    '
  evidence:
  - reference: ORPHA:228305
    reference_title: "Carnitine palmitoyl transferase II deficiency, severe infantile form"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is the early-onset form of the disease
    explanation: Orphanet characterises this as the early-onset form.
- subtype: Myopathic
  phase: Episodic myopathic crises with symptom-free intervals
  age_range: Childhood to adulthood
  notes: 'Crises are episodic and provoked by prolonged exercise, fasting, fever or cold exposure; between crises patients are typically asymptomatic and, importantly, biochemically normal. Onset is more often in childhood than in adulthood despite the label "adult form" - a retrospective cohort found 60% had early-childhood onset. Persistent fixed weakness is characteristically absent. Repeated rhabdomyolysis episodes carry cumulative renal risk through myoglobin nephrotoxicity.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Sixty percent of the patients had an early childhood onset compared to later adolescent or adulthood onsets.
    explanation: Corrects the common assumption that the myopathic form is an adult-onset disease.
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: it is clinically characterized by attacks of myalgia and rhabdomyolysis without persistent muscle weakness and lipid accumulation in muscle fibers
    explanation: Establishes the episodic pattern with absence of fixed interictal weakness.
pathophysiology:
- name: Impaired mitochondrial long-chain fatty acid oxidation
  conforms_to: "metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism"
  biological_scale: MOLECULAR
  description: 'Loss of CPT-II function impairs mitochondrial beta-oxidation of long-chain fatty acids, resulting in accumulation of long-chain acylcarnitines and disruption of energy homeostasis, especially during fasting, illness, fever, or prolonged exercise when reliance on fatty acid oxidation increases.

    '
  genes:
  - preferred_term: CPT2
    term:
      id: hgnc:2330
      label: CPT2
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  - preferred_term: long-chain fatty acid metabolic process
    term:
      id: GO:0001676
      label: long-chain fatty acid metabolic process
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders.
    explanation: Directly supports impaired fatty acid oxidation as the core defect in CPT II deficiency.
  downstream:
  - target: Long-chain acylcarnitines (C16, C18:1)
    description: CPT2 impairment blocks reconversion of long-chain acylcarnitines to long-chain acyl-CoA, producing the characteristic plasma long-chain acylcarnitine signature.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The plasma acylcarnitine profile shows elevated C16, C18:1, and C18:2 carnitine species.
      explanation: Review-level CPT2 deficiency summary identifies elevated long-chain acylcarnitines as the biochemical consequence of the CPT2 block.
  - target: Free carnitine (C0)
    description: Long-chain acyl group trapping as acylcarnitine esters can reduce the free carnitine pool in symptomatic patients.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Accumulated long-chain acyl groups are esterified to carnitine when CPT2 cannot efficiently regenerate acyl-CoA in the mitochondrial matrix.
    evidence:
    - reference: PMID:38650450
      reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines.
      explanation: Human pediatric CPT2 cases show decreased free carnitine alongside elevated long-chain acylcarnitines.
  - target: Palmitoyl-carnitine in muscle
    description: CPT2-deficient oxidative skeletal muscle accumulates palmitoyl-carnitine, providing the upstream substrate for LCAC-mediated calcium handling injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39182841
      reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle.
      explanation: Muscle-specific Cpt2-deficient mice accumulate palmitoyl-carnitine in oxidative muscle.
  - target: LCAC-mediated calcium dyshomeostasis in skeletal muscle
    description: Accumulated LCACs, including palmitoyl-carnitine, inhibit sarcoplasmic reticulum calcium uptake in CPT2-deficient muscle.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Long-chain acylcarnitine accumulation links the mitochondrial beta-oxidation block to sarcoplasmic reticulum calcium uptake defects.
    evidence:
    - reference: PMID:39182841
      reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle.
      explanation: Cpt2-deficient mouse soleus links palmitoyl-carnitine accumulation to reduced calcium uptake.
    - reference: PMID:39182841
      reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake.
      explanation: Isolated sarcoplasmic reticulum data directly support LCAC inhibition of calcium uptake.
  - target: Hypoketotic hypoglycemia
    description: Severe hepatic long-chain FAO impairment reduces fasting energy and ketone production, producing hypoketotic hypoglycemia in neonatal and infantile forms.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatic fatty acid oxidation failure lowers acetyl-CoA supply for ketogenesis and fasting energy homeostasis.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
      explanation: Review-level CPT2 deficiency summary links severe CPT2 deficiency to hypoketotic hypoglycemia.
  - target: Cardiomyopathy
    description: Cardiac long-chain FAO dependence makes severe CPT2 deficiency manifest as cardiomyopathy and heart failure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cardiomyocyte energy failure occurs when long-chain fatty acid oxidation cannot meet cardiac energy demand.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
      explanation: Review-level CPT2 deficiency summary includes cardiomyopathy and heart involvement in severe disease.
  - target: Liver dysfunction
    description: Hepatic long-chain FAO failure contributes to liver dysfunction or failure in severe neonatal and infantile CPT2 deficiency.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatic energy failure during fasting or illness impairs liver function in severe CPT2 deficiency.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Later-onset, infantile disease is characterized by liver failure, cardiomyopathy, myopathy, and ketotic hypoglycemia in the first year of life.
      explanation: Review-level CPT2 deficiency summary supports liver failure as a severe infantile manifestation.
  - target: Myopathy
    description: Skeletal-muscle energy failure in infantile CPT2 deficiency manifests as myopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired long-chain fatty acid oxidation limits ATP supply in skeletal muscle during infancy and metabolic stress.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Later-onset, infantile disease is characterized by liver failure, cardiomyopathy, myopathy, and ketotic hypoglycemia in the first year of life.
      explanation: Review-level CPT2 deficiency summary identifies myopathy as a severe infantile manifestation.
  - target: Abnormality of neuronal migration
    description: Severe neonatal CPT2 deficiency includes neuronal migration defects; the precise developmental intermediates are not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
      explanation: Review-level CPT2 deficiency summary lists neuronal migration defects in severe neonatal disease.
  - target: Renal cyst
    description: Severe neonatal CPT2 deficiency includes cystic kidneys; the direct renal-development mechanism remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
      explanation: Review-level CPT2 deficiency summary lists cystic kidneys in severe neonatal disease.
  - target: Metabolic myofiber injury and rhabdomyolysis
    description: In skeletal muscle, long-chain FAO failure creates ATP stress and toxic lipid intermediate accumulation that lead to episodic myofiber breakdown.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ATP deficit and accumulated long-chain lipid intermediates impair muscle contraction and myofiber integrity under stress.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Partial deficiency of CPT2 activity typically leads to episodes of recurrent rhabdomyolysis in adolescence or adulthood, the most common phenotype in this disorder.
      explanation: Review-level CPT2 deficiency summary links partial CPT2 activity to recurrent rhabdomyolysis.
  - target: Exercise intolerance
    description: During exertion, skeletal muscle reliance on fatty acid oxidation unmasks the CPT2 block, producing exercise intolerance and precipitating rhabdomyolysis attacks.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Exercise increases skeletal-muscle ATP demand and fatty acid oxidation flux, exposing the impaired carnitine shuttle.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Affected individuals present with exercise intolerance and recurrent attacks of rhabdomyolysis triggered by fasting, rigorous exercise, cold, and acute illness.
      explanation: Review-level CPT2 deficiency summary directly links CPT2 deficiency to exercise intolerance and stress-triggered rhabdomyolysis.
- name: Thermolability of mutant CPT-II enzyme
  description: 'The common myopathic variant p.Ser113Leu produces an enzyme with near-normal baseline activity but marked thermolability at elevated temperatures (40-45 degrees C) and abnormal sensitivity to inhibition by malonyl-CoA. This provides a mechanistic rationale for fever- and exertion-triggered metabolic crises, as the mutant enzyme loses activity precisely when fatty acid oxidation demand is greatest.

    '
  molecular_functions:
  - preferred_term: carnitine O-palmitoyltransferase activity
    term:
      id: GO:0004095
      label: carnitine O-palmitoyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the wild-type and the S113L variants showed the same enzymatic activity. However, the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C and an abnormal sensitivity to inhibition by malony-CoA.
    explanation: Demonstrates thermolability of S113L variant and abnormal malonyl-CoA sensitivity using recombinant enzymes.
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The thermolability of the mutant enzyme might explain why symptoms in muscle CPT II deficiency mainly occur during prolonged exercise, infections and exposure to cold.
    explanation: Links thermolability mechanism to clinical trigger factors.
  downstream:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    description: Heat- and inhibitor-sensitive CPT2 variants lose functional activity during stress, reducing cellular beta-oxidation and ATP generation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Cultured fibroblasts of three types of CPT II variants (p.V368I (heterozygous); p.V368I (homozygous); p.F352C (heterozygous) + p.V368I (homozygous)) showed decreased enzyme activities, cellular β-oxidation and ATP generation.
      explanation: Review-level evidence links thermolabile CPT2 variants to reduced beta-oxidation and ATP generation.
- name: LCAC-mediated calcium dyshomeostasis in skeletal muscle
  conforms_to: "metabolic_intoxication_decompensation#Toxic Metabolite Accumulation and Energy Deficit"
  biological_scale: CELLULAR
  description: 'In CPT2-deficient muscle, accumulation of long-chain acylcarnitines (LCACs), particularly palmitoyl-carnitine, directly inhibits sarcoplasmic reticulum calcium uptake, disrupts excitation-contraction coupling structures, and increases mitochondrial calcium stress and permeability transition pore susceptibility. This leads to contractile dysfunction and myofiber injury beyond simple energy failure.

    '
  biological_processes:
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: sarcoplasmic reticulum
    term:
      id: GO:0016529
      label: sarcoplasmic reticulum
  evidence:
  - reference: PMID:39182841
    reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake.
    explanation: Directly demonstrates LCAC-mediated inhibition of SR calcium uptake in CPT2-deficient muscle model.
  downstream:
  - target: Metabolic myofiber injury and rhabdomyolysis
    description: LCAC-driven calcium uptake impairment and contractile proteome disruption compromise muscle structure and function.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39182841
      reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Our data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis.
      explanation: The Cpt2-deficient mouse study supports muscle structural and functional injury downstream of calcium homeostasis disruption.
- name: Metabolic myofiber injury and rhabdomyolysis
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  biological_scale: TISSUE
  description: 'During metabolic stress, CPT2-deficient skeletal muscle cannot meet energy demands from long-chain fatty acid oxidation and accumulates lipid intermediates. The resulting ATP stress, calcium dyshomeostasis, and contractile structure disruption lead to episodic myofiber injury, rhabdomyolysis, leakage of creatine kinase and myoglobin, and secondary renal risk.

    '
  biological_processes:
  - preferred_term: muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Partial deficiency of CPT2 activity typically leads to episodes of recurrent rhabdomyolysis in adolescence or adulthood, the most common phenotype in this disorder.
    explanation: Review-level CPT2 deficiency summary supports recurrent rhabdomyolysis as the main skeletal-muscle outcome of partial CPT2 activity.
  - reference: PMID:39182841
    reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Our data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis.
    explanation: Cpt2-deficient mouse muscle data provide mechanistic support for muscle structural and contractile injury.
  downstream:
  - target: Rhabdomyolysis
    description: Metabolic myofiber injury manifests clinically as recurrent rhabdomyolysis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Partial deficiency of CPT2 activity typically leads to episodes of recurrent rhabdomyolysis in adolescence or adulthood, the most common phenotype in this disorder.
      explanation: Review-level CPT2 deficiency summary directly supports rhabdomyolysis downstream of partial CPT2 activity.
  - target: Myalgia
    description: Recurrent myofiber metabolic injury produces attacks of muscle pain.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure.
      explanation: Review-level clinical summary places myalgia in the same attack phenotype as rhabdomyolysis.
  - target: Muscle weakness
    description: Acute myofiber dysfunction during attacks manifests as episodic muscle weakness.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure.
      explanation: Review-level clinical summary includes muscle weakness during CPT2 attack episodes.
  - target: Episodic muscle stiffness
    description: Attack-related contractile dysfunction manifests as stiffness and cramps during exercise or febrile illness.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37933340
      reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The latter is characterized by muscle pain and weakness and stiffness, typically triggered by exercise or febrile illnesses
      explanation: Human clinical case-report summary links myopathic CPT2 attacks to muscle stiffness.
  - target: Myoglobinuria
    description: Rhabdomyolysis releases myoglobin from damaged myofibers into urine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Myofiber breakdown releases myoglobin that is filtered by the kidney.
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The main clinical symptoms in patients with muscle carnitine palmitoyl transferase II deficiency are attacks of myalgia and myoglobinuria, possibly leading to renal failure.
      explanation: Review-level clinical summary links attack-related muscle symptoms to myoglobinuria and renal failure risk.
  - target: Creatine kinase
    description: Serum CK rises as a biochemical marker of attack-related myofiber injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CK levels are high during rhabdomyolysis but may return to normal or be only mildly elevated when affected individuals are well.
      explanation: Review-level CPT2 deficiency summary supports increased CK as a biochemical marker during rhabdomyolysis.
  - target: Acute kidney injury
    description: Massive rhabdomyolysis can cause AKI through myoglobin-mediated renal injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Myoglobin release during rhabdomyolysis injures renal tubules and can require renal replacement therapy.
    evidence:
    - reference: PMID:37933340
      reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy
      explanation: Human clinical summary directly identifies AKI as a complication following massive rhabdomyolysis.
- name: Carnitine shuttle disruption
  description: 'CPT-II is the final enzyme of the three-component carnitine shuttle that transports long-chain fatty acids into the mitochondrial matrix. CPT-I on the outer mitochondrial membrane converts acyl-CoA to acylcarnitine, CACT translocates acylcarnitine across the inner membrane, and CPT-II regenerates acyl-CoA inside the mitochondrion. Loss of CPT-II activity blocks this shuttle at its terminal step.

    '
  biological_processes:
  - preferred_term: carnitine shuttle
    term:
      id: GO:0006853
      label: carnitine shuttle
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The carnitine palmitoyltransferase (CPT) system consists of two enzymes, CPT I and CPT II, and is involved in the transport of long-chain fatty acids into the mitochondrial compartment. The enzymes are located in the outer (CPT I) and inner mitochondrial membrane (CPT II).
    explanation: Describes the carnitine shuttle system and localization of CPT-I and CPT-II.
  downstream:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    description: Loss of the terminal CPT2 step prevents long-chain acylcarnitines from being regenerated as mitochondrial acyl-CoA substrates for beta-oxidation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CPT2 is located on the inner surface of the inner mitochondrial membrane and catalyzes conversion of long-chain acylcarnitines back into long-chain acyl-CoA species with return of carnitine to the cytoplasm.
      explanation: Review-level mechanistic summary directly defines the CPT2 shuttle reaction that supplies long-chain acyl-CoA for beta-oxidation.
phenotypes:
- name: Rhabdomyolysis
  subtype: Myopathic
  frequency: VERY_FREQUENT
  notes: 'The VERY_FREQUENT band is carried by the myoglobinuria figure (86% of a 50-patient muscle CPT II cohort) used as a proxy, since no source reports a rhabdomyolysis percentage directly; myoglobinuria is the clinical marker of a rhabdomyolysis episode, so the proxy is close but not identical. GeneReviews additionally notes a sex bias in symptomatic expression: males are more likely to be symptomatic than females.

    '
  description: 'Recurrent episodes of skeletal muscle breakdown triggered by prolonged exercise, fasting, fever, or cold exposure. This is the hallmark manifestation of the myopathic form. In a cohort of 50 patients, myoglobinuria was observed in 86%.

    '
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Males are more likely to be symptomatic than females.
    explanation: GeneReviews records a sex bias in symptomatic expression of CPT II deficiency, absent from this entry before review.
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure.
    explanation: Directly lists rhabdomyolysis as a clinical feature of muscle CPT II deficiency.
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%)
    explanation: Quantifies myoglobinuria at 86% in a retrospective cohort of 50 patients with MUSCLE (myopathic) CPT II deficiency; the frequency band applies to the myopathic subtype.
- name: Myalgia
  subtype: Myopathic
  frequency: VERY_FREQUENT
  description: 'Recurrent attacks of muscle pain are the most common symptom, reported in 94% of patients with muscle CPT II deficiency. Typically triggered by exercise, infection, or fasting.

    '
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Almost all patients (94%) described attacks of myalgia.
    explanation: Quantifies myalgia at 94% in a retrospective cohort of 50 patients with MUSCLE (myopathic) CPT II deficiency; the frequency band therefore applies to the myopathic subtype, not to CPT II deficiency as a whole.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report an otherwise healthy 38-year-old patient who presented with severe myalgia, cramps, fatigue, low-grade fever, and transient myoglobinuria, after intense physical training.
    explanation: Case report illustrating typical exercise-triggered myalgia presentation.
- name: Muscle weakness
  subtype: Myopathic
  frequency: FREQUENT
  description: 'Episodic muscle weakness during attacks, reported in 76% of patients. Unlike carnitine deficiency, persistent muscle weakness is not characteristic between episodes.

    '
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%)
    explanation: Quantifies muscle weakness at 76% in myopathic CPT II cohort.
- name: Myoglobinuria
  subtype: Myopathic
  frequency: VERY_FREQUENT
  description: 'Dark urine due to myoglobin release from damaged skeletal muscle, occurring with rhabdomyolysis episodes. Reported in 86% of patients with the myopathic form.

    '
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Following the main clinical symptoms were myoglobinuria (86%) and muscle weakness (76%)
    explanation: Quantifies myoglobinuria at 86% in myopathic CPT II deficiency cohort.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report an otherwise healthy 38-year-old patient who presented with severe myalgia, cramps, fatigue, low-grade fever, and transient myoglobinuria, after intense physical training.
    explanation: Case presentation showing transient myoglobinuria as a presenting feature.
- name: Acute kidney injury
  subtype: Myopathic
  description: 'Renal failure secondary to massive rhabdomyolysis and myoglobin nephrotoxicity. Managed with aggressive fluid resuscitation and occasionally hemodialysis; GeneReviews lists intravenous hydration and/or dialysis for rhabdomyolysis and myoglobinuria among acute inpatient measures.

    '
  notes: 'No frequency band is asserted. The previous OCCASIONAL (5-29%) sat against the cited source describing AKI as "one of the most common complications" of massive rhabdomyolysis, which points higher, but neither source quantifies it. Omitted rather than guessed.

    '
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Clinical features are attacks of muscle weakness, myalgia, pain and rhabdomyolysis with or without renal failure.
    explanation: Lists renal failure as a complication of rhabdomyolysis in CPT II deficiency.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy
    explanation: Directly identifies AKI as a common rhabdomyolysis complication in CPT II deficiency.
- name: Hypoketotic hypoglycemia
  subtypes:
  - Severe infantile
  - Lethal neonatal
  description: 'Fasting intolerance with low ketone production and hypoglycemia, characteristic of severe infantile and neonatal forms due to impaired hepatic fatty acid oxidation.

    '
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  evidence:
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction.
    explanation: Confirms hypoketotic hypoglycemia as a hallmark of severe early-onset CPT II forms.
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lethal neonatal and severe infantile hepatocardiomuscular phenotypes are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death.
    explanation: GeneReviews confirms hypoketotic hypoglycemia as a defining feature of both severe early-onset phenotypes.
  notes: 'No frequency band is asserted - the sources establish hypoketotic hypoglycemia as a defining feature of both severe forms without quantifying it, and the previous disease-level FREQUENT band was scoped to the whole disease while the accompanying context string restricted it to the severe forms.

    '
- name: Cardiomyopathy
  subtypes:
  - Severe infantile
  - Lethal neonatal
  - Myopathic
  notes: 'Characteristic of the two severe forms, where GeneReviews lists it among the defining features, and additionally reported as a complication of the myopathic form - hence all three subtypes. No frequency band is asserted: the previous OCCASIONAL rested on a single case report of reduced ejection fraction in a myopathic patient, which cannot support a disease-level band, and cardiomyopathy is characteristic rather than occasional in the severe forms, so a single band would misdescribe both ends. Omitted per docs/frequency-evidence-guidelines.md.

    '
  description: 'Cardiac involvement in severe early-onset forms, also reported as a complication in the adult myopathic form. One case report documented left ventricular ejection fraction of 40% during acute crisis.

    '
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lethal neonatal and severe infantile hepatocardiomuscular phenotypes are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death.
    explanation: GeneReviews lists cardiomyopathy among the defining features of both severe forms, supporting the subtype assignment.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Echocardiogram showed a left ventricle ejection fraction (LVEF) of 40%.
    explanation: Documents cardiomyopathy with reduced ejection fraction in a myopathic CPT II patient.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction.
    explanation: Identifies cardiomyopathy as a feature of severe early-onset CPT II deficiency.
- name: Liver dysfunction
  subtypes:
  - Severe infantile
  - Lethal neonatal
  description: 'Decreased liver function and liver failure occur in severe neonatal and infantile CPT2 deficiency as part of the hepatocardiomuscular presentation, reflecting impaired hepatic long-chain fatty acid oxidation during metabolic stress.

    '
  phenotype_term:
    preferred_term: Liver dysfunction
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lethal neonatal and severe infantile hepatocardiomuscular phenotypes are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death.
    explanation: GeneReviews lists cardiomyopathy among the defining features of both severe forms, supporting the subtype assignment.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first two are early-onset severe disorders presenting with marked hypoketotic hypoglycemia, cardiomyopathy, and liver dysfunction.
    explanation: Human clinical summary identifies liver dysfunction in severe early-onset CPT II deficiency.
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Later-onset, infantile disease is characterized by liver failure, cardiomyopathy, myopathy, and ketotic hypoglycemia in the first year of life.
    explanation: Review-level CPT2 deficiency summary supports liver failure in infantile disease.
- name: Myopathy
  subtype: Severe infantile
  category: Musculoskeletal
  description: 'Myopathy is a severe infantile CPT2 deficiency manifestation reflecting skeletal-muscle involvement from impaired long-chain fatty acid oxidation.

    '
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Later-onset, infantile disease is characterized by liver failure, cardiomyopathy, myopathy, and ketotic hypoglycemia in the first year of life.
    explanation: Review-level CPT2 deficiency summary identifies myopathy as a severe infantile phenotype.
- name: Abnormality of neuronal migration
  subtype: Lethal neonatal
  category: Neurologic
  description: 'Neuronal migration defects are reported in the severe neonatal CPT2 deficiency presentation.

    '
  phenotype_term:
    preferred_term: Abnormality of neuronal migration
    term:
      id: HP:0002269
      label: Abnormality of neuronal migration
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
    explanation: Review-level CPT2 deficiency summary lists neuronal migration defects in severe neonatal disease.
- name: Renal cyst
  subtype: Lethal neonatal
  category: Renal
  description: 'Cystic kidneys are reported in the severe neonatal CPT2 deficiency presentation.

    '
  phenotype_term:
    preferred_term: Cystic kidneys
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A severe neonatal form presents in the first few days after birth with cardiomyopathy, hypoketotic hypoglycemia, multiorgan dysfunction and failure (including liver and heart), neuronal migration defects, and cystic kidneys.
    explanation: Review-level CPT2 deficiency summary lists cystic kidneys in severe neonatal disease.
- name: Elevated creatine kinase
  subtype: Myopathic
  description: 'Markedly elevated serum creatine kinase during rhabdomyolysis episodes, reflecting skeletal muscle damage. CK levels normalize between episodes, and CK is a GeneReviews-recommended surveillance measurement.

    '
  notes: 'No frequency band is asserted. The available quantitative evidence (3 of 6 children with raised muscle enzymes, PMID:38650450) would indicate roughly 50%, i.e. FREQUENT rather than the VERY_FREQUENT previously recorded, but a denominator of six is too small to band reliably and the figure is not specific to CK. Per docs/frequency-evidence-guidelines.md, omitted rather than guessed.

    '
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 3 cases presented with clinical manifestations of fever, muscle weakness, and increased muscle enzymes.
    explanation: Documents increased muscle enzymes (including CK) as a clinical manifestation in CPT2-deficient children.
  reports_on:
  - target: Metabolic myofiber injury and rhabdomyolysis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Damaged skeletal muscle releases creatine kinase into serum during rhabdomyolysis.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CK levels are high during rhabdomyolysis but may return to normal or be only mildly elevated when affected individuals are well.
      explanation: Review-level CPT2 deficiency summary directly links rhabdomyolysis episodes to high CK.
- name: Episodic muscle stiffness
  subtype: Myopathic
  description: 'Muscle stiffness and cramps occurring during or after exercise or illness episodes, often preceding frank rhabdomyolysis.

    '
  notes: 'No frequency band is asserted. The previous FREQUENT rested on a single case report; no source quantifies stiffness separately from the myalgia band.

    '
  phenotype_term:
    preferred_term: Exercise-induced muscle stiffness
    term:
      id: HP:0008967
      label: Exercise-induced muscle stiffness
  evidence:
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The latter is characterized by muscle pain and weakness and stiffness, typically triggered by exercise or febrile illnesses
    explanation: Directly describes muscle stiffness as a characteristic feature of myopathic CPT II deficiency.
- name: Exercise intolerance
  subtype: Myopathic
  description: 'Exercise intolerance in the myopathic form reflects failure to meet skeletal-muscle energy demand during sustained exertion and often accompanies recurrent rhabdomyolysis attacks.

    '
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected individuals present with exercise intolerance and recurrent attacks of rhabdomyolysis triggered by fasting, rigorous exercise, cold, and acute illness.
    explanation: Review-level CPT2 deficiency summary directly documents exercise intolerance in affected individuals.
biochemical:
- name: Long-chain acylcarnitines (C16, C18:1)
  presence: INCREASED
  context: 'Elevation of long-chain acylcarnitines, particularly palmitoylcarnitine (C16:0) and oleoylcarnitine (C18:1), is the hallmark biochemical signature detectable by tandem mass spectrometry. However, profiles may be normal between crises, and sampling during metabolic stress is critical.

    '
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated long-chain acylcarnitine species are the diagnostic plasma readout of the CPT2 carnitine-shuttle block.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The plasma acylcarnitine profile shows elevated C16, C18:1, and C18:2 carnitine species.
      explanation: Review-level CPT2 deficiency summary identifies elevated long-chain acylcarnitines as the diagnostic biochemical signature.
  evidence:
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines.
    explanation: Documents elevated C16 and C18:1 acylcarnitines in CPT2-deficient children.
- name: Free carnitine (C0)
  presence: DECREASED
  context: 'Free carnitine levels may be decreased or low-normal, reflecting sequestration as long-chain acylcarnitines that cannot be metabolized due to CPT-II dysfunction.

    '
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Decreased free carnitine can accompany the CPT2 block when long-chain acyl groups are trapped as acylcarnitine esters.
    evidence:
    - reference: PMID:38650450
      reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines.
      explanation: Human pediatric CPT2 cases show decreased free carnitine with elevated long-chain acylcarnitines.
  evidence:
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines.
    explanation: Documents decreased free carnitine in CPT2-deficient children alongside elevated acylcarnitines.
- name: Creatine kinase
  presence: INCREASED
  context: 'Markedly elevated during rhabdomyolysis episodes, reflecting skeletal muscle damage. Returns to normal between episodes. Serves as an acute marker of metabolic crisis severity.

    '
  readouts:
  - target: Metabolic myofiber injury and rhabdomyolysis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: CK elevation tracks acute metabolic myofiber injury during rhabdomyolysis episodes.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: CK levels are high during rhabdomyolysis but may return to normal or be only mildly elevated when affected individuals are well.
      explanation: Review-level CPT2 deficiency summary supports CK as an episodic monitoring readout of rhabdomyolysis.
  evidence:
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 3 cases presented with clinical manifestations of fever, muscle weakness, and increased muscle enzymes.
    explanation: Increased muscle enzymes (CK) documented during symptomatic episodes in CPT2 deficiency.
- name: Palmitoyl-carnitine in muscle
  presence: INCREASED
  context: 'Palmitoyl-carnitine (C16:0) accumulates preferentially in oxidative muscle fibers in CPT2 deficiency and directly inhibits sarcoplasmic reticulum calcium uptake, linking it to the pathogenesis of muscle contractile dysfunction.

    '
  evidence:
  - reference: PMID:39182841
    reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle.
    explanation: Cpt2-deficient mouse soleus directly supports palmitoyl-carnitine accumulation in skeletal muscle.
  - reference: PMID:39182841
    reference_title: "Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake.
    explanation: Directly supports palmitoyl-carnitine-mediated inhibition of calcium handling in muscle.
genetic:
- name: CPT2 gene variants
  gene_term:
    preferred_term: CPT2
    term:
      id: hgnc:2330
      label: CPT2
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The disease follows an autosomal recessive mode of inheritance.
      explanation: Directly states autosomal recessive inheritance for CPT II deficiency.
  variants:
  - name: CPT2 - p.Ser113Leu (S113L)
    description: 'The most common pathogenic variant, found in approximately 90% of myopathic CPT II patients with an allele frequency of 60-70%. Produces a thermolabile enzyme with abnormal sensitivity to malonyl-CoA inhibition.

      '
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In approximately 90% the molecular basis is a p. S113L mutation in homozygous or heterozygous state with an allele frequency of 60%–70%
      explanation: Quantifies S113L prevalence and allele frequency in myopathic CPT II cohort.
  - name: CPT2 - c.338C>T and c.482G>A compound heterozygote
    description: 'Compound heterozygous CPT2 variants identified by whole-genome sequencing in a patient with recurrent rhabdomyolysis and normal inter-episode acylcarnitine profiles.

      '
  - name: CPT2 - Various private mutations
    description: 'More than 60 mostly private mutations have been described in CPT2 beyond the common S113L variant. Novel variants include p.F352L, p.R498L, p.F434S, p.A515P, and c.153-2A>G reported in a Chinese pediatric cohort.

      '
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In addition there are more than 60 mostly private mutations
      explanation: Documents the breadth of private CPT2 mutations beyond S113L.
    - reference: PMID:38650450
      reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: including 3 known variants (p.R631C, p.T589M, and p.D255G) and 5 newly reported variants (p.F352L, p.R498L, p.F434S, p.A515P, and c.153-2A>G).
      explanation: Reports novel CPT2 variants identified in a Chinese pediatric cohort.
  features: 'CPT II deficiency results from biallelic pathogenic variants in CPT2 encoding the inner mitochondrial membrane enzyme CPT-II. Unlike CPT-I, there are no tissue-specific isoforms of CPT-II, so clinical heterogeneity reflects different mutations and their impact on enzyme stability and activity. The S113L variant is by far the most common, particularly in the myopathic form.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Three phenotypes of CPT II deficiency are known: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a mild myopathic form'
    explanation: Describes the three clinical phenotypes of CPT II deficiency.
  - reference: PMID:39429887
    reference_title: "Recurrent rhabdomyolysis caused by palmitoyltransferase II (CPT-2) deficiency but complete normal acylcarnitine profile: A patient presentation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms.
    explanation: Quantifies case distribution across the three clinical subtypes.
- name: CPT2
  gene_term:
    preferred_term: CPT2
    term:
      id: hgnc:2330
      label: CPT2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1a57ea10-6ca0-4311-94f1-0ad036a38ca6-2018-03-27T160000.000Z
    reference_title: "CPT2 / carnitine palmitoyltransferase II deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CPT2 | HGNC:2330 | carnitine palmitoyltransferase II deficiency | MONDO:0015515 | AR | Definitive"
    explanation: ClinGen classifies the CPT2-carnitine palmitoyltransferase II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
environmental:
- name: Prolonged exercise
  exposure_term:
    preferred_term: prolonged physical activity
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  influences_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Sustained exercise shifts muscle onto fatty acid oxidation for fuel, so
      it loads the exact pathway this enzyme cannot service. The deficiency is
      silent until demand exceeds residual capacity, which is why attacks are
      exertional rather than constant.
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The most common trigger factors were exercise (87%) and infection (62%)."
      explanation: >-
        Identifies exercise as the most common trigger factor, present in 87%
        of episodes, the demand state that unmasks the enzymatic block.
  description: 'Exercise is the most common trigger for rhabdomyolysis episodes, reported in 87% of patients. Sustained muscle activity increases reliance on fatty acid oxidation, unmasking the enzymatic defect.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The most common trigger factors were exercise (87%) and infection (62%).
    explanation: Quantifies exercise as the most common trigger at 87%.
- name: Fasting
  exposure_term:
    preferred_term: fasting
    term:
      id: XCO:0000102
      label: fasting
  influences_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Fasting withdraws glucose and forces reliance on fatty acid oxidation,
      imposing the same demand on the blocked pathway that exercise does by a
      different route.
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Trigger factors are prolonged exercise, fasting, fever and exposure to cold"
      explanation: >-
        Lists fasting among the trigger factors, alongside prolonged exercise,
        fever and cold, all states that force reliance on fatty acid
        oxidation.
  description: 'Fasting increases dependency on fatty acid oxidation for energy, precipitating metabolic crises.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Trigger factors are prolonged exercise, fasting, fever and exposure to cold
    explanation: Lists fasting as a recognized trigger factor.
- name: Fever and infection
  influences_mechanisms:
  - target: Thermolability of mutant CPT-II enzyme
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Fever is mechanistically distinct from the other triggers in this entry.
      Rather than merely raising fatty acid oxidation demand, a febrile core
      temperature directly destabilises the mutant enzyme, so it targets the
      thermolability node rather than the shared demand node.
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C"
      explanation: >-
        The mutant enzyme showed abnormal thermal destabilization at 40 and 45
        degrees Celsius, the temperature range reached in fever. Support is
        PARTIAL because the demonstration is an in vitro enzyme assay rather
        than a clinical measurement.
  description: 'Fever both increases energy demand and, in thermolabile variants, directly destabilizes the mutant CPT-II enzyme. Infections triggered episodes in 62% of patients.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The most common trigger factors were exercise (87%) and infection (62%).
    explanation: Infection is the second most common trigger at 62%.
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C
    explanation: Thermolability of S113L variant at fever-range temperatures explains fever as a trigger.
- name: Cold exposure
  exposure_term:
    preferred_term: exposure to decreased temperature
    term:
      id: ECTO:0001057
      label: exposure to decreased temperature
  influences_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Cold raises thermogenic demand, which is met by fatty acid oxidation, so
      it loads the blocked pathway through the known intermediate of shivering
      and non-shivering thermogenesis.
    evidence:
    - reference: PMID:28054946
      reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Trigger factors are prolonged exercise, fasting, fever and exposure to cold"
      explanation: >-
        Lists exposure to cold among the trigger factors for metabolic
        decompensation in this disorder.
  description: 'Exposure to cold is a recognized trigger for metabolic crises in CPT II deficiency.

    '
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Trigger factors are prolonged exercise, fasting, fever and exposure to cold
    explanation: Lists cold exposure among recognized trigger factors.
treatments:
- name: Avoidance of metabolic triggers
  description: 'Lifestyle modification to avoid prolonged exercise, fasting, cold exposure, and other metabolic stressors is the primary preventive strategy. Patients should modify daily activities to prevent recurrent rhabdomyolysis episodes. A distinct and easily overlooked hazard is general anaesthesia, which GeneReviews says should proceed with caution because of possible risk of malignant hyperthermia or rhabdomyolysis - to the point that genetic testing of at-risk asymptomatic siblings is advised BEFORE they undergo anaesthesia.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: MODULATES
    description: Avoiding fasting, sustained exercise, fever/illness, and cold exposure reduces stress-induced reliance on the impaired long-chain fatty acid oxidation pathway.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Individuals with CPT2 deficiency should be instructed to avoid prolonged fasting (>10 hours) and sustained, intensive exercise.
      explanation: Review-level management guidance supports trigger avoidance to reduce metabolic stress on the CPT2-deficient pathway.
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  - preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  - preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient was discharged upon the improvement of renal function with lifestyle modification recommendations.
    explanation: Supports lifestyle modification as a key management strategy.
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Trigger factors are prolonged exercise, fasting, fever and exposure to cold
    explanation: Identification of trigger factors directly supports avoidance strategy.
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Agents/circumstances to avoid: Avoid extended fasting and prolonged exercise.'
    explanation: GeneReviews states the core avoidance set for CPT II deficiency.
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: General anesthesia should proceed with caution due to possible risk of malignant hyperthermia or rhabdomyolysis.
    explanation: GeneReviews documents the anaesthesia hazard, a safety point absent from the entry before this review.
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic testing of at-risk asymptomatic sibs is advisable before general anesthesia, as complications of general anesthesia have been observed.
    explanation: GeneReviews extends the anaesthesia caution to presymptomatic at-risk relatives.
- name: High-carbohydrate, low-fat diet
  description: 'Dietary modification emphasizing high carbohydrate and low long-chain fat intake to reduce reliance on fatty acid oxidation. Medium-chain triglyceride (MCT) supplementation may be used as an alternative energy source since MCT can bypass the carnitine shuttle.

    '
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: BYPASSES
    description: Carbohydrate before and during exercise and MCT supplementation provide alternative energy substrate so muscle is less dependent on long-chain fatty acid oxidation.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Carbohydrate intake before and during exercise may prevent attacks.
      explanation: Review-level management guidance supports carbohydrate intake to prevent exertional attacks.
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Dietary supplementation with MCT provides an alternative substrate for FAO.
      explanation: Review-level management guidance supports MCT as an alternative substrate that can bypass the carnitine shuttle.
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MCT oil (0.5 g/kg lean body weight) has been demonstrated to improve exercise tolerance in individuals with long-chain FAODs if administered 20 minutes before exercise
    explanation: Provides the dosing and demonstrated exercise-tolerance benefit of MCT supplementation in long-chain fatty-acid oxidation disorders.
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  notes: Dietary fat restriction and MCT supplementation are standard of care for CPT II deficiency but specific clinical trial evidence from the available abstracts is limited.
- name: Aggressive fluid resuscitation for rhabdomyolysis
  description: 'Emergency management of acute rhabdomyolysis episodes with aggressive intravenous fluid therapy using crystalloid solutions to prevent or treat myoglobin-induced acute kidney injury.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  - preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One of the most common complications is acute kidney injury (AKI) following massive rhabdomyolysis, which is managed with aggressive fluid therapy; crystalloid solutions are preferred.
    explanation: Directly recommends aggressive fluid resuscitation with crystalloids for rhabdomyolysis-associated AKI.
  - reference: PMID:37933340
    reference_title: "Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Rare Cause of Acute Kidney Injury and Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fluid resuscitation was started. Acute kidney injury was diagnosed and managed with plasmapheresis and five sessions of hemodialysis.
    explanation: Documents clinical management of AKI with fluid resuscitation and renal replacement therapy.
- name: Carnitine supplementation
  description: 'L-carnitine supplementation may be used to support conjugation and excretion of accumulated long-chain acyl groups, though its use remains debated in fatty acid oxidation disorders. Free carnitine is often decreased in CPT2 deficiency.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: MODULATES
    description: Carnitine supplementation is a conditional supportive strategy for persistently low free carnitine, but its clinical utility in CPT2 deficiency remains uncertain.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Carnitine supplementation is probably not useful but may be given if levels are persistently low.
      explanation: Review-level guidance partially supports carnitine supplementation only when free carnitine is persistently low.
  evidence:
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines.
    explanation: Decreased free carnitine provides rationale for supplementation.
- name: Bezafibrate
  description: 'A fibrate investigated as pharmacotherapy for CPT II deficiency on the basis of in vitro evidence that fibrates upregulate CPT2 expression. A randomized, double-blind, crossover trial in patients with CPT II (n=5) and VLCAD (n=5) deficiency found NO effect: despite the expected lipid-lowering, there were no changes in palmitate oxidation, total fatty acid oxidation, or heart rate during exercise. The authors graded this Class I evidence that bezafibrate is ineffective, and concluded that the in vitro therapeutic promise does not translate in vivo. Bezafibrate is recorded here as a refuted therapeutic hypothesis, not a candidate treatment.

    '
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bezafibrate
      term:
        id: NCIT:C87449
        label: Bezafibrate
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: MODULATES
    description: >-
      REFUTED MECHANISM, retained as a negative result. Bezafibrate was
      hypothesised to improve fat oxidation during exercise in CPT2 and VLCAD
      deficiency by upregulating CPT2 expression; randomized double-blind testing
      found no change in palmitate oxidation, total fatty acid oxidation, or
      heart rate. treatment_effect is MODULATES only because the enum offers no
      null value - the REFUTE evidence items are what carry the finding.
    evidence:
    - reference: clinicaltrials:NCT00983788
      reference_title: "Evaluation of the Effect of Bezafibrate on Muscle Metabolism During Exercise in Patients With CPTII and VLCAD Deficiency"
      supports: SUPPORT
      snippet: The main criteria for assessing the potential effect of this drug will be the fat oxidation rate studied during a moderate workload on cycle ergometer
      explanation: Trial record supports fat oxidation during exercise as the mechanistic endpoint for bezafibrate in CPT2/VLCAD deficiency.
    - reference: PMID:24453079
      reference_title: "Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise.
      explanation: Randomized crossover trial refutes the proposed mechanism - lipid-lowering occurred but fatty acid oxidation was unchanged.
  target_phenotypes:
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  - preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  notes: 'Bezafibrate is not approved for CPT II deficiency and the controlled evidence is negative, not merely inconclusive. Earlier open-label reports of benefit were not confirmed when the question was tested under randomization and blinding; the trial authors attribute the discrepancy to in vitro findings failing to translate in vivo. Retained in the entry as a documented negative result rather than removed, so that the refuted hypothesis is not silently re-proposed.

    '
  evidence:
  - reference: clinicaltrials:NCT00983788
    reference_title: "Evaluation of the Effect of Bezafibrate on Muscle Metabolism During Exercise in Patients With CPTII and VLCAD Deficiency"
    supports: SUPPORT
    snippet: The investigators propose to evaluate the effect of bezafibrate on metabolism during exercise in 22 adult patients affected with carnitine palmitoyltransferase II (CPTII) or very-long chain acyl-CoA-dehydrogenase (VLCAD) deficiencies.
    explanation: Directly supports bezafibrate as a studied intervention in adults with CPT II deficiency.
  - reference: PMID:24453079
    reference_title: "Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies.
    explanation: The trial's stated conclusion directly refutes clinical benefit of bezafibrate in CPT II deficiency.
  - reference: PMID:24453079
    reference_title: "Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.
    explanation: Class I evidence grading establishes the strength of the negative result.
- name: Triheptanoin (Dojolvi)
  description: 'An odd-chain (C7) triglyceride providing anaplerotic substrate to sustain the TCA cycle, gluconeogenesis and energy production - the rationale being that conventional even-chain MCT supplies acetyl-CoA but does not replenish depleted TCA-cycle intermediates. Unlike bezafibrate, triheptanoin is an approved therapy: it is licensed as a source of calories and fatty acids for long-chain fatty acid oxidation disorders, the class that includes CPT II deficiency. A double-blind randomized comparison against MCT showed a positive cardiac effect, with improvement in major clinical events in open-label extension studies.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: triheptanoin
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: BYPASSES
    description: Triheptanoin is intended to provide alternative odd-chain substrate and anaplerotic support in long-chain fatty acid oxidation disorders.
    evidence:
    - reference: clinicaltrials:NCT01379625
      reference_title: "Phase 2 Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorders"
      supports: SUPPORT
      snippet: This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders.
      explanation: Trial record supports triheptanoin as an intervention aimed at muscle pain, cardiac function, and energy in LC-FAOD.
    - reference: PMID:40633017
      reference_title: "A pharmacological profile of triheptanoin for the treatment of long-chain fatty acid oxidation disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Triheptanoin is an anaplerotic source of calories for treatment of LC-FAODs, providing a source of substrates to sustain the TCA cycle, gluconeogenesis, and energy production.
      explanation: States the anaplerotic mechanism that distinguishes triheptanoin from conventional even-chain MCT.
  target_phenotypes:
  - preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  notes: 'Triheptanoin is approved for long-chain fatty acid oxidation disorders as a class rather than for CPT II deficiency by name, so trial and licensing evidence is drawn from mixed LC-FAOD cohorts that include CPT II patients. Early use should be considered before symptom onset in severe disease. GeneReviews gives the dosing target as triheptanoin for one third of daily calories, with MCT oil substituted where triheptanoin is unavailable. Principal adverse effect is gastrointestinal intolerance, comparable to conventional MCT oil. Ontology note: therapeutic_agent deliberately carries NO term binding. CHEBI has no triheptanoin class, and the only available parent, CHEBI:17855 triglyceride, would be actively misleading here - long-chain triglyceride is precisely the substrate class that CPT II deficiency management restricts, so binding the therapy to it inverts the clinical point. NCIT:C166587 Triheptanoin exists but was rejected by the term validator as not reachable from the ChemicalEntityTerm enum roots. preferred_term carries the agent identity until a usable term is available; an NTR to CHEBI would resolve this.

    '
  evidence:
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Targeted therapies: Low-fat/high-carbohydrate diet as prescribed by metabolic dietician; triheptanoin for one third of daily calories.'
    explanation: GeneReviews gives the triheptanoin dosing target, previously absent from the entry.
  - reference: PMID:20301431
    reference_title: "Carnitine Palmitoyltransferase II Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Medium-chain triglyceride (MCT) oil can be substituted in areas where triheptanoin is not available.
    explanation: Records the substitution guidance where the approved agent is unavailable.
  - reference: clinicaltrials:NCT01379625
    reference_title: "Phase 2 Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorders"
    supports: SUPPORT
    snippet: This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders.
    explanation: Supports triheptanoin as a clinical trial intervention for LC-FAOD populations that include CPT II deficiency.
  - reference: PMID:40633017
    reference_title: "A pharmacological profile of triheptanoin for the treatment of long-chain fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Clinical benefit was thereafter demonstrated in clinical trials, with a positive cardiac effect in a double-blinded, randomized controlled comparison to MCT, and improvement in major clinical events in open-label extension studies.
    explanation: Summarises the controlled and open-label efficacy evidence supporting triheptanoin, in contrast to the negative bezafibrate result.
  - reference: PMID:40633017
    reference_title: "A pharmacological profile of triheptanoin for the treatment of long-chain fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Side effects of triheptanoin are primarily GI intolerance similar to conventional MCT oil.
    explanation: Documents the tolerability profile.
- name: Newborn screening
  description: 'CPT II deficiency is detectable by newborn screening via tandem mass spectrometry using elevated long-chain acylcarnitines (C16, C18:1) as primary markers. Three of six children in one cohort were diagnosed through neonatal screening. However, biochemical abnormalities may only be detectable during metabolic stress.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  - preferred_term: Liver dysfunction
    term:
      id: HP:0001410
      label: Decreased liver function
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three cases were diagnosed at neonatal screening
    explanation: Documents successful neonatal screening diagnosis in CPT2 deficiency.
  - reference: PMID:38650450
    reference_title: "Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An early diagnosis can be facilitated by neonatal blood tandem mass spectrometry screening and genetic testing, and most patients have good prognosis after a timely diagnosis and treatment.
    explanation: Supports the value of newborn screening for early diagnosis and improved outcomes.
- name: Genetic counseling
  description: 'Counseling for affected families regarding autosomal recessive inheritance, carrier testing, recurrence risk, and reproductive options including prenatal genetic testing.

    '
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28054946
    reference_title: "Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The disease follows an autosomal recessive mode of inheritance.
    explanation: Autosomal recessive inheritance directly supports the role of genetic counseling for carrier and recurrence risk assessment.
clinical_trials:
- name: NCT00983788
  phase: PHASE_II
  status: COMPLETED
  description: Randomized, double-blind, placebo-controlled crossover trial evaluating bezafibrate effects on exercise metabolism in adults with CPT II or VLCAD deficiency.
  target_phenotypes:
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  - preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: clinicaltrials:NCT00983788
    reference_title: "Evaluation of the Effect of Bezafibrate on Muscle Metabolism During Exercise in Patients With CPTII and VLCAD Deficiency"
    supports: SUPPORT
    snippet: This study will be an 9-month, randomized, double-blind, placebo-controlled crossover trial.
    explanation: Supports trial design and intervention context for bezafibrate in CPT II/LC-FAOD disease.
- name: NCT01886378
  phase: PHASE_II
  status: COMPLETED
  description: Open-label Phase 2 trial evaluating UX007 (triheptanoin) clinical effects and safety in LC-FAOD.
  target_phenotypes:
  - preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT01886378
    reference_title: "An Open-label Phase 2 Study to Assess Safety and Clinical Effects of UX007 in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)"
    supports: SUPPORT
    snippet: The primary objective of the study was to evaluate the impact of UX007 on acute clinical pathophysiology associated with LC-FAOD following 24 weeks of treatment.
    explanation: Supports UX007/triheptanoin as an evaluated trial intervention in LC-FAOD.
- name: NCT01379625
  phase: PHASE_II
  status: COMPLETED
  description: Phase 2 trial of triheptanoin for long-chain fatty acid oxidation disorders, including outcomes relevant to muscle and cardiac function.
  target_phenotypes:
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT01379625
    reference_title: "Phase 2 Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorders"
    supports: SUPPORT
    snippet: This study will determine if a new experimental oil called Triheptanoin can decrease the muscle pain and increase the heart function and the amount of energy in patients with long-chain fatty acid oxidation disorders.
    explanation: Supports triheptanoin trial targeting clinically relevant muscle and cardiac outcomes in LC-FAOD.
references:
- reference: PMID:20301431
  title: "Carnitine Palmitoyltransferase II Deficiency."
  tags:
  - GeneReviews
notes: 'CPT II deficiency is notable for its clinical heterogeneity arising from a single gene (CPT2) without tissue-specific isoforms. The most common S113L variant is thermolabile, explaining why the myopathic form presents with crisis-driven symptoms during fever or exercise. A key diagnostic pitfall is that acylcarnitine profiles may be completely normal between episodes, necessitating sampling during metabolic stress or definitive genetic testing. Recent mechanistic advances (2024) demonstrate that muscle damage involves LCAC-mediated sarcoplasmic reticulum calcium uptake inhibition beyond simple energy failure, suggesting potential future therapeutic targets.

  Therapeutic status, stated plainly: triheptanoin is an approved anaplerotic therapy for long-chain fatty acid oxidation disorders as a class, with randomized cardiac benefit against MCT. Bezafibrate is NOT a candidate therapy - a randomized double-blind crossover trial produced Class I evidence of no effect on fatty acid oxidation or heart rate during exercise, and the authors concluded that the in vitro promise of fibrates does not translate in vivo. It is retained in this entry as a documented negative result so that the refuted hypothesis is not silently re-proposed.

  '

📚

References & Deep Research

References

1

PMID:20301431

Carnitine Palmitoyltransferase II Deficiency.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 26 citations 2026-02-23T23:42:13.931512

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

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

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

Disease Pathophysiology Research Template

Target Disease

Disease Name: Carnitine Palmitoyltransferase II Deficiency
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Carnitine Palmitoyltransferase II Deficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Carnitine Palmitoyltransferase II (CPT2) Deficiency (Genetic long-chain fatty-acid oxidation disorder)

Publication window emphasized: 2023–2024 (with selected foundational/clinical-trial registry evidence).

Disease definition and key concepts (current understanding)

Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessive inborn error of mitochondrial long-chain fatty-acid oxidation (LC-FAO). It is caused by biallelic pathogenic variants in CPT2, which encodes CPT-II, an inner mitochondrial membrane (IMM) enzyme that reconverts long-chain acylcarnitines back to long-chain acyl-CoA for entry into β-oxidation. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, croce2024cptiideficiencya pages 1-9)

Core concept: the “carnitine shuttle.” Long-chain fatty acids cannot directly enter the mitochondrial matrix; they are transported via a three-component system: (i) CPT-I on the outer mitochondrial membrane (OMM) converts long-chain acyl-CoA to long-chain acylcarnitine; (ii) CACT (carnitine-acylcarnitine translocase) exchanges acylcarnitine across the IMM; (iii) CPT-II on the IMM regenerates acyl-CoA inside the mitochondrion to feed β-oxidation. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, croce2024cptiideficiencya pages 1-9)

Clinical phenotypes are typically classified into three forms: lethal neonatal, severe infantile hepatocardiomuscular, and adult/myopathic (exercise- or illness-triggered myalgia/rhabdomyolysis). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5, croce2024cptiideficiencya pages 1-9)

Core pathophysiology (molecular and cellular mechanisms)

2.1 Primary biochemical lesion: impaired mitochondrial LC-FAO

Loss of CPT-II function impairs mitochondrial β-oxidation of long-chain fatty acids, resulting in accumulation of long-chain acylcarnitines (LCACs) and disruption of energy homeostasis, especially during fasting, illness, fever, or prolonged exercise—states when reliance on fatty-acid oxidation increases. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, croce2024cptiideficiencya pages 1-9)

2.2 Temperature sensitivity (thermolability) and crisis triggering

A major genotype-linked mechanism in the common myopathic form is thermolability of certain missense variants. The p.Ser113Leu (S113L) variant can show near-normal baseline activity in recombinant protein but becomes unstable at higher temperatures (40–45 °C) and exhibits greater sensitivity to inhibitory metabolites (including malonyl-CoA), providing a mechanistic rationale for fever/exertion-triggered decompensation. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

2.3 Skeletal muscle cell injury mechanisms: LCAC-mediated calcium dyshomeostasis and structural instability (2024 mechanistic advance)

A 2024 mechanistic study using muscle-specific Cpt2 knockout (loss of mitochondrial long-chain fatty-acid oxidation in muscle) provides a cellular mechanism for muscle weakness and susceptibility to rhabdomyolysis beyond simple ATP deficiency: LCAC accumulation (particularly palmitoyl-carnitine, C16:0) in oxidative muscle fibers directly inhibits sarcoplasmic reticulum (SR) calcium uptake, slowing cytosolic Ca2+ clearance and impairing contractile function. (pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria pages 6-8)

Key mechanistic findings include:

• Preferential vulnerability of oxidative fibers: oxidative soleus muscle accumulates LCACs far more than glycolytic muscle; palmitoyl-carnitine (C16:0) was reported ~23-fold higher in oxidative muscle versus glycolytic muscle in this model. (pereyra2024lossofmitochondria pages 8-10)

• Direct inhibition of SR Ca2+ uptake by LCACs: excess palmitoyl-carnitine (and palmitoyl-CoA) inhibited SR Ca2+ uptake (~70% reduction) without impairing Ca2+ release, supporting SERCA functional inhibition by LCACs. (pereyra2024lossofmitochondria pages 8-10)

• Disruption of excitation–contraction coupling structures: proteomics and ultrastructure showed reductions in SR–T-tubule tethering proteins and disturbance of myofibril organization, consistent with impaired calcium handling and lateral force transmission. (pereyra2024lossofmitochondria pages 6-8, pereyra2024lossofmitochondria pages 2-4)

• Mitochondrial calcium stress and susceptibility to mPTP: CPT2-deficient muscle mitochondria exhibited altered calcium influx/transporter expression, reduced calcium retention capacity, and susceptibility to permeability transition (reversible with cyclosporin A), linking lipid-driven calcium stress to mitochondrial injury pathways. (pereyra2024lossofmitochondria pages 6-8)

Visual evidence: Figures extracted from Pereyra et al. (2024) show LCAC accumulation and impaired SR Ca2+ uptake/handling in CPT2-deficient muscle, and downregulation of SR tethering and calcium-regulating proteins. (pereyra2024lossofmitochondria media 916e81c8, pereyra2024lossofmitochondria media 75a3793d)

2.4 Energy failure and Ca2+ overload as a general rhabdomyolysis mechanism

Clinical and review literature describe ATP depletion during metabolic stress as a driver of calcium dysregulation and myofiber injury. For example, one clinical discussion states cytotoxicity may arise from “an increase in cytoplasmic and mitochondrial ionized calcium as a result of ATP depletion and/or direct damage to the plasma membrane.” (castillo2023myopathiccarnitinepalmitoyltransferase pages 5-7)

Key molecular players (knowledge-base oriented)

3.1 Genes/proteins (HGNC symbols)

• CPT2 (HGNC:2329): encodes CPT-II; localized to IMM; catalyzes acylcarnitine → acyl-CoA regeneration for β-oxidation. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• CPT1 (family; e.g., CPT1A, CPT1B): OMM enzyme performing acyl-CoA → acylcarnitine conversion. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• SLC25A20 (CACT): IMM transporter exchanging acylcarnitines and carnitine. (risi2025primarylipidmyopathies pages 12-14)

3.2 Chemical entities / metabolites (ChEBI names; representative)

• L-carnitine (free carnitine; C0): substrate/antiporter component of the carnitine shuttle; may be low/variable. (zhang2024clinicalcharacteristicsand pages 1-4)

• Long-chain acylcarnitines used as biomarkers and mechanistic mediators: palmitoylcarnitine (C16:0), oleoylcarnitine (C18:1), and related C12–C18 species. (zhang2024clinicalcharacteristicsand pages 1-4, pereyra2024lossofmitochondria pages 8-10)

• Malonyl-CoA: metabolic regulator that can more strongly inhibit thermolabile variants (mechanistic trigger susceptibility). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

3.3 Cell types (Cell Ontology suggestions; affected cell types)

• Skeletal muscle cells / myofibers (particularly oxidative/type I–enriched): site of exercise-triggered myopathy and rhabdomyolysis; mechanistically linked to LCAC accumulation and SR Ca2+ uptake impairment. (pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria pages 1-2)

• Hepatocytes and cardiomyocytes: prominent in infantile hepatocardiomuscular and neonatal forms, consistent with high FAO dependence in liver/heart. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5, croce2024cptiideficiencya pages 1-9)

3.4 Anatomical locations (UBERON suggestions)

• Skeletal muscle (e.g., soleus in mechanistic models): predominant site of myopathic form manifestations. (pereyra2024lossofmitochondria pages 8-10)

• Liver and heart: major organs involved in severe early-onset phenotypes (hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5, croce2024cptiideficiencya pages 1-9)

• Kidney/brain involvement can occur in neonatal lethal presentations. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5)

Dysregulated pathways and cellular processes (GO-oriented)

The evidence supports disruption of:

• Mitochondrial long-chain fatty-acid β-oxidation / lipid catabolic process (impaired substrate entry and oxidation due to CPT-II dysfunction). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• Acylcarnitine metabolic process and transport across mitochondrial membranes (carnitine shuttle failure). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, croce2024cptiideficiencya pages 1-9)

• Calcium ion homeostasis and sarcoplasmic reticulum calcium ion transport (SR Ca2+ uptake is inhibited by LCACs in muscle-specific Cpt2 deficiency). (pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria pages 6-8)

• Mitochondrial permeability transition / mitochondrial stress susceptibility (reduced calcium retention capacity, mPTP activation sensitivity). (pereyra2024lossofmitochondria pages 6-8)

Cellular components (where key processes occur)

• Outer mitochondrial membrane: CPT-I activity (acyl-CoA → acylcarnitine). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• Inner mitochondrial membrane: CACT transport and CPT-II activity (acylcarnitine → acyl-CoA regeneration). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, croce2024cptiideficiencya pages 1-9)

• Mitochondrial matrix: β-oxidation downstream of CPT-II function (implied by shuttle function and FAO coupling). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• Sarcoplasmic reticulum: impaired Ca2+ uptake linked to LCAC accumulation in muscle. (pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria media 916e81c8)

Disease progression model (sequence of events)

6.1 Trigger phase

Common triggers include fever/infection, fasting, prolonged/intense exercise, and other metabolic stressors. (lu2024recurrentrhabdomyolysiscaused pages 2-3, croce2024cptiideficiencya pages 1-9)

6.2 Biochemical decompensation

Under stress, impaired CPT-II function reduces LC-FAO flux and promotes accumulation of long-chain acylcarnitines; thermolabile variants (e.g., S113L) further lose activity at elevated temperature. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

6.3 Cellular injury

In skeletal muscle, LCAC accumulation can directly inhibit SR Ca2+ uptake, disrupt excitation–contraction coupling structures, and increase mitochondrial calcium stress/mPTP susceptibility—contributing to contractile dysfunction and myofiber injury. (pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria pages 6-8)

6.4 Clinical manifestations

• Myopathic form: recurrent myalgia, weakness, rhabdomyolysis/myoglobinuria; complications can include acute kidney injury from myoglobinuria. (castillo2023myopathiccarnitinepalmitoyltransferase pages 5-7, lu2024recurrentrhabdomyolysiscaused pages 2-3)

• Infantile/neonatal forms: hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy/arrhythmia, multi-organ failure, with high lethality in the neonatal form. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5, croce2024cptiideficiencya pages 1-9)

Phenotypic manifestations (HP-oriented, representative)

Evidence-supported phenotype groupings:

• Rhabdomyolysis / myoglobinuria (exercise/illness-triggered). (lu2024recurrentrhabdomyolysiscaused pages 2-3, castillo2023myopathiccarnitinepalmitoyltransferase pages 5-7)

• Cardiomyopathy and arrhythmias (especially early-onset forms; also reported complications). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5, castillo2023myopathiccarnitinepalmitoyltransferase pages 5-7)

• Hypoketotic hypoglycemia and liver dysfunction (infantile/neonatal forms). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5, croce2024cptiideficiencya pages 1-9)

Recent developments and latest research (prioritizing 2023–2024)

8.1 Mechanistic advance: LCAC → SERCA inhibition → Ca2+ dyshomeostasis

The 2024 Molecular Metabolism study provides strong mechanistic evidence linking defective mitochondrial LC-FAO to calcium-handling dysfunction via LCACs and demonstrates that muscle weakness can occur despite relatively preserved mitochondrial ATP production capacity, shifting emphasis from “energy failure alone” to “lipid-mediated excitation–contraction coupling disruption.” (pereyra2024lossofmitochondria pages 2-4, pereyra2024lossofmitochondria pages 8-10)

8.2 Diagnostic insight: normal acylcarnitine profiles between crises

A 2024 case report and literature review highlights that CPT2 deficiency can present with recurrent rhabdomyolysis yet have repeatedly normal acylcarnitine profiles outside acute episodes, with definitive diagnosis made by genome sequencing; the authors emphasize that biochemical abnormalities may only be detectable during active rhabdomyolysis. (lu2024recurrentrhabdomyolysiscaused pages 1-2, lu2024recurrentrhabdomyolysiscaused pages 2-3)

8.3 Updated case-count synthesis (2024)

A 2024 PubMed-based literature synthesis identified 245 documented CPT2 cases, distributed as 21 lethal neonatal, 32 severe infantile hepatocardiomuscular, and 192 myopathic. (lu2024recurrentrhabdomyolysiscaused pages 2-3)

Current applications and real-world implementations

9.1 Newborn screening and biochemical diagnosis

Tandem mass spectrometry is used in newborn screening and diagnostic workups, with typical CPT2 biochemical signatures including elevation of long-chain acylcarnitines (C12–C18), particularly C16 and C18:1, often with normal or low free carnitine (C0). (zhang2024clinicalcharacteristicsand pages 1-4)

Important implementation limitation: CPT2 deficiency may yield normal profiles when patients are not metabolically stressed; thus sampling during an acute event and/or genetic testing is critical when clinical suspicion persists. (lu2024recurrentrhabdomyolysiscaused pages 1-2, ambrose2025energymetabolismdefects pages 54-58)

Direct quote (diagnostic timing): “the abnormal acylcarnitine profile is more significant if individuals are metabolically stressed,” supporting the practice of collecting biochemical samples during/soon after crises. (ambrose2025energymetabolismdefects pages 54-58)

9.2 Patient management (expert consensus themes reflected in recent reviews/case discussions)

Common management principles described in 2023–2024 sources include avoidance of fasting and other triggers, and dietary strategies (high-carbohydrate/low-fat approaches, MCT supplementation), with carnitine supplementation used in some settings and additional carbohydrate during illness/exercise. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, croce2024cptiideficiencya pages 1-9, lu2024recurrentrhabdomyolysiscaused pages 1-2)

Therapeutic landscape and clinical trials (applications in practice)

10.1 Triheptanoin (UX007)

Triheptanoin is an odd-chain triglyceride intended to provide anaplerotic substrate (propionyl-CoA generation) to support energy metabolism in LC-FAOD. A Phase 2 open-label Ultragenyx study (NCT01886378) included CPT II deficiency among LC-FAOD diagnoses; dosing was titrated to ~25–35% of total calories, with a primary objective to evaluate impact on acute clinical pathophysiology after 24 weeks and exercise-tolerance-related outcomes. (NCT01886378 chunk 1)

An earlier Phase 2 randomized, double-masked trial (NCT01379625; completed; n=32; ages ~7–40) compared triheptanoin vs standard MCT oil at ~20% of caloric needs for 4 months, with outcomes including total energy expenditure and resting ejection fraction. (NCT01379625 chunk 1)

10.2 Bezafibrate

A Phase 2 randomized, quadruple-masked crossover trial (NCT00983788; completed) evaluated bezafibrate in adults with CPT II or VLCAD deficiency, using fatty-acid oxidation during moderate exercise as a primary outcome and safety monitoring including CK and liver enzymes. (NCT00983788 chunk 3)

The registry record also summarizes prior translational evidence: a pilot open study of six adult CPT II patients treated with bezafibrate 400 mg daily for 6 months reported improved muscular symptoms in 5/6 and induction of LCFA oxidation in isolated muscle mitochondria. (NCT00983788 chunk 1)

Epidemiology and statistics (recently cited)

• Literature-compiled case counts: 245 reported CPT2 cases (21 neonatal lethal; 32 severe infantile; 192 myopathic) in a 2024 literature review. (lu2024recurrentrhabdomyolysiscaused pages 2-3)

• Prevalence estimate: one narrative review cites ~1–9 per 100,000 (note: this is a review-derived estimate and may vary by population and ascertainment). (risi2025primarylipidmyopathies pages 12-14)

Knowledge-base entry elements (structured annotations)

12.1 Pathophysiology summary (narrative)

CPT2 deficiency results from loss-of-function or destabilizing variants in CPT2 encoding the IMM enzyme CPT-II, a required component of the carnitine shuttle that enables mitochondrial import and oxidation of long-chain fatty acids. Under metabolic stress (fasting, fever/infection, prolonged exercise), impaired CPT-II activity reduces LC-FAO and promotes long-chain acylcarnitine accumulation. Thermolabile variants such as p.Ser113Leu can exacerbate crisis susceptibility by losing activity at elevated temperature and showing increased sensitivity to inhibition. In skeletal muscle, recent mechanistic evidence demonstrates that LCAC accumulation—especially palmitoyl-carnitine—can directly inhibit SR calcium uptake, disrupt excitation–contraction coupling protein networks, and increase mitochondrial calcium stress and mPTP susceptibility, leading to contractile dysfunction, myofiber injury, and rhabdomyolysis. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria pages 6-8)

12.2 Gene/protein annotations (examples)

• CPT2 (HGNC:2329): mitochondrial inner membrane CPT-II; molecular function: acyltransferase activity within carnitine shuttle enabling LC-FAO; disease mechanism includes thermolability in common myopathic variants. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• SLC25A20 (CACT): inner mitochondrial membrane acylcarnitine translocase supporting carnitine shuttle. (risi2025primarylipidmyopathies pages 12-14)

12.3 Candidate GO terms (process-focused; suggested mapping)

• Mitochondrial fatty acid β-oxidation; long-chain fatty acid metabolic process; acylcarnitine metabolic process; carnitine transmembrane transport; calcium ion homeostasis; sarcoplasmic reticulum calcium ion transport; mitochondrial permeability transition pore complex opening (stress response). Evidence basis: mechanistic and review evidence as above. (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, pereyra2024lossofmitochondria pages 8-10, pereyra2024lossofmitochondria pages 6-8)

12.4 Candidate cellular components (suggested mapping)

• Mitochondrial inner membrane (CPT-II, CACT), outer mitochondrial membrane (CPT-I), mitochondrial matrix (β-oxidation enzymes downstream), sarcoplasmic reticulum (calcium uptake machinery). (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7, pereyra2024lossofmitochondria pages 8-10)

12.5 Evidence items and PMIDs

PMID availability was not consistently provided in the retrieved full-text snippets for all sources in this run. Where PMIDs are required for mechanistic claims, the most relevant primary mechanistic evidence here is the 2024 Molecular Metabolism study (Pereyra et al., 2024; DOI: 10.1016/j.molmet.2024.102015) and the mechanistic variant thermolability synthesis (Yao et al., 2023; DOI: 10.3748/wjg.v29.i12.1765). (pereyra2024lossofmitochondria pages 8-10, yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

(If strict PMID-only evidence is mandatory for downstream ingestion, additional PubMed-specific retrieval would be needed to map each cited DOI to PMID and to add classic enzymology/genotype papers.)

Key 2023–2024 sources (with URLs and dates)

• Yao M et al. “Mitochondrial carnitine palmitoyltransferase-II dysfunction…” World Journal of Gastroenterology. March 2023. https://doi.org/10.3748/wjg.v29.i12.1765 (yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7)

• Castillo E et al. “Myopathic Carnitine Palmitoyltransferase II (CPT II) Deficiency…” Cureus. October 2023. https://doi.org/10.7759/cureus.46595 (castillo2023myopathiccarnitinepalmitoyltransferase pages 5-7)

• Zhang Y et al. “Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency.” April 2024. https://doi.org/10.3724/zdxbyxb-2023-0611 (zhang2024clinicalcharacteristicsand pages 1-4)

• Lu C-H et al. “Recurrent rhabdomyolysis caused by… CPT-2 deficiency but complete normal acylcarnitine profile…” December 2024. https://doi.org/10.1016/j.ymgmr.2024.101151 (lu2024recurrentrhabdomyolysiscaused pages 1-2)

• Pereyra AS et al. “Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility…” November 2024. https://doi.org/10.1016/j.molmet.2024.102015 (pereyra2024lossofmitochondria pages 8-10)

• ClinicalTrials.gov: Triheptanoin Phase 2 (NCT01886378) https://clinicaltrials.gov/study/NCT01886378 (NCT01886378 chunk 1); Triheptanoin randomized Phase 2 (NCT01379625) https://clinicaltrials.gov/study/NCT01379625 (NCT01379625 chunk 1); Bezafibrate crossover Phase 2 (NCT00983788) https://clinicaltrials.gov/study/NCT00983788 (NCT00983788 chunk 3)

MONDO ID

A MONDO identifier for CPT-II deficiency was not retrieved within the tool context used in this run; therefore it is not asserted here.

References

(yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 5-7): Min Yao, Ping Zhou, Yan-Yan Qin, Li Wang, and Dengbing Yao. Mitochondrial carnitine palmitoyltransferase-ii dysfunction: a possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis. World Journal of Gastroenterology, 29:1765-1778, Mar 2023. URL: https://doi.org/10.3748/wjg.v29.i12.1765, doi:10.3748/wjg.v29.i12.1765. This article has 13 citations.
(croce2024cptiideficiencya pages 1-9): MMC Croce. Cptii deficiency: a therapeutical approach. Unknown journal, 2024.
(yao2023mitochondrialcarnitinepalmitoyltransferaseii pages 4-5): Min Yao, Ping Zhou, Yan-Yan Qin, Li Wang, and Dengbing Yao. Mitochondrial carnitine palmitoyltransferase-ii dysfunction: a possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis. World Journal of Gastroenterology, 29:1765-1778, Mar 2023. URL: https://doi.org/10.3748/wjg.v29.i12.1765, doi:10.3748/wjg.v29.i12.1765. This article has 13 citations.
(pereyra2024lossofmitochondria pages 8-10): Andrea S. Pereyra, Regina F. Fernandez, Adam Amorese, Jasmine N. Castro, Chien-Te Lin, Espen E. Spangenburg, and Jessica M. Ellis. Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Nov 2024. URL: https://doi.org/10.1016/j.molmet.2024.102015, doi:10.1016/j.molmet.2024.102015. This article has 7 citations and is from a domain leading peer-reviewed journal.
(pereyra2024lossofmitochondria pages 6-8): Andrea S. Pereyra, Regina F. Fernandez, Adam Amorese, Jasmine N. Castro, Chien-Te Lin, Espen E. Spangenburg, and Jessica M. Ellis. Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Nov 2024. URL: https://doi.org/10.1016/j.molmet.2024.102015, doi:10.1016/j.molmet.2024.102015. This article has 7 citations and is from a domain leading peer-reviewed journal.
(pereyra2024lossofmitochondria pages 2-4): Andrea S. Pereyra, Regina F. Fernandez, Adam Amorese, Jasmine N. Castro, Chien-Te Lin, Espen E. Spangenburg, and Jessica M. Ellis. Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Nov 2024. URL: https://doi.org/10.1016/j.molmet.2024.102015, doi:10.1016/j.molmet.2024.102015. This article has 7 citations and is from a domain leading peer-reviewed journal.
(pereyra2024lossofmitochondria media 916e81c8): Andrea S. Pereyra, Regina F. Fernandez, Adam Amorese, Jasmine N. Castro, Chien-Te Lin, Espen E. Spangenburg, and Jessica M. Ellis. Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Nov 2024. URL: https://doi.org/10.1016/j.molmet.2024.102015, doi:10.1016/j.molmet.2024.102015. This article has 7 citations and is from a domain leading peer-reviewed journal.
(pereyra2024lossofmitochondria media 75a3793d): Andrea S. Pereyra, Regina F. Fernandez, Adam Amorese, Jasmine N. Castro, Chien-Te Lin, Espen E. Spangenburg, and Jessica M. Ellis. Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Nov 2024. URL: https://doi.org/10.1016/j.molmet.2024.102015, doi:10.1016/j.molmet.2024.102015. This article has 7 citations and is from a domain leading peer-reviewed journal.
(castillo2023myopathiccarnitinepalmitoyltransferase pages 5-7): Efrain Castillo, Debbie Medina, and Nick Schoenmann. Myopathic carnitine palmitoyltransferase ii (cpt ii) deficiency: a rare cause of acute kidney injury and cardiomyopathy. Cureus, Oct 2023. URL: https://doi.org/10.7759/cureus.46595, doi:10.7759/cureus.46595. This article has 6 citations.
(risi2025primarylipidmyopathies pages 12-14): B RISI, F CARIA, L POLI, and A PADOVANI. Primary lipid myopathies: a narrative review. Unknown journal, 2025.
(zhang2024clinicalcharacteristicsand pages 1-4): Yan Zhang, W. Qiu, Huiwen Zhang, Ting Chen, Feng Xu, Suhong Yang, Jianmei Zhang, Xuefan Gu, and Lianshu Han. Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency. Journal of Zhejiang University (Medical Sciences), 53:207-212, Apr 2024. URL: https://doi.org/10.3724/zdxbyxb-2023-0611, doi:10.3724/zdxbyxb-2023-0611. This article has 0 citations.
(pereyra2024lossofmitochondria pages 1-2): Andrea S. Pereyra, Regina F. Fernandez, Adam Amorese, Jasmine N. Castro, Chien-Te Lin, Espen E. Spangenburg, and Jessica M. Ellis. Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Nov 2024. URL: https://doi.org/10.1016/j.molmet.2024.102015, doi:10.1016/j.molmet.2024.102015. This article has 7 citations and is from a domain leading peer-reviewed journal.
(lu2024recurrentrhabdomyolysiscaused pages 2-3): Chih-Hsuan Lu, Chia-Feng Yang, Yun-Ru Chen, Yann-Jang Chen, Yung-Hsiu Lu, and Dau-Ming Niu. Recurrent rhabdomyolysis caused by palmitoyltransferase ii (cpt-2) deficiency but complete normal acylcarnitine profile: a patient presentation and review of the literature. Molecular Genetics and Metabolism Reports, 41:101151, Dec 2024. URL: https://doi.org/10.1016/j.ymgmr.2024.101151, doi:10.1016/j.ymgmr.2024.101151. This article has 4 citations.
(lu2024recurrentrhabdomyolysiscaused pages 1-2): Chih-Hsuan Lu, Chia-Feng Yang, Yun-Ru Chen, Yann-Jang Chen, Yung-Hsiu Lu, and Dau-Ming Niu. Recurrent rhabdomyolysis caused by palmitoyltransferase ii (cpt-2) deficiency but complete normal acylcarnitine profile: a patient presentation and review of the literature. Molecular Genetics and Metabolism Reports, 41:101151, Dec 2024. URL: https://doi.org/10.1016/j.ymgmr.2024.101151, doi:10.1016/j.ymgmr.2024.101151. This article has 4 citations.
(ambrose2025energymetabolismdefects pages 54-58): A Ambrose. Energy metabolism defects in childhood and adulthood. Unknown journal, 2025.
(NCT01886378 chunk 1): A Study of UX007 (Triheptanoin) in Participants With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD). Ultragenyx Pharmaceutical Inc. 2014. ClinicalTrials.gov Identifier: NCT01886378
(NCT01379625 chunk 1): Melanie B Gillingham. Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorder. Oregon Health and Science University. 2011. ClinicalTrials.gov Identifier: NCT01379625
(NCT00983788 chunk 3): Mette Cathrine Oerngreen. Effect of Bezafibrate on Muscle Metabolism in Patients With Fatty Acid Oxidation Defects. Rigshospitalet, Denmark. 2009. ClinicalTrials.gov Identifier: NCT00983788
(NCT00983788 chunk 1): Mette Cathrine Oerngreen. Effect of Bezafibrate on Muscle Metabolism in Patients With Fatty Acid Oxidation Defects. Rigshospitalet, Denmark. 2009. ClinicalTrials.gov Identifier: NCT00983788

Carnitine Palmitoyltransferase II Deficiency

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