RARE DISEASE
Carnitine palmitoyltransferase II deficiency
Carnitine palmitoyltransferase II deficiency
Carnitine palmitoyltransferase II deficiency
Synonyms: CPT2, CPTII, Carnitine palmitoyltransferase deficiency type 2
Synonyms: CPT2, CPTII, Carnitine palmitoyltransferase deficiency type 2
Synonyms: CPT2, CPTII, Carnitine palmitoyltransferase deficiency type 2
Drug discovery
1
drug
With orphan designation
Overview
Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder impairing mitochondrial long-chain fatty acid oxidation. It manifests in three forms: lethal neonatal (multiorgan failure), severe infantile (hepatocardiomuscular involvement), and myopathic (recurrent rhabdomyolysis). Symptoms include hypoketotic hypoglycemia, cardiomyopathy, muscle pain, and myoglobinuria. Diagnosis involves acylcarnitine profiling, genetic testing, and enzyme assays. Management focuses on dietary modifications, avoidance of metabolic stressors, and emergency glucose support during crises [1][2][6][11].
Burden
Neonatal/infantile forms: High mortality (~100% neonatal mortality within months) [1][6][16].
Myopathic form: Recurrent hospitalizations for rhabdomyolysis-induced acute kidney injury [4][9].
Chronic comorbidities: Cardiomyopathy, liver failure, and reduced quality of life due to activity restrictions [2][4][6].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
160 drug discovery papers about Carnitine palmitoyltransferase II deficiency, with 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
160 drug discovery papers about Carnitine palmitoyltransferase II deficiency, with 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Carnitine palmitoyltransferase II deficiency: a case of post-infectious rhabdomyolysis and respiratory failure
Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessive inherited metabolic disorder and represents the most common genetic cause of recurrent rhabdomyolysis in adulthood. The clinical course is characterized by episodic attacks precipitated by intense physical exertion, infections, psychological stress, or other physical and emotional stressors. Although avoidance or early recognition of triggering factors plays a critical role in prognosis, many patients continue to experience recurrent episodes of rhabdomyolysis. Management primarily focuses on elimination of precipitating factors and meticulous correction of fluid and electrolyte imbalances. Prompt recognition of CPT-II deficiency and rapid identification and management of rhabdomyolysis triggers are essential for preventing life-threatening complications. We report the clinical characteristics, therapeutic interventions, and outcome of a 31-year-old male patient with known CPT-II deficiency. The patient presented with dyspnea and generalized muscle weakness following an infectious episode. Laboratory evaluation revealed markedly elevated creatine kinase levels, and rhabdomyolysis secondary to CPT-II deficiency was diagnosed. The patient received supportive management, including intravenous fluid therapy for electrolyte stabilization, close monitoring in the intensive care unit, and treatment with triheptanoin. His symptoms improved gradually, and he was discharged in stable condition with recommendations emphasizing avoidance of known triggers and long-term disease management. This report aims to underscore the importance of early diagnosis and timely therapeutic intervention in the management of CPT-II deficiency.
2026-08-24 | Nicotinamide Mononucleotide (NMN) Prevents Age-Associated Transcriptional Drift in a Tissue-Dependent Manner: Mechanistic Leads From Ras-Related Protein Rab-11A-Mediated Trafficking and Carnitine Palmitoyltransferase 2-Linked Fatty Acid Oxidation.
This study is a secondary computational reanalysis of the publicly available GSE85718 microarray dataset generated during the long-term nicotinamide mononucleotide (NMN) study. NMN has been reported to improve several age-sensitive physiological traits in mice, including energy metabolism, insulin sensitivity, plasma lipid profiles, and skeletal-muscle mitochondrial function. However, the transcriptional mechanisms behind these effects remain less clear than the broader nicotinamide adenine dinucleotide (NAD+) and sirtuin-centered model often used to explain NMN biology. The present analysis used a per-tissue age-by-treatment interaction model to test whether NMN modifies the rate of age-associated transcriptional change rather than simply shifting expression at one age. The model was expression ~ age × treatment, with the age-by-treatment term used as the central test. A gene was considered an NMN-rescue candidate only when it changed with age in control mice and showed an opposite-signed interaction term, consistent with NMN shifting old-age expression toward the young-control state. No individual gene reached genome-wide false discovery rate (FDR) <0.05 for age, NMN at six months, or the interaction term in skeletal muscle, liver, or white adipose tissue (WAT). Therefore, all gene-level results should be treated as hypothesis-generating. Using relaxed nominal criteria, 421 rescue candidates were identified in skeletal muscle, 355 in liver, and 397 in WAT. Only 35 genes were rescued in at least two tissues, 26 of which were direction-consistent, and none were rescued in all three tissues. Ras-related protein Rab-11A (RAB11A) emerged as the strongest cross-tissue candidate, with rescue in skeletal muscle and WAT, high confidence in at least one tissue, consistent directionality, and involvement in 39 gene set enrichment analysis (GSEA) leading-edge terms, largely related to trafficking and cellular transport. Carnitine palmitoyltransferase 2 (CPT2) was the only mitochondrial gene among the robust cross-tissue candidates and was consistently rescued in skeletal muscle and WAT, supporting a focused fatty-acid oxidation and substrate-handling hypothesis rather than broad mitochondrial activation. At the pathway level, liver showed the clearest signal: NMN was associated with suppression of fatty-acyl-coenzyme A (CoA) and long-chain fatty-acyl-CoA metabolic programs. These findings do not establish that NMN prevents transcriptional aging or that RAB11A or CPT2 mediates the physiological effects of NMN. Instead, they identify tissue-specific, testable candidates from a secondary reanalysis of an existing animal dataset. In particular, they support moving beyond a generic "NAD+ improves mitochondria" model toward testable mechanisms involving cellular logistics, membrane recycling, and substrate utilization.
2026-08-06 | A covalent PFKL activator suppresses tumor growth.
Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile-drug conjugates is analogous to that of antibody-drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.
2026-07-19 | CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to Nicotinamide Mononucleotide (NMN)-Induced Expression Rescue in Metabolic Tissues.
Age-related decline in mitochondrial function and disruption of epigenetic regulation are two closely connected features of biological aging. In neurons, age-associated remodeling of repressive H3K27me3 chromatin may constrain genes needed for metabolic, synaptic, and stress-adaptive maintenance. In parallel, nicotinamide mononucleotide (NMN), an NAD+ precursor, has been reported to mitigate age-associated physiological and transcriptional changes in peripheral metabolic tissues. However, direct links between neuronal epigenetic aging programs and NMN-responsive transcriptional rescue remain unclear. Here, we performed a secondary integrative analysis of two public datasets: GSE190102, focused on age-associated neuronal H3K27me3 targets mapped through an activity-by-contact-style region-gene framework, and GSE85718, a long-term NMN transcriptomic dataset from skeletal muscle, liver, and white adipose tissue in mice. The analysis identified 23 genes shared between 21,155 aging H3K27me3-associated targets and 35 robust NMN-rescue genes. Because the aging target set was extremely broad, gene-level overlap was not statistically persuasive, and pathway-level convergence was absent. Under repressive-mark direction logic, 14 of the 23 shared genes were concordant, meaning that the NMN expression effect opposed the expected consequence of age-associated H3K27me3 remodeling. Objectives were to quantify overlap between neuronal age-associated H3K27me3 targets and robust NMN-responsive genes in peripheral metabolic tissues, classify shared genes by directional concordance under repressive chromatin logic, and identify high-priority mechanistic candidates. The analysis supports limited global convergence and nominates CPT2 as the leading convergent node for targeted validation. CPT2 emerged as the leading candidate. It showed age-associated H3K27me3 gain, a large K27me3 log-fold change of +3.504, NMN-induced expression increase in old animals, a positive NMN interaction coefficient of +0.201, and membership in the mitochondrial fatty-acid oxidation pathway. Within the downstream shared-gene mitochondrial analysis, CPT2 was the only mitochondrial-core gene, with nominal enrichment only. These findings do not support a broad reversal of neuronal epigenetic aging by NMN. Instead, they identify CPT2 as a biologically coherent and experimentally tractable candidate linking age-related repressive chromatin remodeling to NMN-responsive mitochondrial metabolism.
2026-07-01 | CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to NMN-Induced Expression Rescue in Metabolic Tissues
Age-related decline in mitochondrial function and disruption of epigenetic regulation are two closely connected features of biological aging. In neurons, age-associated remodeling of repressive H3K27me3 chromatin may constrain genes needed for metabolic, synaptic, and stress-adaptive maintenance. In parallel, nicotinamide mononucleotide (NMN), an NAD+ precursor, has been reported to mitigate age-associated physiological and transcriptional changes in peripheral metabolic tissues. However, direct links between neuronal epigenetic aging programs and NMN-responsive transcriptional rescue remain unclear.Here, we performed a secondary integrative analysis of two public datasets: GSE190102, focused on age-associated neuronal H3K27me3 targets mapped through an activity-by-contact-style region–gene framework, and GSE85718, a long-term NMN transcriptomic dataset from skeletal muscle, liver, and white adipose tissue in mice. The analysis identified 23 genes shared between 21,155 aging H3K27me3-associated targets and 35 robust NMN-rescue genes. Because the aging target set was extremely broad, gene-level overlap was not statistically persuasive, and pathway-level convergence was absent. Under repressive-mark direction logic, 14 of the 23 shared genes were concordant, meaning that the NMN expression effect opposed the expected consequence of age-associated H3K27me3 remodeling.CPT2 emerged as the leading candidate. It showed age-associated H3K27me3 gain, a large K27me3 log-fold change of +3.504, NMN-induced expression increase in old animals, a positive NMN interaction coefficient of +0.201, and membership in the mitochondrial fatty-acid oxidation pathway. Within the downstream shared-gene mitochondrial analysis, CPT2 was the only mitochondrial-core gene, with nominal enrichment only. These findings do not support broad reversal of neuronal epigenetic aging by NMN. Instead, they identify CPT2 as a biologically coherent and experimentally tractable candidate linking age-related repressive chromatin remodeling to NMN-responsive mitochondrial metabolism.
antibodies
2025-07-01 | Migratory and intermittent polyarthritis as an atypical presentation of carnitine palmitoyltransferase II deficiency with positive response to treatment with Interleukin-1 receptor antagonist: a case presentation and case-based review.
Carnitine palmitoyltransferase 2 (CPT2) deficiency is an autosomal recessive disorder affecting fatty-acid metabolism that manifests in three phenotypes: lethal neonatal, infantile and adult. In the adult population, CPT2 deficiency is characterized as the commonest cause of recurrent episodes of rhabdomyolysis. Although inflammatory arthritis has not been previously associated with CPT2 deficiency, existing literature suggests a potential mechanism involving synovial inflammation secondary to the accumulation of fatty acids and acylcarnitine. Attacks are most commonly triggered by infections, strenuous exercise, fasting and consumption of a fat-rich meal. Management in typically conservative, involving dietary modification (high-carbohydrate, low-fat diet) and personalized exercise regimens. The following article describes the case of 43-year old male patient with chronic, intermittent arthritis who was diagnosed with CPT2 deficiency and is currently receiving treatment with interleukin 1 receptor antagonist (IL-1Ra). In addition, a case-based review was conducted to evaluate the possible, underlying mechanisms of inflammatory arthritis in patients with CPT2 deficiency, along with any nuances in the treatment strategy. The presented case, along with the associated case-based literature review, highlight the inflammatory changes taking place in the synovial cells upon accumulation of fatty acids and acylcarnitine molecules that release IL-1β. Finally, the report explores potential future therapeutic strategies.
small molecules
2026-09-24 | Carnitine palmitoyltransferase II deficiency: a case of post-infectious rhabdomyolysis and respiratory failure
Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessive inherited metabolic disorder and represents the most common genetic cause of recurrent rhabdomyolysis in adulthood. The clinical course is characterized by episodic attacks precipitated by intense physical exertion, infections, psychological stress, or other physical and emotional stressors. Although avoidance or early recognition of triggering factors plays a critical role in prognosis, many patients continue to experience recurrent episodes of rhabdomyolysis. Management primarily focuses on elimination of precipitating factors and meticulous correction of fluid and electrolyte imbalances. Prompt recognition of CPT-II deficiency and rapid identification and management of rhabdomyolysis triggers are essential for preventing life-threatening complications. We report the clinical characteristics, therapeutic interventions, and outcome of a 31-year-old male patient with known CPT-II deficiency. The patient presented with dyspnea and generalized muscle weakness following an infectious episode. Laboratory evaluation revealed markedly elevated creatine kinase levels, and rhabdomyolysis secondary to CPT-II deficiency was diagnosed. The patient received supportive management, including intravenous fluid therapy for electrolyte stabilization, close monitoring in the intensive care unit, and treatment with triheptanoin. His symptoms improved gradually, and he was discharged in stable condition with recommendations emphasizing avoidance of known triggers and long-term disease management. This report aims to underscore the importance of early diagnosis and timely therapeutic intervention in the management of CPT-II deficiency.
2026-08-24 | Nicotinamide Mononucleotide (NMN) Prevents Age-Associated Transcriptional Drift in a Tissue-Dependent Manner: Mechanistic Leads From Ras-Related Protein Rab-11A-Mediated Trafficking and Carnitine Palmitoyltransferase 2-Linked Fatty Acid Oxidation.
This study is a secondary computational reanalysis of the publicly available GSE85718 microarray dataset generated during the long-term nicotinamide mononucleotide (NMN) study. NMN has been reported to improve several age-sensitive physiological traits in mice, including energy metabolism, insulin sensitivity, plasma lipid profiles, and skeletal-muscle mitochondrial function. However, the transcriptional mechanisms behind these effects remain less clear than the broader nicotinamide adenine dinucleotide (NAD+) and sirtuin-centered model often used to explain NMN biology. The present analysis used a per-tissue age-by-treatment interaction model to test whether NMN modifies the rate of age-associated transcriptional change rather than simply shifting expression at one age. The model was expression ~ age × treatment, with the age-by-treatment term used as the central test. A gene was considered an NMN-rescue candidate only when it changed with age in control mice and showed an opposite-signed interaction term, consistent with NMN shifting old-age expression toward the young-control state. No individual gene reached genome-wide false discovery rate (FDR) <0.05 for age, NMN at six months, or the interaction term in skeletal muscle, liver, or white adipose tissue (WAT). Therefore, all gene-level results should be treated as hypothesis-generating. Using relaxed nominal criteria, 421 rescue candidates were identified in skeletal muscle, 355 in liver, and 397 in WAT. Only 35 genes were rescued in at least two tissues, 26 of which were direction-consistent, and none were rescued in all three tissues. Ras-related protein Rab-11A (RAB11A) emerged as the strongest cross-tissue candidate, with rescue in skeletal muscle and WAT, high confidence in at least one tissue, consistent directionality, and involvement in 39 gene set enrichment analysis (GSEA) leading-edge terms, largely related to trafficking and cellular transport. Carnitine palmitoyltransferase 2 (CPT2) was the only mitochondrial gene among the robust cross-tissue candidates and was consistently rescued in skeletal muscle and WAT, supporting a focused fatty-acid oxidation and substrate-handling hypothesis rather than broad mitochondrial activation. At the pathway level, liver showed the clearest signal: NMN was associated with suppression of fatty-acyl-coenzyme A (CoA) and long-chain fatty-acyl-CoA metabolic programs. These findings do not establish that NMN prevents transcriptional aging or that RAB11A or CPT2 mediates the physiological effects of NMN. Instead, they identify tissue-specific, testable candidates from a secondary reanalysis of an existing animal dataset. In particular, they support moving beyond a generic "NAD+ improves mitochondria" model toward testable mechanisms involving cellular logistics, membrane recycling, and substrate utilization.
2026-08-06 | A covalent PFKL activator suppresses tumor growth.
Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile-drug conjugates is analogous to that of antibody-drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.
2026-07-19 | CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to Nicotinamide Mononucleotide (NMN)-Induced Expression Rescue in Metabolic Tissues.
Age-related decline in mitochondrial function and disruption of epigenetic regulation are two closely connected features of biological aging. In neurons, age-associated remodeling of repressive H3K27me3 chromatin may constrain genes needed for metabolic, synaptic, and stress-adaptive maintenance. In parallel, nicotinamide mononucleotide (NMN), an NAD+ precursor, has been reported to mitigate age-associated physiological and transcriptional changes in peripheral metabolic tissues. However, direct links between neuronal epigenetic aging programs and NMN-responsive transcriptional rescue remain unclear. Here, we performed a secondary integrative analysis of two public datasets: GSE190102, focused on age-associated neuronal H3K27me3 targets mapped through an activity-by-contact-style region-gene framework, and GSE85718, a long-term NMN transcriptomic dataset from skeletal muscle, liver, and white adipose tissue in mice. The analysis identified 23 genes shared between 21,155 aging H3K27me3-associated targets and 35 robust NMN-rescue genes. Because the aging target set was extremely broad, gene-level overlap was not statistically persuasive, and pathway-level convergence was absent. Under repressive-mark direction logic, 14 of the 23 shared genes were concordant, meaning that the NMN expression effect opposed the expected consequence of age-associated H3K27me3 remodeling. Objectives were to quantify overlap between neuronal age-associated H3K27me3 targets and robust NMN-responsive genes in peripheral metabolic tissues, classify shared genes by directional concordance under repressive chromatin logic, and identify high-priority mechanistic candidates. The analysis supports limited global convergence and nominates CPT2 as the leading convergent node for targeted validation. CPT2 emerged as the leading candidate. It showed age-associated H3K27me3 gain, a large K27me3 log-fold change of +3.504, NMN-induced expression increase in old animals, a positive NMN interaction coefficient of +0.201, and membership in the mitochondrial fatty-acid oxidation pathway. Within the downstream shared-gene mitochondrial analysis, CPT2 was the only mitochondrial-core gene, with nominal enrichment only. These findings do not support a broad reversal of neuronal epigenetic aging by NMN. Instead, they identify CPT2 as a biologically coherent and experimentally tractable candidate linking age-related repressive chromatin remodeling to NMN-responsive mitochondrial metabolism.
2026-07-01 | CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to NMN-Induced Expression Rescue in Metabolic Tissues
Age-related decline in mitochondrial function and disruption of epigenetic regulation are two closely connected features of biological aging. In neurons, age-associated remodeling of repressive H3K27me3 chromatin may constrain genes needed for metabolic, synaptic, and stress-adaptive maintenance. In parallel, nicotinamide mononucleotide (NMN), an NAD+ precursor, has been reported to mitigate age-associated physiological and transcriptional changes in peripheral metabolic tissues. However, direct links between neuronal epigenetic aging programs and NMN-responsive transcriptional rescue remain unclear.Here, we performed a secondary integrative analysis of two public datasets: GSE190102, focused on age-associated neuronal H3K27me3 targets mapped through an activity-by-contact-style region–gene framework, and GSE85718, a long-term NMN transcriptomic dataset from skeletal muscle, liver, and white adipose tissue in mice. The analysis identified 23 genes shared between 21,155 aging H3K27me3-associated targets and 35 robust NMN-rescue genes. Because the aging target set was extremely broad, gene-level overlap was not statistically persuasive, and pathway-level convergence was absent. Under repressive-mark direction logic, 14 of the 23 shared genes were concordant, meaning that the NMN expression effect opposed the expected consequence of age-associated H3K27me3 remodeling.CPT2 emerged as the leading candidate. It showed age-associated H3K27me3 gain, a large K27me3 log-fold change of +3.504, NMN-induced expression increase in old animals, a positive NMN interaction coefficient of +0.201, and membership in the mitochondrial fatty-acid oxidation pathway. Within the downstream shared-gene mitochondrial analysis, CPT2 was the only mitochondrial-core gene, with nominal enrichment only. These findings do not support broad reversal of neuronal epigenetic aging by NMN. Instead, they identify CPT2 as a biologically coherent and experimentally tractable candidate linking age-related repressive chromatin remodeling to NMN-responsive mitochondrial metabolism.
antibodies
2025-07-01 | Migratory and intermittent polyarthritis as an atypical presentation of carnitine palmitoyltransferase II deficiency with positive response to treatment with Interleukin-1 receptor antagonist: a case presentation and case-based review.
Carnitine palmitoyltransferase 2 (CPT2) deficiency is an autosomal recessive disorder affecting fatty-acid metabolism that manifests in three phenotypes: lethal neonatal, infantile and adult. In the adult population, CPT2 deficiency is characterized as the commonest cause of recurrent episodes of rhabdomyolysis. Although inflammatory arthritis has not been previously associated with CPT2 deficiency, existing literature suggests a potential mechanism involving synovial inflammation secondary to the accumulation of fatty acids and acylcarnitine. Attacks are most commonly triggered by infections, strenuous exercise, fasting and consumption of a fat-rich meal. Management in typically conservative, involving dietary modification (high-carbohydrate, low-fat diet) and personalized exercise regimens. The following article describes the case of 43-year old male patient with chronic, intermittent arthritis who was diagnosed with CPT2 deficiency and is currently receiving treatment with interleukin 1 receptor antagonist (IL-1Ra). In addition, a case-based review was conducted to evaluate the possible, underlying mechanisms of inflammatory arthritis in patients with CPT2 deficiency, along with any nuances in the treatment strategy. The presented case, along with the associated case-based literature review, highlight the inflammatory changes taking place in the synovial cells upon accumulation of fatty acids and acylcarnitine molecules that release IL-1β. Finally, the report explores potential future therapeutic strategies.
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Drug Discovery Landscape
1 orphan drug designation for Carnitine palmitoyltransferase II deficiency.
1 orphan drug designation for Carnitine palmitoyltransferase II deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Triheptanoin | small molecules | EMA | Ultragenyx Netherlands B.V. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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