Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

Mendelian MONDO:0008723 Pathograph 31 Show in embeddings browser Fatty Acid Oxidation Disorder Inborn Error of Metabolism

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of mitochondrial long-chain fatty acid beta-oxidation caused by biallelic pathogenic variants in ACADVL. VLCAD catalyzes the first dehydrogenation step in the beta-oxidation spiral for long-chain acyl-CoAs (C12-C20). Deficient oxidation leads to energy failure during fasting or catabolic stress, accumulation of long-chain acylcarnitines, and impaired ketogenesis, with clinical manifestations ranging from severe neonatal cardiomyopathy and multiorgan failure to childhood hypoketotic hypoglycemia to later-onset exercise-induced rhabdomyolysis. A 2025 review estimates that VLCADD affects 1 to 2 individuals per 100,000.

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7
Pathophys.
15
Phenotypes
1
Gaps
31
Pathograph
1
Genes
11
Medical Actions
3
Subtypes
3
Models
14
References
1
Deep Research
◆

Subtypes

3
Neonatal severe cardiac form
Early-onset cardiomyopathy and metabolic instability presenting in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, arrhythmias, and multiorgan failure.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy"
Directly supports the early severe cardiac VLCAD subtype.
Infantile or childhood hepatic-hypoketotic form
Episodic hypoketotic hypoglycemia and liver dysfunction presenting during early childhood, typically without cardiomyopathy.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy."
Directly supports the infantile/childhood hepatic-hypoketotic subtype.
Later-onset myopathic form
Exercise intolerance and recurrent rhabdomyolysis provoked by exercise, fasting, cold, or illness. This is the most common presentation in adults.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance."
Directly supports the later-onset myopathic VLCAD subtype.
PMID:38015438 SUPPORT Human Clinical
"The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness."
Adult cohort confirms myopathic presentations as the predominant adult phenotype.
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Discussions and Knowledge Gaps

1
How much do secondary OXPHOS dysfunction, oxidative stress, abnormal lipid handling, and attenuated TLR4 responses contribute to the cardiac, hepatic, and myopathic VLCAD presentations in humans?
HUMAN MODEL MISMATCH OPEN gap_vlcad_cellular_branches_to_clinical_subtypes
Attached to
pathophysiology#Secondary mitochondrial dysfunction and OXPHOS impairment pathophysiology#Oxidative stress and glutathione vulnerability pathophysiology#Long-chain lipid metabolite accumulation pathophysiology#Attenuated TLR4 inflammatory response
The primary ACADVL/FAO defect and three clinical presentations are established, but the secondary branches are supported by reviews, patient fibroblasts, targeted cell perturbation, metabolomics, and mouse work rather than direct causal tests in affected human heart, liver, or skeletal muscle.
Proposed experiments
Isogenic ACADVL rescue across cardiac, hepatic, and skeletal-muscle models
exp_vlcad_isogenic_multilineage_rescue
Compare patient-derived and corrected iPSC cardiomyocytes, hepatocytes, and myotubes under matched catabolic stress, measuring FAO flux, OXPHOS, lipid species, glutathione, cytokine responses, and cell injury.
Branch-specific rescue of VLCAD cellular phenotypes
exp_vlcad_branch_specific_perturbation
Rescue lipid balance, redox capacity, or OXPHOS independently to determine which interventions prevent lineage-specific injury without restoring ACADVL itself.
Show evidence (1 reference)
PMID:40149952 SUPPORT Other
"there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function."
Frames the secondary mitochondrial branch as growing rather than definitive evidence.
⚙

Pathophysiology

7
ACADVL molecular function deficiency
Biallelic ACADVL pathogenic variants reduce very long-chain acyl-CoA dehydrogenase catalytic activity.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology. cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
ACADVL Relation: this pathophysiological event involves this gene This pathophysiological event involves ACADVL.
fatty acid beta-oxidation GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology.
very-long-chain fatty acyl-CoA dehydrogenase activity GO:0017099 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves very-long-chain fatty acyl-CoA dehydrogenase activity (GO:0017099). GO:0017099 is a molecular function from the Gene Ontology.
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in mitochondrion (GO:0005739). GO:0005739 is an anatomical location from the Gene Ontology.
Downstream
Impaired very-long-chain fatty acid beta-oxidation Reduced ACADVL activity blocks initial dehydrogenation of C12-C20 acyl-CoAs.
Secondary mitochondrial dysfunction and OXPHOS impairment Loss of VLCAD-OXPHOS supercomplex interactions contributes to secondary OXPHOS dysfunction.
Oxidative stress and glutathione vulnerability VLCAD-deficient cells develop oxidative burden and glutathione depletion under metabolic stress.
Attenuated TLR4 inflammatory response ACADVL loss attenuates TLR4 signaling and cytokine induction after LPS stimulation.
Cardiomyopathy VLCAD deficiency causes severe early-onset cardiac disease through unresolved intermediates.
Hypoketotic hypoglycemia VLCAD deficiency causes a hepatic/hypoketotic presentation through unresolved intermediates.
Hepatomegaly Hepatomegaly belongs to the childhood hepatic VLCAD presentation through unresolved intermediates.
Rhabdomyolysis VLCAD deficiency causes an episodic myopathic presentation through unresolved intermediates.
Exercise intolerance Exercise intolerance belongs to the later-onset myopathic VLCAD presentation.
Myalgia Muscle pain belongs to the later-onset myopathic VLCAD presentation.
Show evidence (1 reference)
PMID:20301763 SUPPORT Other
"Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20"
Directly defines the deficient enzyme function and substrate range.
Impaired very-long-chain fatty acid beta-oxidation
Impaired mitochondrial oxidation of long-chain fatty acyl-CoA substrates (C12-C20), especially during fasting and other catabolic states, reduces acetyl-CoA generation, limits ATP production, and impairs hepatic ketogenesis.
very long-chain fatty acid metabolic process GO:0000038 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves very long-chain fatty acid metabolic process (GO:0000038). GO:0000038 is a biological process from the Gene Ontology. fatty acid beta-oxidation GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology.
Downstream
Tissue energy deficit in high-demand organs Impaired mitochondrial FAO reduces metabolic flexibility and ATP-generating capacity.
Long-chain lipid metabolite accumulation The ACADVL beta-oxidation block produces abnormal long-chain acylcarnitine accumulation.
Ketone bodies Impaired hepatic long-chain FAO limits ketogenesis, producing the hypoketotic biochemical state.
Long-chain acylcarnitines (C14, C16, C18 species) Impaired long-chain acyl-CoA oxidation leads to abnormal long-chain acylcarnitine profiles.
Show evidence (1 reference)
PMID:40149952 SUPPORT Other
"Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are crucial metabolic processes involved in generating ATP, with defects in these pathways causing mitochondrial disease."
Supports the central role of FAO in mitochondrial ATP generation.
Tissue energy deficit in high-demand organs
Energy deficiency affects myocardium, skeletal muscle, and liver. Impaired FAO reduces availability of reducing equivalents and acetyl-CoA for mitochondrial ATP production and hepatic ketogenesis, forcing compensatory reliance on glucose utilization and gluconeogenesis.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. gluconeogenesis GO:0006094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves gluconeogenesis (GO:0006094). GO:0006094 is a biological process from the Gene Ontology.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology. skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology. liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia."
Supports high-energy-organ involvement including heart, liver, and systemic metabolic failure.
PMID:37960342 SUPPORT Model Organism
"Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis."
Demonstrates impaired metabolic flexibility and energy homeostasis in VLCAD deficiency.
Long-chain lipid metabolite accumulation
The long-chain fatty-acid oxidation block produces abnormal long-chain acylcarnitine and dicarboxylic-acid profiles. The retained sources establish this biochemical accumulation but do not isolate its contribution to individual clinical manifestations.
lipid metabolic process GO:0006629 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves lipid metabolic process (GO:0006629). GO:0006629 is a biological process from the Gene Ontology.
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in mitochondrion (GO:0005739). GO:0005739 is an anatomical location from the Gene Ontology.
Show evidence (1 reference)
PMID:37367883 SUPPORT Human Clinical
"VLCADD is a rare inherited metabolic disorder associated with fatty acid β-oxidation and characterized by genetic mutations in the ACADVL gene and accumulations of acylcarnitines."
Directly supports acylcarnitine accumulation in ACADVL-related VLCADD.
Secondary mitochondrial dysfunction and OXPHOS impairment
VLCAD interacts physically with OXPHOS supercomplexes; VLCAD deficiency disrupts these interactions and impairs electron transport chain function, worsening bioenergetics beyond the primary FAO defect.
mitochondrial electron transport, NADH to ubiquinone GO:0006120 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves mitochondrial electron transport, NADH to ubiquinone (GO:0006120). GO:0006120 is a biological process from the Gene Ontology.
mitochondrial respiratory chain complex I GO:0045271 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrial respiratory chain complex I, annotated with respiratory chain complex I (GO:0045271). GO:0045271 is a cellular component from the Gene Ontology.
Show evidence (2 references)
PMID:40149952 SUPPORT Other
"there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function."
Supports secondary OXPHOS dysfunction beyond the primary FAO defect.
PMID:40149952 SUPPORT Other
"we describe what is now known about the protein-protein interactions between VLCAD and the OXPHOS supercomplex and how their disruption contributes to overall VLCADD pathogenesis."
Directly supports VLCAD-OXPHOS supercomplex interaction disruption.
Oxidative stress and glutathione vulnerability
VLCAD deficiency increases reactive oxygen species production and renders cells vulnerable to glutathione depletion under metabolic stress. Mitochondrial NADPH production is relevant to GSH recycling and cellular resilience.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. glutathione metabolic process GO:0006749 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves glutathione metabolic process (GO:0006749). GO:0006749 is a biological process from the Gene Ontology.
Experimental models
VLCAD-deficient patient-fibroblast oxidative-stress model PRIMARY CELL CULTURE Metabolic stress exposes the glutathione-dependent cellular vulnerability.
Downstream
Glutathione Oxidative stress in VLCAD deficiency is reflected by glutathione pathway vulnerability and altered glutathione levels.
Show evidence (1 reference)
PMID:36356723 SUPPORT In Vitro
"metabolic stress increases the oxidative burden in VLCAD-deficient cell lines and can deplete the antioxidant glutathione (GSH)."
Directly supports oxidative burden and GSH vulnerability in VLCAD-deficient cells.
Attenuated TLR4 inflammatory response
VLCAD-deficient cells show impaired TLR4 signaling and reduced pro-inflammatory cytokine induction after LPS stimulation, connecting long-chain FAO to innate immune competence and helping explain why infection and inflammation trigger metabolic decompensation.
toll-like receptor 4 signaling pathway GO:0034142 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased toll-like receptor 4 signaling pathway (GO:0034142). GO:0034142 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
ACADVL-loss inflammatory-response model PRIMARY CELL CULTURE ACADVL loss tests whether the inflammatory-response defect is gene dependent.
Show evidence (1 reference)
PMID:39399475 SUPPORT In Vitro
"The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6."
Details specific TLR4 pathway impairment in VLCAD deficiency.
⬡

Pathograph

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

15
Cardiovascular 2
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy"
Directly supports cardiomyopathy in severe VLCAD.
Cardiac arrhythmia HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias"
Directly supports arrhythmias in severe neonatal VLCAD.
Digestive 2
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly"
Directly supports hepatomegaly as a feature of the hepatic VLCAD subtype.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Vomiting is a common symptom during metabolic decompensation in FAODs, triggered by fasting or intercurrent illness. A VLCAD case report documents emesis during a severe decompensation event, but frequency is not quantified.
Show evidence (1 reference)
PMID:19333779 SUPPORT Human Clinical
"was admitted with emesis, severe lethargy, limpness in extremities, loss of muscle tone and an elevated CK level."
Case evidence supports emesis/vomiting during VLCAD metabolic decompensation.
Metabolism 4
Hypoketotic hypoglycemia HP:0001985 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoketotic hypoglycemia (HP:0001985). HP:0001985 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy."
Directly supports hypoketotic hypoglycemia as a core VLCAD phenotype.
PMID:37512487 SUPPORT Human Clinical
"Hypoketotic hypoglycemia is a feared clinical complication and the treatment focuses on avoiding hypoglycemia."
Confirms hypoketotic hypoglycemia as a feared complication of VLCAD.
Hyperammonemia HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987). HP:0001987 is a phenotype from the Human Phenotype Ontology.
Hyperammonemia can occur during severe metabolic decompensation in FAODs, though it is less prominent than in urea cycle disorders. The available evidence supports occurrence but does not quantify hyperammonemia frequency in VLCAD.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Early childhood disease may manifest with hypoketotic hypoglycemia, hyperammonemia, lactic acidosis, and elevated transaminases."
Review evidence directly supports hyperammonemia as an early VLCAD manifestation.
Lactic acidosis HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Early childhood disease may manifest with hypoketotic hypoglycemia, hyperammonemia, lactic acidosis, and elevated transaminases."
Review evidence directly supports lactic acidosis in early VLCAD disease.
Elevated creatine kinase Elevated circulating creatine kinase concentration HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase concentration (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38015438 SUPPORT Human Clinical
"Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L"
Quantifies elevated CK during rhabdomyolysis in adult FAOD cohort.
Musculoskeletal 3
Rhabdomyolysis HP:0003201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhabdomyolysis (HP:0003201). HP:0003201 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise"
Directly supports recurrent rhabdomyolysis in later-onset VLCAD.
PMID:38015438 SUPPORT Human Clinical
"Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L"
Quantifies rhabdomyolysis frequency and severity in adult FAOD cohort.
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38015438 SUPPORT Human Clinical
"The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness."
Supports permanent muscle weakness as a complication of the myopathic form.
Muscular hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia."
Directly supports hypotonia in severe neonatal VLCAD.
Nervous System 2
Lethargy HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19333779 SUPPORT Human Clinical
"was admitted with emesis, severe lethargy, limpness in extremities, loss of muscle tone and an elevated CK level."
Case evidence directly supports severe lethargy during VLCAD metabolic decompensation.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38157116 SUPPORT Human Clinical
"Super-Refractory Status Epilepticus Progressing to Infantile Epileptic Spasms Syndrome Secondary to Very Long Chain Acyl-CoA Dehydrogenase Deficiency."
Case-report title supports seizure/status epilepticus as secondary to VLCAD deficiency.
Constitutional 2
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38015438 SUPPORT Human Clinical
"The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness."
Directly supports exercise intolerance as a principal symptom in adult VLCAD.
PMID:20301763 SUPPORT Human Clinical
"The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance."
Supports exercise intolerance in the myopathic form.
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38015438 SUPPORT Human Clinical
"The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness."
Directly supports myalgia as a principal symptom in adult FAOD including VLCAD.
PMID:20301763 SUPPORT Human Clinical
"The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance."
Supports muscle pain in the myopathic form.
🧬

Genetic Associations

1
ACADVL variants (Biallelic pathogenic variants)
Gene: ACADVL hgnc:92 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACADVL (hgnc:92). hgnc:92 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in ACADVL by molecular genetic testing."
Directly supports ACADVL biallelic pathogenic variants as causal.
CGGV:assertion_130ca053-9f40-4fd5-b89c-b9b374694fda-2018-02-20T170000.000Z SUPPORT Other
"ACADVL | HGNC:92 | very long chain acyl-CoA dehydrogenase deficiency | MONDO:0008723 | AR | Definitive"
ClinGen classifies the ACADVL-very long chain acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Medical Actions

11
Avoidance of fasting
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Frequent feeding and fasting avoidance reduce catabolic stress and are routine VLCAD management measures.
Mechanism Target:
MODULATES Tissue energy deficit in high-demand organs — Avoiding fasting reduces catabolic long-chain fatty acid mobilization and preserves glucose availability.
Show evidence (1 reference)
PMID:39203843 SUPPORT Other
"Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake."
Nutritional guidance supports fasting prevention to maintain energy supply in FAODs.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"Agents/circumstances to avoid: Fasting"
Directly supports fasting avoidance in VLCAD management.
PMID:39203843 SUPPORT Other
"Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake."
Expert nutritional review supports fasting avoidance as a primary intervention.
Medium-chain triglyceride supplementation
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
MCT supplementation provides an alternative energy substrate that bypasses the VLCAD enzyme block. In long-chain FAODs, MCT is supplemented at 10-25% of total energy, with total MCT plus LCT maintained at 20-35% of energy.
Mechanism Target:
BYPASSES ACADVL molecular function deficiency — Medium-chain triglycerides provide fatty-acid substrates that bypass the very-long-chain ACADVL enzyme block.
Show evidence (1 reference)
PMID:40149952 SUPPORT Other
"symptomatic treatment comprising dietary management and supplementation with medium-chain fatty acids to bypass the enzyme deficiency."
Review evidence directly supports medium-chain fatty acid supplementation as bypass therapy.
Show evidence (1 reference)
PMID:39203843 SUPPORT Other
"In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy"
Provides quantitative dietary guidance for MCT supplementation.
Long-chain fat restriction
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Dietary restriction of long-chain triglycerides to approximately 10% of total energy intake, while maintaining the cited essential-fatty-acid intake.
Mechanism Target:
MODULATES Long-chain lipid metabolite accumulation — Restricting long-chain triglycerides reduces substrate flux into the blocked long-chain FAO pathway.
Show evidence (1 reference)
PMID:39203843 SUPPORT Other
"In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy"
Nutritional guidance supports reducing long-chain triglyceride exposure in long-chain FAODs.
Show evidence (2 references)
PMID:39203843 SUPPORT Other
"In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1%"
Directly supports quantitative LCT restriction guidance.
PMID:38651394 SUPPORT Human Clinical
"Patients who had a high C14:1 value at diagnosis were started on a diet with a lower percentage of energy from long-chain triglycerides."
Supports clinical practice of LCT restriction guided by C14:1 levels.
Triheptanoin (UX007)
Action: nutritional supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Triheptanoin is an odd-chain triglyceride therapeutic option for long-chain FAODs. Its heptanoate substrate supports glucose production in VLCAD-deficient mice; the retained evidence does not establish a specific dose or adverse-effect-management claim.
Mechanism Target:
BYPASSES Tissue energy deficit in high-demand organs — Triheptanoin/heptanoate supplies gluconeogenic substrate and supports glucose production despite the long-chain FAO defect.
Show evidence (1 reference)
PMID:37960342 SUPPORT Model Organism
"Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect."
Mouse-model evidence supports heptanoate as substrate support for glucose production in long-chain FAO defects.
Show evidence (2 references)
PMID:37960342 SUPPORT Model Organism
"Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect."
Demonstrates heptanoate supports glucose homeostasis in VLCAD-deficient mice.
PMID:39203843 SUPPORT Other
"Trihepatnoin is a new therapeutic option with a good safety and efficacy profile."
Expert review supports triheptanoin as a therapeutic option with good profile. Note "Trihepatnoin" is a typo in the original publication (correct spelling is triheptanoin).
Emergency glucose therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Rapid carbohydrate support during illness or decompensation via intravenous glucose (at least 10% dextrose) to reverse catabolism and prevent further lipolysis.
Mechanism Target:
BYPASSES Tissue energy deficit in high-demand organs — Intravenous glucose supplies carbohydrate energy during decompensation and suppresses lipolysis-driven fatty acid demand.
Show evidence (1 reference)
PMID:39203843 SUPPORT Other
"The main measure in emergency hospital treatment is the administration of IV glucose."
Nutritional guidance supports IV glucose as emergency energy support.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"Acute inpatient treatment: Administration of high-energy fluids (≥10% IV dextrose)"
Directly supports emergency dextrose therapy during catabolic crises.
PMID:39203843 SUPPORT Other
"The main measure in emergency hospital treatment is the administration of IV glucose."
Expert review confirms IV glucose as the primary emergency measure.
Pre-exercise carbohydrate or MCT loading
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both approximately 20 minutes before exercise to provide alternative energy substrates and reduce reliance on impaired long-chain FAO.
Mechanism Target:
BYPASSES Tissue energy deficit in high-demand organs — Pre-exercise MCT or carbohydrate loading provides alternative substrate before exertion and is intended to reduce reliance on long-chain FAO.
Show evidence (1 reference)
PMID:39203843 SUPPORT Other
"Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise."
Nutritional guidance supports pre-exercise substrate loading for rhabdomyolysis prevention.
Show evidence (1 reference)
PMID:39203843 SUPPORT Other
"Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise."
Directly supports pre-exercise caloric loading as a management strategy.
Supportive care for cardiomyopathy
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Standard cardiomyopathy treatment for patients with cardiac involvement.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"standard treatment of cardiomyopathy; supportive developmental therapies as needed."
Supports organ-specific supportive management for cardiac complications.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, carrier testing, and prenatal diagnostic options.
Show evidence (2 references)
PMID:20301763 SUPPORT Human Clinical
"VLCAD deficiency is inherited in an autosomal recessive manner."
Autosomal recessive inheritance supports the role of genetic counseling.
PMID:20301763 SUPPORT Other
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation..."
Directly supports recurrence-risk counseling and family testing options.
Catabolic and anesthetic risk avoidance
Category: Counseling / Informational Action: behavioral counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is behavioral counseling (NCIT:C181743). NCIT:C181743 is a clinical intervention from the NCI Thesaurus. Ontology label: Behavioral Counseling NCIT:C181743
Counsel patients and procedural teams to avoid dehydration, myocardial irritation, high-fat diets, volatile anesthetics, and anesthetics containing high doses of long-chain fatty acids such as propofol and etomidate. The metabolic center should be involved before anesthesia or surgery.
Show evidence (2 references)
PMID:20301763 SUPPORT Other
"Agents/circumstances to avoid: Fasting; myocardial irritation; dehydration; high-fat diet; and volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate."
GeneReviews directly lists the avoidable metabolic and anesthetic risks.
PMID:20301763 SUPPORT Other
"if a surgery or procedure is required, notify designated metabolic center in advance of the procedure to discuss perioperative management with surgeons and anesthesiologists; some anesthetics may be contraindicated."
Supports advance metabolic-team coordination for procedures and anesthesia.
Acute rhabdomyolysis renal protection
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Treat acute rhabdomyolysis with ample hydration and urine alkalization to protect renal function and reduce the risk of myoglobinuric acute kidney failure.
Target Phenotypes: Rhabdomyolysis HP:0003201 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rhabdomyolysis (HP:0003201). HP:0003201 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301763 SUPPORT Other
"Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect kidney function and to prevent acute kidney failure secondary to myoglobinuria"
GeneReviews directly supports hydration and urine alkalization for renal protection during acute rhabdomyolysis.
Age-structured metabolic and cardiac surveillance
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Monitor plasma carnitine, acylcarnitines, and creatine kinase every three months in the first year, every three to six months from ages one through seven, and every six to 12 months thereafter. Obtain echocardiography at least annually or as clinically indicated and DXA every five years in adults.
Show evidence (2 references)
PMID:20301763 SUPPORT Other
"plasma carnitine panel, acylcarnitine profile, and creatine kinase level every three months for the first year of life, every three to six months for those between age one and seven years, and every six to 12 months for those older than age seven years"
GeneReviews supplies the age-specific biochemical surveillance intervals.
PMID:20301763 SUPPORT Other
"echocardiogram at least annually or as clinically indicated; DXA scan every five years in adults"
GeneReviews supplies the cardiac and adult bone-density surveillance intervals.
🔬

Biochemical Markers

7
Tetradecenoylcarnitine (C14:1) (INCREASED)
Context: C14:1 acylcarnitine is the primary diagnostic biomarker for VLCAD deficiency, detectable on newborn screening and elevated during metabolic decompensation. At newborn screening, C14:1 strongly correlates with residual enzyme activity (p=0.0003). Neonatal case values as high as 5.053 micromol/L have been reported.
Pathograph Readouts
Readout Of Impaired very-long-chain fatty acid beta-oxidation Positive Diagnostic
Elevated C14:1 acylcarnitine reports the blocked long-chain FAO step in VLCAD deficiency.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species."
Review evidence supports C14:1 elevation as the diagnostic acylcarnitine-profile signal.
Predicts ACADVL molecular function deficiency Positive Prognostic
Higher newborn-screening C14:1 predicts lower residual VLCAD enzyme activity, linking the biomarker to molecular-function deficiency.
Show evidence (1 reference)
PMID:38651394 SUPPORT Human Clinical
"However, the newborn screening C14:1 value is the most sensitive predictor of low enzyme activity and may help guide dietary management."
Patient chart-review data support C14:1 as a predictor of low VLCAD enzyme activity.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species."
Review evidence directly supports C14:1 elevation in the characteristic VLCAD acylcarnitine profile.
Long-chain acylcarnitines (C14, C16, C18 species) (INCREASED)
Context: Accumulation of a range of long-chain acylcarnitine species including C14, C14:2, C16, and C18 species reflects the impaired beta-oxidation of long-chain fatty acyl-CoA substrates. Systemic levels decrease with effective treatment.
Pathograph Readouts
Readout Of Long-chain lipid metabolite accumulation Positive Diagnostic
Elevated long-chain acylcarnitine species report accumulation of incompletely oxidized long-chain FAO intermediates.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species."
Review evidence supports long-chain acylcarnitines as the diagnostic metabolite-accumulation profile.
Long-chain carboxylic and dicarboxylic acids (INCREASED)
Context: Elevated long-chain carboxylic and dicarboxylic acids accumulate due to impaired mitochondrial oxidation and are detectable on urine organic acid analysis during episodes.
Pathograph Readouts
Readout Of Long-chain lipid metabolite accumulation Positive Diagnostic
Elevated urinary long-chain carboxylic and dicarboxylic acids report abnormal long-chain substrate handling during VLCAD decompensation.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Urine organic acids are notable for extremely reduced or absent ketones, with elevated long-chain carboxylic and dicarboxylic acids."
Review evidence directly supports dicarboxylic acid accumulation as part of the urine organic-acid profile.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Urine organic acids are notable for extremely reduced or absent ketones, with elevated long-chain carboxylic and dicarboxylic acids."
Review evidence directly supports elevated long-chain carboxylic and dicarboxylic acids in VLCAD.
Ketone bodies (DECREASED)
Context: Inappropriately low ketone body production during fasting, reflecting impaired hepatic ketogenesis from reduced acetyl-CoA generation. This hypoketotic state underlies the characteristic hypoglycemia.
Pathograph Readouts
Readout Of Impaired very-long-chain fatty acid beta-oxidation Negative Diagnostic
Inappropriately low ketone bodies report impaired hepatic ketogenesis downstream of the long-chain FAO block.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Urine organic acids are notable for extremely reduced or absent ketones, with elevated long-chain carboxylic and dicarboxylic acids."
Review evidence supports absent or markedly reduced ketones in VLCAD biochemical testing.
Readout Of Hypoketotic hypoglycemia Negative Diagnostic
Low ketone production is the biochemical readout of the hypoketotic component of VLCAD-associated hypoglycemia.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy."
GeneReviews supports hypoketotic hypoglycemia as a VLCAD clinical-biochemical presentation.
Show evidence (1 reference)
PMID:20301763 SUPPORT Human Clinical
"The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy."
Directly supports hypoketotic state from impaired ketogenesis.
Glucagon (DECREASED)
Context: Fasting glucagon concentrations are significantly lower in VLCAD patients compared to controls, suggesting impaired glucagon secretion related to FAO defects.
Pathograph Readouts
Correlates With Tissue energy deficit in high-demand organs Negative Monitoring
Lower fasting glucagon is associated with VLCAD-related FAO impairment and may reflect reduced counter-regulatory support during fasting.
Show evidence (1 reference)
PMID:37512487 SUPPORT Human Clinical
"Low fasting concentrations of glucagon are present in patients with VLCAD and cannot be explained by altered stimuli in plasma."
Patient data support low fasting glucagon as associated with VLCAD pathophysiology.
Show evidence (2 references)
PMID:37512487 SUPPORT Human Clinical
"The glucagon and insulin levels were significantly lower in the VLCAD group compared to the CUD group"
Directly supports low fasting glucagon in VLCAD.
PMID:37512487 SUPPORT Human Clinical
"Low fasting concentrations of glucagon are present in patients with VLCAD and cannot be explained by altered stimuli in plasma."
Confirms glucagon deficit is intrinsic to VLCAD pathophysiology.
Glutathione (DYSREGULATED)
Context: Glutathione levels are elevated in VLCADD newborns on metabolomics analysis, suggesting ongoing oxidative stress. Under metabolic stress conditions, VLCAD-deficient cells show increased susceptibility to GSH depletion.
Pathograph Readouts
Readout Of Oxidative stress and glutathione vulnerability Threshold Dependent Monitoring
Glutathione is best interpreted as a stress-context-dependent readout: VLCAD-deficient cells can deplete GSH under metabolic stress even when broader metabolomic profiles suggest oxidative-stress remodeling.
Show evidence (1 reference)
PMID:36356723 SUPPORT In Vitro
"metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells"
In vitro VLCAD-deficient cells directly demonstrate GSH depletion vulnerability under metabolic stress.
Show evidence (1 reference)
PMID:36356723 SUPPORT In Vitro
"metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells"
Supports glutathione dysregulation under metabolic stress in VLCAD-deficient cells.
VLCAD enzyme activity (DECREASED)
Context: Lymphocyte VLCAD enzyme activity is used for confirmatory diagnosis and phenotypic stratification. Patients with less than 10% residual activity tend to have more severe presentations.
Pathograph Readouts
Readout Of ACADVL molecular function deficiency Negative Diagnostic
Reduced measured VLCAD enzyme activity reports loss of ACADVL molecular function and helps stratify residual activity.
Show evidence (1 reference)
PMID:38651394 SUPPORT Human Clinical
"The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%."
Patient chart-review data document residual enzyme activity strata in VLCAD deficiency.
Show evidence (1 reference)
PMID:38651394 SUPPORT Human Clinical
"The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%."
Documents enzyme activity stratification and clinical correlation.
🔬

Diagnosis

3
Newborn bloodspot screening
Tandem-mass-spectrometry newborn screening uses the long-chain acylcarnitine profile, particularly C14:1, to identify infants who require confirmatory biochemical and molecular testing. A screening result alone is not diagnostic.
disease screening NCIT:C15419 NCI Thesaurus (NCIT)
Results: Abnormal long-chain acylcarnitine pattern with elevated C14:1.
Show evidence (2 references)
PMID:37367883 SUPPORT Human Clinical
"VLCADD, developed in neonates or later adults, can be diagnosed using newborn bloodspot screening (NBS) or genetic sequencing."
Supports newborn bloodspot screening as an ascertainment route.
PMID:38651394 SUPPORT Human Clinical
"the newborn screening C14:1 value is the most sensitive predictor of low enzyme activity and may help guide dietary management."
Supports C14:1 as the principal screening marker.
Biochemical and molecular confirmation
Diagnosis is established by a characteristic acylcarnitine pattern and/or biallelic pathogenic ACADVL variants. The two evidence types are complementary because biochemical profiles can vary with physiologic state.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Characteristic acylcarnitines and/or biallelic pathogenic ACADVL variants.
Show evidence (1 reference)
PMID:20301763 SUPPORT Other
"The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in ACADVL by molecular genetic testing."
Directly states the confirmatory diagnostic routes.
Specialized VLCAD enzyme testing
Cultured-fibroblast or lymphocyte biochemical testing can confirm VLCAD deficiency when only one pathogenic ACADVL variant is found but clinical and biochemical suspicion remains high.
enzyme activity assay
Results: Reduced VLCAD enzyme activity in cultured fibroblasts or lymphocytes.
Show evidence (1 reference)
PMID:20301763 SUPPORT Other
"If one ACADVL pathogenic variant is found and suspicion of VLCAD deficiency is high, specialized biochemical testing using cultured fibroblasts or lymphocytes may be needed for confirmation of the diagnosis."
Directly supports escalation to specialized cellular biochemical testing.
📈

Progression

1
Catabolic triggers increase reliance on fatty-acid oxidation. Clinical presentations range from severe early cardiac and multiorgan disease to childhood hepatic/hypoketotic episodes and later episodic myopathy. The reviewed sources separately establish the primary FAO block, abnormal metabolites, secondary OXPHOS effects, and stress-dependent cellular phenotypes; they do not establish a single evidenced causal chain from each cellular branch to every clinical manifestation.
📊

Prevalence

1
Global
Point Prevalence 1.0–2.0 per 100,000 1–9 per 100,000
A 2025 pathogenesis review reports that VLCADD affects 1 to 2 individuals per 100,000.
Show evidence (1 reference)
PMID:40149952 SUPPORT Other
"Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000."
Directly supports the structured global prevalence range.
🧫

Experimental Models

2
VLCAD-deficient patient-fibroblast oxidative-stress model PRIMARY_CELL_CULTURE
Patient fibroblasts under metabolic stress model glutathione depletion, viability loss, and rescue by medium-chain fatty acids.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Fibroblasts from individuals with VLCAD deficiency
Pathograph links
Oxidative stress and glutathione vulnerability Metabolic stress exposes the glutathione-dependent cellular vulnerability.
Show evidence (1 reference)
PMID:36356723 SUPPORT In Vitro
"metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells, which could be rescued by both heptanoate and octanoate in a dose-dependent manner."
Directly supports the stress phenotype and medium-chain-fatty-acid rescue.
Findings
Heptanoate and octanoate rescue stress-induced GSH depletion and viability loss.
"metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells, which could be rescued by both heptanoate and octanoate in a dose-dependent manner."
Show evidence (1 reference)
PMID:36356723 SUPPORT In Vitro
"metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells, which could be rescued by both heptanoate and octanoate in a dose-dependent manner."
The model contains a dose-dependent rescue experiment.
Show evidence (1 reference)
PMID:36356723 SUPPORT In Vitro
"We investigated whether medium-chain fatty acids provide protection against GSH depletion during metabolic stress in VLCAD-deficient fibroblasts."
Establishes the patient-fibroblast experimental system.
ACADVL-loss inflammatory-response model PRIMARY_CELL_CULTURE
LPS stimulation tests TLR4 signaling and cytokine induction in lcFAOD patient cells, with targeted ACADVL loss in control cells used for causal replication.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient cells and targeted ACADVL-loss healthy-control cells
Pathograph links
Attenuated TLR4 inflammatory response ACADVL loss tests whether the inflammatory-response defect is gene dependent.
Show evidence (1 reference)
PMID:39399475 SUPPORT In Vitro
"The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss-of-function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS."
Targeted loss reproduces the patient-cell response defect.
Show evidence (1 reference)
PMID:39399475 SUPPORT In Vitro
"The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6."
Defines the experimental immune-response readouts.
🐁

Animal Models

1
VLCAD-knockout mouse heptanoate-tracing model
VLCAD-deficient mice were used to trace glycerol contribution to glucose production with and without a heptanoate bolus, testing the anaplerotic basis of triheptanoin therapy.
Species
Mus musculus
Genotype
AcadvL knockout (VLCAD-/-)
Genes
ACADVL hgnc:92 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ACADVL (hgnc:92). hgnc:92 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37960342 SUPPORT Model Organism
"we injected VLCAD-deficient (VLCAD-/-) mice with 13C3-glycerol in the presence and absence of heptanoate (C7)."
Directly establishes the knockout-mouse intervention model.
{ }

Source YAML

click to show 
name: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
category: Mendelian
creation_date: '2026-02-23T23:04:38Z'
synonyms:
- VLCAD deficiency
- VLCADD
- ACADVL deficiency
- Very long-chain acyl-coenzyme A dehydrogenase deficiency
description: 'Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of mitochondrial long-chain fatty acid beta-oxidation caused by biallelic pathogenic variants in ACADVL. VLCAD catalyzes the first dehydrogenation step in the beta-oxidation spiral for long-chain acyl-CoAs (C12-C20). Deficient oxidation leads to energy failure during fasting or catabolic stress, accumulation of long-chain acylcarnitines, and impaired ketogenesis, with clinical manifestations ranging from severe neonatal cardiomyopathy and multiorgan failure to childhood hypoketotic hypoglycemia to later-onset exercise-induced rhabdomyolysis. A 2025 review estimates that VLCADD affects 1 to 2 individuals per 100,000.

  '
disease_term:
  preferred_term: very long chain acyl-CoA dehydrogenase deficiency
  term:
    id: MONDO:0008723
    label: very long chain acyl-CoA dehydrogenase deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
prevalence:
- population: Global
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 2.0
  notes: A 2025 pathogenesis review reports that VLCADD affects 1 to 2 individuals per 100,000.
  evidence:
  - reference: PMID:40149952
    reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid
      β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000.
    explanation: Directly supports the structured global prevalence range.
has_subtypes:
- name: Neonatal severe cardiac form
  description: 'Early-onset cardiomyopathy and metabolic instability presenting in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, arrhythmias, and multiorgan failure.

    '
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy
    explanation: Directly supports the early severe cardiac VLCAD subtype.
- name: Infantile or childhood hepatic-hypoketotic form
  description: 'Episodic hypoketotic hypoglycemia and liver dysfunction presenting during early childhood, typically without cardiomyopathy.

    '
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy.
    explanation: Directly supports the infantile/childhood hepatic-hypoketotic subtype.
- name: Later-onset myopathic form
  description: 'Exercise intolerance and recurrent rhabdomyolysis provoked by exercise, fasting, cold, or illness. This is the most common presentation in adults.

    '
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance.
    explanation: Directly supports the later-onset myopathic VLCAD subtype.
  - reference: PMID:38015438
    reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness.
    explanation: Adult cohort confirms myopathic presentations as the predominant adult phenotype.
pathophysiology:
- name: ACADVL molecular function deficiency
  biological_scale: MOLECULAR
  description: 'Biallelic ACADVL pathogenic variants reduce very long-chain acyl-CoA dehydrogenase catalytic activity.

    '
  genes:
  - preferred_term: ACADVL
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  molecular_functions:
  - preferred_term: very-long-chain fatty acyl-CoA dehydrogenase activity
    term:
      id: GO:0017099
      label: very-long-chain fatty acyl-CoA dehydrogenase activity
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which
      catalyzes the initial step of mitochondrial beta-oxidation of long-chain
      fatty acids with a chain length of 14 to 20
    explanation: Directly defines the deficient enzyme function and substrate range.
  downstream:
  - target: Impaired very-long-chain fatty acid beta-oxidation
    description: Reduced ACADVL activity blocks initial dehydrogenation of C12-C20 acyl-CoAs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD),
        which catalyzes the initial step of mitochondrial beta-oxidation of
        long-chain fatty acids with a chain length of 14 to 20
      explanation: The enzyme's initial beta-oxidation step directly licenses this edge.
  - target: Secondary mitochondrial dysfunction and OXPHOS impairment
    description: Loss of VLCAD-OXPHOS supercomplex interactions contributes to secondary OXPHOS dysfunction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Disrupted VLCAD-OXPHOS supercomplex protein interactions
    evidence:
    - reference: PMID:40149952
      reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        we describe what is now known about the protein-protein interactions
        between VLCAD and the OXPHOS supercomplex and how their disruption
        contributes to overall VLCADD pathogenesis.
      explanation: The review explicitly supports this interaction-mediated branch.
  - target: Oxidative stress and glutathione vulnerability
    description: VLCAD-deficient cells develop oxidative burden and glutathione depletion under metabolic stress.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36356723
      reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        metabolic stress increases the oxidative burden in VLCAD-deficient cell
        lines and can deplete the antioxidant glutathione (GSH).
      explanation: VLCAD-deficient cell data directly support the stress-dependent branch.
  - target: Attenuated TLR4 inflammatory response
    description: ACADVL loss attenuates TLR4 signaling and cytokine induction after LPS stimulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39399475
      reference_title: "Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The insufficient responses to LPS were reproduced in cells from healthy
        controls by targeted loss-of-function of either ETFDH or ACADVL,
        supporting that the deleterious ETFDH and ACADVL variants cause the
        attenuated responses to LPS.
      explanation: Targeted ACADVL loss reproduces the immune-response defect.
  - target: Cardiomyopathy
    description: VLCAD deficiency causes severe early-onset cardiac disease through unresolved intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The severe early-onset cardiac and multiorgan failure form typically
        presents in the first months of life with hypertrophic or dilated
        cardiomyopathy
      explanation: Establishes cardiomyopathy as a defining manifestation of VLCAD deficiency.
  - target: Hypoketotic hypoglycemia
    description: VLCAD deficiency causes a hepatic/hypoketotic presentation through unresolved intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The hepatic or hypoketotic hypoglycemic form typically presents during
        early childhood with hypoketotic hypoglycemia and hepatomegaly, but
        without cardiomyopathy.
      explanation: Establishes hypoketotic hypoglycemia as a defining VLCAD presentation.
  - target: Hepatomegaly
    description: Hepatomegaly belongs to the childhood hepatic VLCAD presentation through unresolved intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The hepatic or hypoketotic hypoglycemic form typically presents during
        early childhood with hypoketotic hypoglycemia and hepatomegaly, but
        without cardiomyopathy.
      explanation: Establishes hepatomegaly as part of the hepatic VLCAD presentation.
  - target: Rhabdomyolysis
    description: VLCAD deficiency causes an episodic myopathic presentation through unresolved intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The later-onset episodic myopathic form presents with intermittent
        rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or
        exercise intolerance.
      explanation: Establishes episodic rhabdomyolysis as a defining VLCAD presentation.
  - target: Exercise intolerance
    description: Exercise intolerance belongs to the later-onset myopathic VLCAD presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The later-onset episodic myopathic form presents with intermittent
        rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or
        exercise intolerance.
      explanation: Establishes exercise intolerance as part of the myopathic VLCAD presentation.
  - target: Myalgia
    description: Muscle pain belongs to the later-onset myopathic VLCAD presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The later-onset episodic myopathic form presents with intermittent
        rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or
        exercise intolerance.
      explanation: Establishes muscle pain as part of the myopathic VLCAD presentation.
- name: Impaired very-long-chain fatty acid beta-oxidation
  biological_scale: CELLULAR
  description: 'Impaired mitochondrial oxidation of long-chain fatty acyl-CoA substrates (C12-C20), especially during fasting and other catabolic states, reduces acetyl-CoA generation, limits ATP production, and impairs hepatic ketogenesis.

    '
  biological_processes:
  - preferred_term: very long-chain fatty acid metabolic process
    term:
      id: GO:0000038
      label: very long-chain fatty acid metabolic process
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  chemical_entities:
  - preferred_term: tetradecenoylcarnitine
    term:
      id: CHEBI:86066
      label: O-tetradecenoylcarnitine
    modifier: INCREASED
  - preferred_term: long-chain acylcarnitines
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
    modifier: INCREASED
  - preferred_term: ketone bodies
    term:
      id: CHEBI:73693
      label: ketone body
    modifier: DECREASED
  evidence:
  - reference: PMID:40149952
    reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are crucial metabolic processes involved in generating ATP, with defects in these pathways causing mitochondrial disease.
    explanation: Supports the central role of FAO in mitochondrial ATP generation.
  downstream:
  - target: Tissue energy deficit in high-demand organs
    description: Impaired mitochondrial FAO reduces metabolic flexibility and ATP-generating capacity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced fatty-acid-derived acetyl-CoA and reducing equivalents
    evidence:
    - reference: PMID:40149952
      reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative
        phosphorylation (OXPHOS) are crucial metabolic processes involved in
        generating ATP
      explanation: Supports the ATP-generating role lost when FAO is impaired.
  - target: Long-chain lipid metabolite accumulation
    description: The ACADVL beta-oxidation block produces abnormal long-chain acylcarnitine accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37367883
      reference_title: "A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        VLCADD is a rare inherited metabolic disorder associated with fatty acid
        β-oxidation and characterized by genetic mutations in the ACADVL gene and
        accumulations of acylcarnitines.
      explanation: Directly supports acylcarnitine accumulation in ACADVL-related VLCADD.
  - target: Ketone bodies
    description: Impaired hepatic long-chain FAO limits ketogenesis, producing the hypoketotic biochemical state.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy.
      explanation: GeneReviews supports the hypoketotic state in VLCAD deficiency.
  - target: Long-chain acylcarnitines (C14, C16, C18 species)
    description: Impaired long-chain acyl-CoA oxidation leads to abnormal long-chain acylcarnitine profiles.
    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: HUMAN_CLINICAL
      snippet: Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species.
      explanation: Review evidence supports the characteristic long-chain acylcarnitine profile in VLCAD deficiency.
- name: Tissue energy deficit in high-demand organs
  biological_scale: TISSUE
  description: 'Energy deficiency affects myocardium, skeletal muscle, and liver. Impaired FAO reduces availability of reducing equivalents and acetyl-CoA for mitochondrial ATP production and hepatic ketogenesis, forcing compensatory reliance on glucose utilization and gluconeogenesis.

    '
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
  chemical_entities:
  - preferred_term: glucagon
    term:
      id: CHEBI:5391
      label: glucagon
    modifier: DECREASED
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia.
    explanation: Supports high-energy-organ involvement including heart, liver, and systemic metabolic failure.
  - reference: PMID:37960342
    reference_title: "Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis.
    explanation: Demonstrates impaired metabolic flexibility and energy homeostasis in VLCAD deficiency.
- name: Long-chain lipid metabolite accumulation
  biological_scale: CELLULAR
  description: 'The long-chain fatty-acid oxidation block produces abnormal long-chain acylcarnitine and dicarboxylic-acid profiles. The retained sources establish this biochemical accumulation but do not isolate its contribution to individual clinical manifestations.

    '
  biological_processes:
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
  chemical_entities:
  - preferred_term: long-chain acylcarnitines
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
    modifier: INCREASED
  - preferred_term: long-chain dicarboxylic acids
    term:
      id: CHEBI:35692
      label: dicarboxylic acid
    modifier: INCREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:37367883
    reference_title: "A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VLCADD is a rare inherited metabolic disorder associated with fatty acid
      β-oxidation and characterized by genetic mutations in the ACADVL gene and
      accumulations of acylcarnitines.
    explanation: Directly supports acylcarnitine accumulation in ACADVL-related VLCADD.
- name: Secondary mitochondrial dysfunction and OXPHOS impairment
  biological_scale: CELLULAR
  description: 'VLCAD interacts physically with OXPHOS supercomplexes; VLCAD deficiency disrupts these interactions and impairs electron transport chain function, worsening bioenergetics beyond the primary FAO defect.

    '
  biological_processes:
  - preferred_term: mitochondrial electron transport, NADH to ubiquinone
    term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
  cellular_components:
  - preferred_term: mitochondrial respiratory chain complex I
    term:
      id: GO:0045271
      label: respiratory chain complex I
  evidence:
  - reference: PMID:40149952
    reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function.
    explanation: Supports secondary OXPHOS dysfunction beyond the primary FAO defect.
  - reference: PMID:40149952
    reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: we describe what is now known about the protein-protein interactions between VLCAD and the OXPHOS supercomplex and how their disruption contributes to overall VLCADD pathogenesis.
    explanation: Directly supports VLCAD-OXPHOS supercomplex interaction disruption.
- name: Oxidative stress and glutathione vulnerability
  biological_scale: CELLULAR
  description: 'VLCAD deficiency increases reactive oxygen species production and renders cells vulnerable to glutathione depletion under metabolic stress. Mitochondrial NADPH production is relevant to GSH recycling and cellular resilience.

    '
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:36356723
    reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      metabolic stress increases the oxidative burden in VLCAD-deficient cell
      lines and can deplete the antioxidant glutathione (GSH).
    explanation: Directly supports oxidative burden and GSH vulnerability in VLCAD-deficient cells.
  downstream:
  - target: Glutathione
    description: Oxidative stress in VLCAD deficiency is reflected by glutathione pathway vulnerability and altered glutathione levels.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36356723
      reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells
      explanation: In vitro evidence directly supports glutathione depletion vulnerability in VLCAD-deficient cells.
- name: Attenuated TLR4 inflammatory response
  biological_scale: CELLULAR
  description: 'VLCAD-deficient cells show impaired TLR4 signaling and reduced pro-inflammatory cytokine induction after LPS stimulation, connecting long-chain FAO to innate immune competence and helping explain why infection and inflammation trigger metabolic decompensation.

    '
  biological_processes:
  - preferred_term: toll-like receptor 4 signaling pathway
    modifier: DECREASED
    term:
      id: GO:0034142
      label: toll-like receptor 4 signaling pathway
  evidence:
  - reference: PMID:39399475
    reference_title: "Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6.
    explanation: Details specific TLR4 pathway impairment in VLCAD deficiency.
phenotypes:
- name: Hypoketotic hypoglycemia
  description: 'Hypoglycemia with inadequate ketone production during fasting or catabolic stress, particularly in the hepatic/hypoketotic presentation.

    '
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy.
    explanation: Directly supports hypoketotic hypoglycemia as a core VLCAD phenotype.
  - reference: PMID:37512487
    reference_title: "Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypoketotic hypoglycemia is a feared clinical complication and the treatment focuses on avoiding hypoglycemia.
    explanation: Confirms hypoketotic hypoglycemia as a feared complication of VLCAD.
- name: Cardiomyopathy
  description: 'Dilated or hypertrophic cardiomyopathy predominantly in severe neonatal form. May present with pericardial effusion and arrhythmias.

    '
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy
    explanation: Directly supports cardiomyopathy in severe VLCAD.
- name: Rhabdomyolysis
  description: 'Recurrent muscle breakdown, often triggered by exercise, fasting, cold, or illness. In an adult FAOD cohort, rhabdomyolysis occurred in 84% of patients, with mean CK 68,958 U/L. VLCAD subgroup had 4.9 episodes per year pre-diagnosis, declining to 2.5 per year post-diagnosis.

    '
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise
    explanation: Directly supports recurrent rhabdomyolysis in later-onset VLCAD.
  - reference: PMID:38015438
    reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L
    explanation: Quantifies rhabdomyolysis frequency and severity in adult FAOD cohort.
- name: Hepatomegaly
  description: 'Liver enlargement reported in the childhood hepatic/hypoketotic presentation.

    '
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly
    explanation: Directly supports hepatomegaly as a feature of the hepatic VLCAD subtype.
- name: Exercise intolerance
  description: 'Reduced exercise capacity and exercise-induced muscle symptoms. In adult cohorts, exercise intolerance is a principal symptom.

    '
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:38015438
    reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness.
    explanation: Directly supports exercise intolerance as a principal symptom in adult VLCAD.
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance.
    explanation: Supports exercise intolerance in the myopathic form.
- name: Myalgia
  description: 'Muscle pain occurs in the later-onset myopathic presentation.

    '
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:38015438
    reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness.
    explanation: Directly supports myalgia as a principal symptom in adult FAOD including VLCAD.
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance.
    explanation: Supports muscle pain in the myopathic form.
- name: Muscle weakness
  description: 'Permanent proximal muscle weakness may develop in some patients, sometimes associated with the myopathic form.

    '
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:38015438
    reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness.
    explanation: Supports permanent muscle weakness as a complication of the myopathic form.
- name: Cardiac arrhythmia
  description: 'Arrhythmias may occur in the severe early-onset cardiac presentation.

    '
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias
    explanation: Directly supports arrhythmias in severe neonatal VLCAD.
- name: Lethargy
  description: 'Severe lethargy was reported during metabolic decompensation after accidental long-chain fat loading.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:19333779
    reference_title: "Very long-chain acyl-CoA dehydrogenase deficiency: the effects of accidental fat loading in a patient detected through newborn screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: was admitted with emesis, severe lethargy, limpness in extremities, loss of muscle tone and an elevated CK level.
    explanation: Case evidence directly supports severe lethargy during VLCAD metabolic decompensation.
- name: Hyperammonemia
  description: 'Hyperammonemia may occur during early-childhood metabolic decompensation.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  notes: >-
    Hyperammonemia can occur during severe metabolic decompensation in FAODs, though it is less
    prominent than in urea cycle disorders. The available evidence supports occurrence but does
    not quantify hyperammonemia frequency in VLCAD.
  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: Early childhood disease may manifest with hypoketotic hypoglycemia, hyperammonemia, lactic acidosis, and elevated transaminases.
    explanation: Review evidence directly supports hyperammonemia as an early VLCAD manifestation.
- name: Lactic acidosis
  description: 'Lactic acidosis may occur during early-childhood metabolic decompensation.

    '
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  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: Early childhood disease may manifest with hypoketotic hypoglycemia, hyperammonemia, lactic acidosis, and elevated transaminases.
    explanation: Review evidence directly supports lactic acidosis in early VLCAD disease.
- name: Muscular hypotonia
  description: 'Hypotonia is reported in the severe early-onset presentation.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia.
    explanation: Directly supports hypotonia in severe neonatal VLCAD.
- name: Seizure
  description: 'Seizures, including status epilepticus or epileptic spasms, can occur as severe neurologic presentations in VLCAD deficiency.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38157116
    reference_title: "Super-Refractory Status Epilepticus Progressing to Infantile Epileptic Spasms Syndrome Secondary to Very Long Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Super-Refractory Status Epilepticus Progressing to Infantile Epileptic Spasms Syndrome Secondary to Very Long Chain Acyl-CoA Dehydrogenase Deficiency.
    explanation: Case-report title supports seizure/status epilepticus as secondary to VLCAD deficiency.
- name: Elevated creatine kinase
  description: 'Elevated serum CK during rhabdomyolysis episodes. In an adult cohort, mean CK was 68,958 U/L; pediatric cases report peaks up to 76,656 U/L.

    '
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:38015438
    reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L
    explanation: Quantifies elevated CK during rhabdomyolysis in adult FAOD cohort.
  reports_on:
  - target: Tissue energy deficit in high-demand organs
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Rhabdomyolysis from skeletal muscle energy failure raises serum creatine kinase.
    evidence:
    - reference: PMID:38015438
      reference_title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L
      explanation: Adult FAOD cohort evidence links rhabdomyolysis episodes to elevated creatine kinase.
- name: Vomiting
  description: 'Vomiting was reported during decompensation after accidental long-chain fat loading.

    '
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  notes: >-
    Vomiting is a common symptom during metabolic decompensation in FAODs, triggered by fasting
    or intercurrent illness. A VLCAD case report documents emesis during a severe decompensation
    event, but frequency is not quantified.
  evidence:
  - reference: PMID:19333779
    reference_title: "Very long-chain acyl-CoA dehydrogenase deficiency: the effects of accidental fat loading in a patient detected through newborn screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: was admitted with emesis, severe lethargy, limpness in extremities, loss of muscle tone and an elevated CK level.
    explanation: Case evidence supports emesis/vomiting during VLCAD metabolic decompensation.
biochemical:
- name: Tetradecenoylcarnitine (C14:1)
  presence: INCREASED
  context: 'C14:1 acylcarnitine is the primary diagnostic biomarker for VLCAD deficiency, detectable on newborn screening and elevated during metabolic decompensation. At newborn screening, C14:1 strongly correlates with residual enzyme activity (p=0.0003). Neonatal case values as high as 5.053 micromol/L have been reported.

    '
  biomarker_term:
    preferred_term: tetradecenoylcarnitine
    term:
      id: CHEBI:86066
      label: O-tetradecenoylcarnitine
  readouts:
  - target: Impaired very-long-chain fatty acid beta-oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated C14:1 acylcarnitine reports the blocked long-chain FAO step in
      VLCAD 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: HUMAN_CLINICAL
      snippet: Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species.
      explanation: Review evidence supports C14:1 elevation as the diagnostic acylcarnitine-profile signal.
  - target: ACADVL molecular function deficiency
    relationship: PREDICTS
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher newborn-screening C14:1 predicts lower residual VLCAD enzyme
      activity, linking the biomarker to molecular-function deficiency.
    evidence:
    - reference: PMID:38651394
      reference_title: "Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: However, the newborn screening C14:1 value is the most sensitive predictor of low enzyme activity and may help guide dietary management.
      explanation: Patient chart-review data support C14:1 as a predictor of low VLCAD enzyme activity.
  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: Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species.
    explanation: Review evidence directly supports C14:1 elevation in the characteristic VLCAD acylcarnitine profile.
- name: Long-chain acylcarnitines (C14, C16, C18 species)
  presence: INCREASED
  context: 'Accumulation of a range of long-chain acylcarnitine species including C14, C14:2, C16, and C18 species reflects the impaired beta-oxidation of long-chain fatty acyl-CoA substrates. Systemic levels decrease with effective treatment.

    '
  biomarker_term:
    preferred_term: long-chain acylcarnitines
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
  readouts:
  - target: Long-chain lipid metabolite accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated long-chain acylcarnitine species report accumulation of
      incompletely oxidized long-chain FAO 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: HUMAN_CLINICAL
      snippet: Plasma acylcarnitine profile shows characteristic elevation of C14:1, C14:2, C14, and C12:1 species.
      explanation: Review evidence supports long-chain acylcarnitines as the diagnostic metabolite-accumulation profile.
- name: Long-chain carboxylic and dicarboxylic acids
  presence: INCREASED
  context: 'Elevated long-chain carboxylic and dicarboxylic acids accumulate due to impaired mitochondrial oxidation and are detectable on urine organic acid analysis during episodes.

    '
  biomarker_term:
    preferred_term: long-chain dicarboxylic acids
    term:
      id: CHEBI:35692
      label: dicarboxylic acid
  readouts:
  - target: Long-chain lipid metabolite accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated urinary long-chain carboxylic and dicarboxylic acids report
      abnormal long-chain substrate handling during VLCAD decompensation.
    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: Urine organic acids are notable for extremely reduced or absent ketones, with elevated long-chain carboxylic and dicarboxylic acids.
      explanation: Review evidence directly supports dicarboxylic acid accumulation as part of the urine organic-acid profile.
  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: Urine organic acids are notable for extremely reduced or absent ketones, with elevated long-chain carboxylic and dicarboxylic acids.
    explanation: Review evidence directly supports elevated long-chain carboxylic and dicarboxylic acids in VLCAD.
- name: Ketone bodies
  presence: DECREASED
  context: 'Inappropriately low ketone body production during fasting, reflecting impaired hepatic ketogenesis from reduced acetyl-CoA generation. This hypoketotic state underlies the characteristic hypoglycemia.

    '
  biomarker_term:
    preferred_term: ketone bodies
    term:
      id: CHEBI:73693
      label: ketone body
  readouts:
  - target: Impaired very-long-chain fatty acid beta-oxidation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Inappropriately low ketone bodies report impaired hepatic ketogenesis
      downstream of the long-chain FAO 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: Urine organic acids are notable for extremely reduced or absent ketones, with elevated long-chain carboxylic and dicarboxylic acids.
      explanation: Review evidence supports absent or markedly reduced ketones in VLCAD biochemical testing.
  - target: Hypoketotic hypoglycemia
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low ketone production is the biochemical readout of the hypoketotic
      component of VLCAD-associated hypoglycemia.
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy.
      explanation: GeneReviews supports hypoketotic hypoglycemia as a VLCAD clinical-biochemical presentation.
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy.
    explanation: Directly supports hypoketotic state from impaired ketogenesis.
- name: Glucagon
  presence: DECREASED
  context: 'Fasting glucagon concentrations are significantly lower in VLCAD patients compared to controls, suggesting impaired glucagon secretion related to FAO defects.

    '
  biomarker_term:
    preferred_term: glucagon
    term:
      id: CHEBI:5391
      label: glucagon
  readouts:
  - target: Tissue energy deficit in high-demand organs
    relationship: CORRELATES_WITH
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: >-
      Lower fasting glucagon is associated with VLCAD-related FAO impairment
      and may reflect reduced counter-regulatory support during fasting.
    evidence:
    - reference: PMID:37512487
      reference_title: "Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Low fasting concentrations of glucagon are present in patients with VLCAD and cannot be explained by altered stimuli in plasma.
      explanation: Patient data support low fasting glucagon as associated with VLCAD pathophysiology.
  evidence:
  - reference: PMID:37512487
    reference_title: "Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The glucagon and insulin levels were significantly lower in the VLCAD group compared to the CUD group
    explanation: Directly supports low fasting glucagon in VLCAD.
  - reference: PMID:37512487
    reference_title: "Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Low fasting concentrations of glucagon are present in patients with VLCAD and cannot be explained by altered stimuli in plasma.
    explanation: Confirms glucagon deficit is intrinsic to VLCAD pathophysiology.
- name: Glutathione
  presence: DYSREGULATED
  notes: 'Elevated glutathione detected in newborn DBS metabolomics is interpreted as an oxidative stress response. In vitro, VLCAD-deficient cells show vulnerability to GSH depletion under metabolic stress.

    '
  context: 'Glutathione levels are elevated in VLCADD newborns on metabolomics analysis, suggesting ongoing oxidative stress. Under metabolic stress conditions, VLCAD-deficient cells show increased susceptibility to GSH depletion.

    '
  biomarker_term:
    preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  readouts:
  - target: Oxidative stress and glutathione vulnerability
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: MONITORING
    interpretation: >-
      Glutathione is best interpreted as a stress-context-dependent readout:
      VLCAD-deficient cells can deplete GSH under metabolic stress even when
      broader metabolomic profiles suggest oxidative-stress remodeling.
    evidence:
    - reference: PMID:36356723
      reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells
      explanation: In vitro VLCAD-deficient cells directly demonstrate GSH depletion vulnerability under metabolic stress.
  evidence:
  - reference: PMID:36356723
    reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells
    explanation: Supports glutathione dysregulation under metabolic stress in VLCAD-deficient cells.
- name: VLCAD enzyme activity
  presence: DECREASED
  context: 'Lymphocyte VLCAD enzyme activity is used for confirmatory diagnosis and phenotypic stratification. Patients with less than 10% residual activity tend to have more severe presentations.

    '
  biomarker_term:
    preferred_term: VLCAD enzyme activity
    term:
      id: NCIT:C190531
      label: Very Long-Chain Specific Acyl-CoA Dehydrogenase, Mitochondrial
  readouts:
  - target: ACADVL molecular function deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reduced measured VLCAD enzyme activity reports loss of ACADVL molecular
      function and helps stratify residual activity.
    evidence:
    - reference: PMID:38651394
      reference_title: "Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%.
      explanation: Patient chart-review data document residual enzyme activity strata in VLCAD deficiency.
  evidence:
  - reference: PMID:38651394
    reference_title: "Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%.
    explanation: Documents enzyme activity stratification and clinical correlation.
genetic:
- name: ACADVL variants
  association: Biallelic pathogenic variants
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: ACADVL
    term:
      id: hgnc:92
      label: ACADVL
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20301763
      reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: VLCAD deficiency is inherited in an autosomal recessive manner.
      explanation: Directly supports autosomal recessive inheritance.
  features: 'Biallelic pathogenic variants in ACADVL cause a phenotypic spectrum ranging from neonatal cardiac disease to later-onset myopathic presentations. Residual enzyme activity correlates with clinical severity. C14:1 acylcarnitine at newborn screening is the most sensitive predictor of low enzyme activity.

    '
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in ACADVL by molecular genetic testing.
    explanation: Directly supports ACADVL biallelic pathogenic variants as causal.
  - reference: CGGV:assertion_130ca053-9f40-4fd5-b89c-b9b374694fda-2018-02-20T170000.000Z
    reference_title: "ACADVL / very long chain acyl-CoA dehydrogenase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACADVL | HGNC:92 | very long chain acyl-CoA dehydrogenase deficiency | MONDO:0008723 | AR | Definitive"
    explanation: ClinGen classifies the ACADVL-very long chain acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
diagnosis:
- name: Newborn bloodspot screening
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  description: >-
    Tandem-mass-spectrometry newborn screening uses the long-chain
    acylcarnitine profile, particularly C14:1, to identify infants who require
    confirmatory biochemical and molecular testing. A screening result alone is
    not diagnostic.
  results: Abnormal long-chain acylcarnitine pattern with elevated C14:1.
  evidence:
  - reference: PMID:37367883
    reference_title: "A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VLCADD, developed in neonates or later adults, can be diagnosed using
      newborn bloodspot screening (NBS) or genetic sequencing.
    explanation: Supports newborn bloodspot screening as an ascertainment route.
  - reference: PMID:38651394
    reference_title: "Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the newborn screening C14:1 value is the most sensitive predictor of low
      enzyme activity and may help guide dietary management.
    explanation: Supports C14:1 as the principal screening marker.
- name: Biochemical and molecular confirmation
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis is established by a characteristic acylcarnitine pattern and/or
    biallelic pathogenic ACADVL variants. The two evidence types are
    complementary because biochemical profiles can vary with physiologic state.
  results: Characteristic acylcarnitines and/or biallelic pathogenic ACADVL variants.
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of VLCAD deficiency is established in a proband with a
      specific pattern of abnormal acylcarnitine levels on biochemical testing
      and/or by identification of biallelic pathogenic variants in ACADVL by
      molecular genetic testing.
    explanation: Directly states the confirmatory diagnostic routes.
- name: Specialized VLCAD enzyme testing
  diagnosis_term:
    preferred_term: enzyme activity assay
  description: >-
    Cultured-fibroblast or lymphocyte biochemical testing can confirm VLCAD
    deficiency when only one pathogenic ACADVL variant is found but clinical and
    biochemical suspicion remains high.
  results: Reduced VLCAD enzyme activity in cultured fibroblasts or lymphocytes.
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If one ACADVL pathogenic variant is found and suspicion of VLCAD
      deficiency is high, specialized biochemical testing using cultured
      fibroblasts or lymphocytes may be needed for confirmation of the diagnosis.
    explanation: Directly supports escalation to specialized cellular biochemical testing.
experimental_models:
- name: VLCAD-deficient patient-fibroblast oxidative-stress model
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Fibroblasts from individuals with VLCAD deficiency
  description: >-
    Patient fibroblasts under metabolic stress model glutathione depletion,
    viability loss, and rescue by medium-chain fatty acids.
  modeled_mechanisms:
  - target: Oxidative stress and glutathione vulnerability
    description: Metabolic stress exposes the glutathione-dependent cellular vulnerability.
    evidence:
    - reference: PMID:36356723
      reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        metabolic stress led to GSH depletion and decreased viability in VLCAD
        deficient cells, which could be rescued by both heptanoate and octanoate
        in a dose-dependent manner.
      explanation: Directly supports the stress phenotype and medium-chain-fatty-acid rescue.
  findings:
  - statement: Heptanoate and octanoate rescue stress-induced GSH depletion and viability loss.
    supporting_text: >-
      metabolic stress led to GSH depletion and decreased viability in VLCAD
      deficient cells, which could be rescued by both heptanoate and octanoate
      in a dose-dependent manner.
    evidence:
    - reference: PMID:36356723
      reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        metabolic stress led to GSH depletion and decreased viability in VLCAD
        deficient cells, which could be rescued by both heptanoate and octanoate
        in a dose-dependent manner.
      explanation: The model contains a dose-dependent rescue experiment.
  evidence:
  - reference: PMID:36356723
    reference_title: "Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We investigated whether medium-chain fatty acids provide protection against
      GSH depletion during metabolic stress in VLCAD-deficient fibroblasts.
    explanation: Establishes the patient-fibroblast experimental system.
- name: ACADVL-loss inflammatory-response model
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient cells and targeted ACADVL-loss healthy-control cells
  description: >-
    LPS stimulation tests TLR4 signaling and cytokine induction in lcFAOD patient
    cells, with targeted ACADVL loss in control cells used for causal replication.
  modeled_mechanisms:
  - target: Attenuated TLR4 inflammatory response
    description: ACADVL loss tests whether the inflammatory-response defect is gene dependent.
    evidence:
    - reference: PMID:39399475
      reference_title: "Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The insufficient responses to LPS were reproduced in cells from healthy
        controls by targeted loss-of-function of either ETFDH or ACADVL,
        supporting that the deleterious ETFDH and ACADVL variants cause the
        attenuated responses to LPS.
      explanation: Targeted loss reproduces the patient-cell response defect.
  evidence:
  - reference: PMID:39399475
    reference_title: "Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The insufficiencies included reduced TLR4 expression levels, impaired TLR4
      signaling, and reduced or absent induction of pro-inflammatory cytokines
      such as IL-6.
    explanation: Defines the experimental immune-response readouts.
animal_models:
- name: VLCAD-knockout mouse heptanoate-tracing model
  species: Mus musculus
  genotype: AcadvL knockout (VLCAD-/-)
  description: >-
    VLCAD-deficient mice were used to trace glycerol contribution to glucose
    production with and without a heptanoate bolus, testing the anaplerotic basis
    of triheptanoin therapy.
  genes:
  - preferred_term: ACADVL
    term:
      id: hgnc:92
      label: ACADVL
  evidence:
  - reference: PMID:37960342
    reference_title: "Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we injected VLCAD-deficient (VLCAD-/-) mice with 13C3-glycerol in the
      presence and absence of heptanoate (C7).
    explanation: Directly establishes the knockout-mouse intervention model.
treatments:
- name: Avoidance of fasting
  description: 'Frequent feeding and fasting avoidance reduce catabolic stress and are routine VLCAD management measures.

    '
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Tissue energy deficit in high-demand organs
    treatment_effect: MODULATES
    description: Avoiding fasting reduces catabolic long-chain fatty acid mobilization and preserves glucose availability.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake.
      explanation: Nutritional guidance supports fasting prevention to maintain energy supply in FAODs.
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Agents/circumstances to avoid: Fasting'
    explanation: Directly supports fasting avoidance in VLCAD management.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake.
    explanation: Expert nutritional review supports fasting avoidance as a primary intervention.
- name: Medium-chain triglyceride supplementation
  description: 'MCT supplementation provides an alternative energy substrate that bypasses the VLCAD enzyme block. In long-chain FAODs, MCT is supplemented at 10-25% of total energy, with total MCT plus LCT maintained at 20-35% of energy.

    '
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: ACADVL molecular function deficiency
    treatment_effect: BYPASSES
    description: Medium-chain triglycerides provide fatty-acid substrates that bypass the very-long-chain ACADVL enzyme block.
    evidence:
    - reference: PMID:40149952
      reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: symptomatic treatment comprising dietary management and supplementation with medium-chain fatty acids to bypass the enzyme deficiency.
      explanation: Review evidence directly supports medium-chain fatty acid supplementation as bypass therapy.
  evidence:
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy
    explanation: Provides quantitative dietary guidance for MCT supplementation.
- name: Long-chain fat restriction
  description: 'Dietary restriction of long-chain triglycerides to approximately 10% of total energy intake, while maintaining the cited essential-fatty-acid intake.

    '
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Long-chain lipid metabolite accumulation
    treatment_effect: MODULATES
    description: Restricting long-chain triglycerides reduces substrate flux into the blocked long-chain FAO pathway.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy
      explanation: Nutritional guidance supports reducing long-chain triglyceride exposure in long-chain FAODs.
  evidence:
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1%
    explanation: Directly supports quantitative LCT restriction guidance.
  - reference: PMID:38651394
    reference_title: "Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients who had a high C14:1 value at diagnosis were started on a diet with a lower percentage of energy from long-chain triglycerides.
    explanation: Supports clinical practice of LCT restriction guided by C14:1 levels.
- name: Triheptanoin (UX007)
  description: 'Triheptanoin is an odd-chain triglyceride therapeutic option for long-chain FAODs. Its heptanoate substrate supports glucose production in VLCAD-deficient mice; the retained evidence does not establish a specific dose or adverse-effect-management claim.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Tissue energy deficit in high-demand organs
    treatment_effect: BYPASSES
    description: Triheptanoin/heptanoate supplies gluconeogenic substrate and supports glucose production despite the long-chain FAO defect.
    evidence:
    - reference: PMID:37960342
      reference_title: "Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.
      explanation: Mouse-model evidence supports heptanoate as substrate support for glucose production in long-chain FAO defects.
  evidence:
  - reference: PMID:37960342
    reference_title: "Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.
    explanation: Demonstrates heptanoate supports glucose homeostasis in VLCAD-deficient mice.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Trihepatnoin is a new therapeutic option with a good safety and efficacy profile.
    explanation: Expert review supports triheptanoin as a therapeutic option with good profile. Note "Trihepatnoin" is a typo in the original publication (correct spelling is triheptanoin).
- name: Emergency glucose therapy
  description: 'Rapid carbohydrate support during illness or decompensation via intravenous glucose (at least 10% dextrose) to reverse catabolism and prevent further lipolysis.

    '
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Tissue energy deficit in high-demand organs
    treatment_effect: BYPASSES
    description: Intravenous glucose supplies carbohydrate energy during decompensation and suppresses lipolysis-driven fatty acid demand.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The main measure in emergency hospital treatment is the administration of IV glucose.
      explanation: Nutritional guidance supports IV glucose as emergency energy support.
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Acute inpatient treatment: Administration of high-energy fluids (≥10% IV dextrose)'
    explanation: Directly supports emergency dextrose therapy during catabolic crises.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The main measure in emergency hospital treatment is the administration of IV glucose.
    explanation: Expert review confirms IV glucose as the primary emergency measure.
- name: Pre-exercise carbohydrate or MCT loading
  description: 'Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both approximately 20 minutes before exercise to provide alternative energy substrates and reduce reliance on impaired long-chain FAO.

    '
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Tissue energy deficit in high-demand organs
    treatment_effect: BYPASSES
    description: Pre-exercise MCT or carbohydrate loading provides alternative substrate before exertion and is intended to reduce reliance on long-chain FAO.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise.
      explanation: Nutritional guidance supports pre-exercise substrate loading for rhabdomyolysis prevention.
  evidence:
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise.
    explanation: Directly supports pre-exercise caloric loading as a management strategy.
- name: Supportive care for cardiomyopathy
  description: 'Standard cardiomyopathy treatment for patients with cardiac involvement.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: standard treatment of cardiomyopathy; supportive developmental therapies as needed.
    explanation: Supports organ-specific supportive management for cardiac complications.
- name: Genetic counseling
  description: 'Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, carrier testing, and prenatal diagnostic options.

    '
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: VLCAD deficiency is inherited in an autosomal recessive manner.
    explanation: Autosomal recessive inheritance supports the role of genetic counseling.
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      each sib of an affected individual has at conception a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance
      of inheriting neither of the familial pathogenic variants. Molecular
      genetic carrier testing for at-risk relatives and prenatal and
      preimplantation genetic testing are possible if the pathogenic variants in
      the family are known.
    explanation: Directly supports recurrence-risk counseling and family testing options.
- name: Catabolic and anesthetic risk avoidance
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counsel patients and procedural teams to avoid dehydration, myocardial
    irritation, high-fat diets, volatile anesthetics, and anesthetics containing
    high doses of long-chain fatty acids such as propofol and etomidate. The
    metabolic center should be involved before anesthesia or surgery.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Agents/circumstances to avoid: Fasting; myocardial irritation; dehydration;
      high-fat diet; and volatile anesthetics and anesthetics that contain high
      doses of long-chain fatty acids such as propofol and etomidate.
    explanation: >-
      GeneReviews directly lists the avoidable metabolic and anesthetic risks.
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      if a surgery or procedure is required, notify designated metabolic center
      in advance of the procedure to discuss perioperative management with
      surgeons and anesthesiologists; some anesthetics may be contraindicated.
    explanation: >-
      Supports advance metabolic-team coordination for procedures and anesthesia.
- name: Acute rhabdomyolysis renal protection
  action_category: THERAPEUTIC
  description: >-
    Treat acute rhabdomyolysis with ample hydration and urine alkalization to
    protect renal function and reduce the risk of myoglobinuric acute kidney
    failure.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute rhabdomyolysis is treated with ample hydration and alkalization of
      the urine to protect kidney function and to prevent acute kidney failure
      secondary to myoglobinuria
    explanation: >-
      GeneReviews directly supports hydration and urine alkalization for renal
      protection during acute rhabdomyolysis.
- name: Age-structured metabolic and cardiac surveillance
  action_category: MONITORING
  description: >-
    Monitor plasma carnitine, acylcarnitines, and creatine kinase every three
    months in the first year, every three to six months from ages one through
    seven, and every six to 12 months thereafter. Obtain echocardiography at
    least annually or as clinically indicated and DXA every five years in adults.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      plasma carnitine panel, acylcarnitine profile, and creatine kinase level
      every three months for the first year of life, every three to six months
      for those between age one and seven years, and every six to 12 months for
      those older than age seven years
    explanation: >-
      GeneReviews supplies the age-specific biochemical surveillance intervals.
  - reference: PMID:20301763
    reference_title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      echocardiogram at least annually or as clinically indicated; DXA scan every
      five years in adults
    explanation: >-
      GeneReviews supplies the cardiac and adult bone-density surveillance
      intervals.
progression:
- notes: 'Catabolic triggers increase reliance on fatty-acid oxidation. Clinical presentations range from severe early cardiac and multiorgan disease to childhood hepatic/hypoketotic episodes and later episodic myopathy. The reviewed sources separately establish the primary FAO block, abnormal metabolites, secondary OXPHOS effects, and stress-dependent cellular phenotypes; they do not establish a single evidenced causal chain from each cellular branch to every clinical manifestation.'
notes: 'Genotype-phenotype prediction in VLCAD deficiency is imperfect. Functional testing (residual enzyme activity) and the C14:1 newborn-screening value can aid stratification and initial management. With expanded newborn screening, milder phenotypes are increasingly detected, so biochemical and molecular confirmation remains important.

  '
discussions:
- discussion_id: gap_vlcad_cellular_branches_to_clinical_subtypes
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    How much do secondary OXPHOS dysfunction, oxidative stress, abnormal lipid
    handling, and attenuated TLR4 responses contribute to the cardiac, hepatic,
    and myopathic VLCAD presentations in humans?
  attaches_to:
  - pathophysiology#Secondary mitochondrial dysfunction and OXPHOS impairment
  - pathophysiology#Oxidative stress and glutathione vulnerability
  - pathophysiology#Long-chain lipid metabolite accumulation
  - pathophysiology#Attenuated TLR4 inflammatory response
  rationale: >-
    The primary ACADVL/FAO defect and three clinical presentations are
    established, but the secondary branches are supported by reviews, patient
    fibroblasts, targeted cell perturbation, metabolomics, and mouse work rather
    than direct causal tests in affected human heart, liver, or skeletal muscle.
  proposed_experiments:
  - experiment_id: exp_vlcad_isogenic_multilineage_rescue
    name: Isogenic ACADVL rescue across cardiac, hepatic, and skeletal-muscle models
    description: >-
      Compare patient-derived and corrected iPSC cardiomyocytes, hepatocytes,
      and myotubes under matched catabolic stress, measuring FAO flux, OXPHOS,
      lipid species, glutathione, cytokine responses, and cell injury.
  - experiment_id: exp_vlcad_branch_specific_perturbation
    name: Branch-specific rescue of VLCAD cellular phenotypes
    description: >-
      Rescue lipid balance, redox capacity, or OXPHOS independently to determine
      which interventions prevent lineage-specific injury without restoring
      ACADVL itself.
  evidence:
  - reference: PMID:40149952
    reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      there is growing evidence that other aspects of mitochondrial function are
      also affected in VLCADD, including secondary defects in OXPHOS function.
    explanation: Frames the secondary mitochondrial branch as growing rather than definitive evidence.
review_notes: >-
  The 2026 review removed disease-wide phenotype frequency bands that were
  inferred from subtype prose, an adult FAOD cohort, or single cases rather than
  measured for VLCAD deficiency as a whole. The causal graph now contains only
  evidence-backed edges: the ACADVL enzyme defect connects to the primary FAO
  block, secondary OXPHOS, oxidative-stress, and immunometabolic findings, while
  six defining clinical manifestations connect through explicitly unknown
  intermediates. Rare or case-level phenotypes remain observational rather than
  being forced downstream of a generic energy-deficit node. Pure diagnostic
  readouts remain in the biochemical `readouts` structure instead of duplicate
  causal arrows. Newborn screening was moved from treatments into a three-step
  diagnosis section; the unsupported “more than 400 variants” and mRNA-therapy
  claims were removed; prevalence was replaced with an evidence-backed 1–2 per
  100,000 range; and triheptanoin wording was narrowed to the retained human
  review and knockout-mouse evidence. Patient-fibroblast, targeted ACADVL-loss,
  and VLCAD-knockout mouse models are now structured explicitly. No new
  reference cache was created or edited.
  No differential diagnosis or disease-specific dataset was added because the
  retained cached sources do not provide a precise, directly quotable basis for
  either section.
references:
- reference: PMID:20301763
  title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
  tags:
  - GeneReviews
  findings: []
- reference: CGGV:assertion_130ca053-9f40-4fd5-b89c-b9b374694fda-2018-02-20T170000.000Z
  title: ACADVL / very long chain acyl-CoA dehydrogenase deficiency (Definitive)
- reference: PMID:19333779
  title: "Very long-chain acyl-CoA dehydrogenase deficiency: the effects of accidental fat loading in a patient detected through newborn screening."
- reference: PMID:29502916
  title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
- reference: PMID:36356723
  title: Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency.
- reference: PMID:37367883
  title: A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns.
- reference: PMID:37512487
  title: Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
- reference: PMID:37960342
  title: Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect.
- reference: PMID:38015438
  title: "Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available."
- reference: PMID:38157116
  title: Super-Refractory Status Epilepticus Progressing to Infantile Epileptic Spasms Syndrome Secondary to Very Long Chain Acyl-CoA Dehydrogenase Deficiency.
- reference: PMID:38651394
  title: "Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review."
- reference: PMID:39203843
  title: Nutritional Management of Patients with Fatty Acid Oxidation Disorders.
- reference: PMID:39399475
  title: Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS.
- reference: PMID:40149952
  title: The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
📚

References & Deep Research

References

14
PMID:20301763
Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency.
No top-level findings curated for this source.
CGGV:assertion_130ca053-9f40-4fd5-b89c-b9b374694fda-2018-02-20T170000.000Z
ACADVL / very long chain acyl-CoA dehydrogenase deficiency (Definitive)
No top-level findings curated for this source.
PMID:19333779
Very long-chain acyl-CoA dehydrogenase deficiency: the effects of accidental fat loading in a patient detected through newborn screening.
No top-level findings curated for this source.
PMID:29502916
Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System.
No top-level findings curated for this source.
PMID:36356723
Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency.
No top-level findings curated for this source.
PMID:37367883
A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns.
No top-level findings curated for this source.
PMID:37512487
Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
No top-level findings curated for this source.
PMID:37960342
Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect.
No top-level findings curated for this source.
PMID:38015438
Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available.
No top-level findings curated for this source.
PMID:38157116
Super-Refractory Status Epilepticus Progressing to Infantile Epileptic Spasms Syndrome Secondary to Very Long Chain Acyl-CoA Dehydrogenase Deficiency.
No top-level findings curated for this source.
PMID:38651394
Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review.
No top-level findings curated for this source.
PMID:39203843
Nutritional Management of Patients with Fatty Acid Oxidation Disorders.
No top-level findings curated for this source.
PMID:39399475
Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS.
No top-level findings curated for this source.
PMID:40149952
The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 37 citations 2026-02-23T23:29:28.653480

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: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Very Long-Chain Acyl-CoA Dehydrogenase 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 Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD)

Publication window emphasized: 2023–2024, with mechanistic primary studies and authoritative reviews.

  1. Disease definition, identifiers, and current understanding

Disease and identifiers VLCAD deficiency (VLCADD) is an autosomal recessive inborn error of mitochondrial long-chain fatty-acid β-oxidation (LC-FAO) caused by pathogenic variants in ACADVL (HGNC:92), encoding very long-chain acyl-CoA dehydrogenase (VLCAD). It is characterized biochemically by accumulation of long-chain acylcarnitines (classically C14:1 and related ratios) and clinically by energy failure and lipotoxicity in high-energy-demand organs (heart, skeletal muscle, liver), particularly during catabolic stress. (sebaa2023adistinctivemetabolomics pages 1-2, bandari2024managementandoutcomes pages 1-2)

MONDO ID OpenTargets lists “very long chain acyl-CoA dehydrogenase deficiency” as MONDO:0008723. (bandari2024managementandoutcomes pages 1-2)

Canonical biochemical defect VLCAD catalyzes the first dehydrogenation step in the β-oxidation spiral for long-chain acyl-CoAs (reported as chain length 12–20 carbons in a 2023 metabolomics paper, and broader long-chain ranges in other sources). Impaired VLCAD function reduces LC-FAO flux, decreases acetyl-CoA generation (thereby limiting ketogenesis), and promotes accumulation of long-chain acylcarnitines, fatty acids, and related lipid intermediates that can be toxic and arrhythmogenic. (sebaa2023adistinctivemetabolomics pages 1-2, nurjanah2023modificationofdietary pages 14-17)

Epidemiology (recently reported ranges) A 2024 clinical cohort review reports prevalence ~1:30,000–1:100,000 births. (bandari2024managementandoutcomes pages 1-2) A 2024 immunometabolism study reports worldwide prevalence 1:31,500–1:94,569. (mosegaard2024humaninbornerrors pages 1-2) A 2024 genetics paper reports region-specific prevalence ranges and cites China incidence estimates (e.g., 1/236,655–1/70,424) and broader Europe/America vs Asia differences. (li2024fournovelvariants pages 1-2)

  1. Core pathophysiology (molecular/cellular mechanisms)

2.1 Energy failure and impaired metabolic flexibility Loss of LC-FAO reduces availability of reducing equivalents and acetyl-CoA for mitochondrial ATP production and hepatic ketogenesis, forcing compensatory reliance on glucose utilization and gluconeogenesis. In long-chain FAO defects, liver FAO normally supports gluconeogenesis and ureagenesis; when FAO is impaired, hypoketotic hypoglycemia and hyperammonemia can occur in decompensation. (penaquintana2024nutritionalmanagementof pages 1-3, nurjanah2023modificationofdietary pages 14-17)

2.2 Lipotoxic metabolite accumulation and mitochondrial dysfunction Accumulating long-chain acylcarnitines (e.g., C14:1 and longer C14–C18 species) are central biochemical hallmarks and may contribute directly to pathology. A 2023 metabolomics study explicitly links acylcarnitine accumulation to increased cellular permeability, inflammation, reduced insulin-stimulated glucose uptake via Ca2+-mediated pathways, lipid toxicity, cellular stress, and cell death—providing a mechanistic bridge from biochemistry to organ dysfunction. (sebaa2023adistinctivemetabolomics pages 1-2)

A 2023 mRNA-therapy study discusses additional mitochondrial toxicity hypotheses: saturated/unsaturated dicarboxylic acids and long-chain fatty acids (e.g., cis-5-tetradecenoic, myristic acids) may act as metabolic inhibitors, uncouplers, or modulators of mitochondrial permeability transition, and VLCAD deficiency is associated with reduced electron transport chain (ETC) supercomplexes and disruption of an FAO–ETC macromolecular complex. (zhao2023syntheticmrnarescues pages 6-8)

2.3 Oxidative stress and glutathione vulnerability Oxidative stress is increasingly highlighted as a component of VLCAD pathophysiology. A 2023 study focusing on VLCAD patient fibroblasts describes secondary mitochondrial defects including increased reactive oxygen species (ROS) and vulnerability of the glutathione (GSH) antioxidant system; it frames mitochondrial NADPH production (e.g., via isocitrate dehydrogenase 2, IDH2) as relevant to GSH recycling and cellular resilience under metabolic stress. (lund2023oddandevennumbered pages 1-3)

Consistent with oxidative stress in vivo, an untargeted dried-blood-spot metabolomics study reports elevated glutathione in VLCADD newborns, interpreted as suggesting oxidative stress events resulting from the disease pathology. (sebaa2023adistinctivemetabolomics pages 8-10)

2.4 Immunometabolic dysregulation (2024 advance) A 2024 FASEB BioAdvances study provides human genetic evidence that LC-FAO genes are required for adequate innate immune responses: patient fibroblasts with deleterious ACADVL variants show “reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6” after LPS stimulation. This ties VLCADD to impaired inflammatory signaling and helps explain why infection/inflammation is a common trigger of metabolic decompensation. (mosegaard2024humaninbornerrors pages 1-2, mosegaard2024humaninbornerrors pages 2-4)

  1. Key molecular players (genes/proteins), metabolites, cells, and anatomy

3.1 Genes/proteins Causal gene: • ACADVL (VLCAD). (bandari2024managementandoutcomes pages 1-2, sebaa2023adistinctivemetabolomics pages 1-2)

Mechanistically implicated (from 2023–2024 mechanistic sources in context): • Carnitine shuttle / fatty acid import machinery (CPT1/CPT2/CACT as a system-level requirement for long-chain FAO). (penaquintana2024nutritionalmanagementof pages 1-3, nurjanah2023modificationofdietary pages 14-17) • ETFDH (electron transfer flavoprotein dehydrogenase) and ETF/ETF-QO (used as comparative lcFAOD evidence in immune study). (mosegaard2024humaninbornerrors pages 1-2) • TLR4 signaling axis (immune trigger response). (mosegaard2024humaninbornerrors pages 1-2, mosegaard2024humaninbornerrors pages 2-4) • TCA cycle enzymes/metabolites relevant to immunometabolism: SDH, succinate, itaconate, HIF1α. (mosegaard2024humaninbornerrors pages 1-2) • ETC supercomplexes and adenine nucleotide translocator (mitochondrial inner membrane bioenergetics). (zhao2023syntheticmrnarescues pages 6-8) • Antioxidant/redox support: glutathione, NADPH, and mitochondrial matrix NADPH sources (e.g., IDH2 discussed in oxidative-stress study). (lund2023oddandevennumbered pages 1-3)

3.2 Chemical entities (metabolites, nutritional therapeutics) Key diagnostic/pathogenic lipid intermediates: • Tetradecenoylcarnitine (C14:1 acylcarnitine) and related long-chain acylcarnitines (C14, C14:2; C16, C18 species). (sebaa2023adistinctivemetabolomics pages 1-2, zhao2023syntheticmrnarescues pages 6-8) • Long-chain fatty acids; saturated/unsaturated dicarboxylic acids (proposed toxic intermediates). (zhao2023syntheticmrnarescues pages 6-8)

Oxidative stress / immunometabolism: • Glutathione (elevated in newborn DBS metabolomics; mechanistically central in fibroblast stress model). (sebaa2023adistinctivemetabolomics pages 8-10, lund2023oddandevennumbered pages 1-3) • Succinate (immunometabolic signaling after LPS). (mosegaard2024humaninbornerrors pages 1-2)

Therapeutic nutritional substrates: • Medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) as modulated dietary inputs. (bandari2024managementandoutcomes pages 1-2) • Triheptanoin (heptanoate triglyceride; “UX007”; “C7 oil”), providing propionyl-CoA for anaplerosis and supporting gluconeogenesis. (nurjanah2023heptanoateimprovescompensatory pages 1-2, NCT01886378 chunk 1)

3.3 Cell types (CL-oriented) Evidence directly includes: • Dermal fibroblasts (patient-derived mechanistic and immune-response assays). (mosegaard2024humaninbornerrors pages 2-4, zhao2023syntheticmrnarescues pages 6-8)

Pathophysiology and clinical manifestations implicate (organ-demand driven): • Hepatocytes/liver metabolic cells (gluconeogenesis/ketogenesis; mRNA therapy hepatic targeting). (nurjanah2023heptanoateimprovescompensatory pages 1-2, zhao2023syntheticmrnarescues pages 6-8) • Cardiomyocytes and skeletal myocytes (myopathy, cardiomyopathy, rhabdomyolysis). (bandari2024managementandoutcomes pages 1-2, mosegaard2024humaninbornerrors pages 1-2)

3.4 Anatomical locations (UBERON-oriented) Primary affected tissues: • Heart (cardiomyopathy/arrhythmia). (bandari2024managementandoutcomes pages 1-2, liu2024casereporton pages 2-3) • Skeletal muscle (exercise intolerance, rhabdomyolysis). (mosegaard2024humaninbornerrors pages 1-2, rouyer2024long‐termprognosisof pages 7-9) • Liver (hypoketotic hypoglycemia, hyperammonemia; supports gluconeogenesis). (penaquintana2024nutritionalmanagementof pages 1-3, liu2024casereporton pages 2-3)

  1. Biological processes and cellular components (GO-ready)

4.1 Disrupted biological processes (GO: Biological Process) Core: • Mitochondrial long-chain fatty acid β-oxidation / fatty acid oxidation. (bandari2024managementandoutcomes pages 1-2, nurjanah2023modificationofdietary pages 14-17) • Ketone body metabolic process (impaired ketogenesis; contributing to hypoketotic hypoglycemia). (nurjanah2023modificationofdietary pages 14-17) • Oxidative phosphorylation / mitochondrial respiration / ATP production. (zhao2023syntheticmrnarescues pages 6-8)

Secondary/associated: • Response to oxidative stress; glutathione metabolic process; ROS handling. (lund2023oddandevennumbered pages 1-3, sebaa2023adistinctivemetabolomics pages 8-10) • Tricarboxylic acid cycle (anaplerosis and immune-metabolic coupling). (mosegaard2024humaninbornerrors pages 1-2, lund2023oddandevennumbered pages 1-3) • Gluconeogenesis and endogenous glucose production compensation. (nurjanah2023heptanoateimprovescompensatory pages 1-2) • Innate immune response pathways: TLR4 signaling pathway; cytokine production (IL-6; IL-1β context). (mosegaard2024humaninbornerrors pages 1-2, mosegaard2024humaninbornerrors pages 2-4)

4.2 Cellular components (GO: Cellular Component) • Mitochondrial matrix and inner mitochondrial membrane (β-oxidation enzymes and ETC coupling). (nurjanah2023modificationofdietary pages 14-17, zhao2023syntheticmrnarescues pages 6-8) • Respiratory chain complexes / ETC supercomplexes (bioenergetic assemblies). (zhao2023syntheticmrnarescues pages 6-8) • Plasma membrane TLR4 complex (immune recognition/signaling). (mosegaard2024humaninbornerrors pages 1-2) • Endoplasmic reticulum (as a site of fatty-acid elongation in lcFAOD biomarker work; relevant to lipid remodeling when FAO is impaired). (schwantje2024tracerbasedlipidomicsenablesa pages 14-14)

  1. Disease progression: sequence of events from trigger to clinical manifestation

Triggering conditions Catabolic stressors (fasting, illness/infection/inflammation, and exercise) increase reliance on FAO; VLCADD patients often decompensate under these triggers, with infection recognized clinically as a trigger that can precipitate metabolic decompensation and rhabdomyolysis. (mosegaard2024humaninbornerrors pages 1-2, rouyer2024long‐termprognosisof pages 11-12)

Stepwise pathophysiological cascade (integrated) 1) Trigger increases FA mobilization and mitochondrial LC-FAO demand. 2) VLCAD block reduces LC-FAO flux → reduced acetyl-CoA and ATP generation; ketogenesis fails to increase appropriately → hypoketotic hypoglycemia risk, especially with fasting. (nurjanah2023modificationofdietary pages 14-17, nurjanah2023heptanoateimprovescompensatory pages 1-2) 3) Long-chain acylcarnitines and lipid intermediates accumulate (C14:1 and longer) → proposed direct cellular toxicity, altered membrane integrity/permeability, Ca2+-linked signaling disruption, and arrhythmogenic potential. (sebaa2023adistinctivemetabolomics pages 1-2, nurjanah2023modificationofdietary pages 14-17) 4) Secondary mitochondrial defects emerge (ETC supercomplex disruption, permeability transition/uncoupling hypotheses) → worsened bioenergetics and oxidative stress. (zhao2023syntheticmrnarescues pages 6-8, lund2023oddandevennumbered pages 1-3) 5) Tissue-level failure in heart/skeletal muscle/liver manifests as cardiomyopathy/arrhythmias, rhabdomyolysis, hepatic dysfunction, hyperammonemia, and multi-organ crisis. (bandari2024managementandoutcomes pages 1-2, liu2024casereporton pages 2-3) 6) Immune/inflammatory coupling: impaired TLR4 signaling and cytokine induction in VLCADD cells may alter host response to infection and influence how inflammatory triggers precipitate crisis. (mosegaard2024humaninbornerrors pages 1-2)

Distinct clinical phases A 2024 clinical review summarizes a spectrum including: severe early-onset cardiac phenotype, hepatic/hypoketotic hypoglycemia phenotype, and later-onset myopathic phenotype with intermittent rhabdomyolysis. (bandari2024managementandoutcomes pages 1-2)

  1. Phenotypic manifestations (mechanism-linked; HP-ready)

Key clinical phenotypes • Hypoketotic hypoglycemia (HP:0001943) as a feared complication; in a severe neonatal case, glucose reached 0.02 mmol/L. (stenlid2023lowfastingconcentrations pages 1-2, liu2024casereporton pages 2-3) • Rhabdomyolysis (HP:0003201) / hyperCKemia: neonatal case CK 19,448 U/L; cohort peak CK as high as 76,656 U/L; adult FAOD cohort mean CK during rhabdomyolysis 68,958 U/L. (liu2024casereporton pages 2-3, bandari2024managementandoutcomes pages 7-8, rouyer2024long‐termprognosisof pages 1-2) • Cardiomyopathy (HP:0001638) and arrhythmia/ventricular fibrillation (HP:0001663): neonatal case had ventricular fibrillation with echocardiographic dysfunction and pulmonary hypertension. (liu2024casereporton pages 2-3) • Hyperammonemia (HP:0001987) and lactic acidosis (HP:0003128) during crisis. (liu2024casereporton pages 2-3, penaquintana2024nutritionalmanagementof pages 1-3)

Adult/long-term outcomes (recent cohort statistics) In a 2024 adult cohort of muscular FAODs including VLCAD, rhabdomyolysis occurred in 84% of patients overall, with mean pre-diagnosis rhabdomyolysis rate 1.92 episodes/year (VLCAD subgroup reported 4.9) declining to 0.82/year post-diagnosis (VLCAD subgroup 2.5). Only one new ICU admission occurred after diagnosis (VLCAD). (rouyer2024long‐termprognosisof pages 7-9)

  1. Recent developments and latest research (2023–2024 prioritized)

7.1 Metabolomics-based biomarker refinement (2023) Untargeted LC-HRMS metabolomics in dried blood spots (n=15 VLCADD vs n=15 controls) identified 206 dysregulated metabolites and proposed high-performing biomarkers: 3,4-dihydroxytetradecanoylcarnitine (AUC=1), PIP(20:1)/PGF1alpha (AUC=0.982), PIP2(16:0/22:3) (AUC=0.978). Pathway enrichment and biomarker ROC visualizations are shown in Figures 4–5. (sebaa2023adistinctivemetabolomics pages 1-2, sebaa2023adistinctivemetabolomics media cf95c180, sebaa2023adistinctivemetabolomics media f4e325fd)

7.2 Immunometabolic mechanism (2024) Patient-cell evidence that ACADVL variants impair TLR4 pathway responsiveness to LPS (lower TLR4 expression/signaling and IL-6 induction), connecting LC-FAO to innate immune competence and supporting the clinical observation that infections can trigger crises. (mosegaard2024humaninbornerrors pages 1-2, mosegaard2024humaninbornerrors pages 2-4)

7.3 Triheptanoin/heptanoate mechanism (2023) Tracer studies in VLCAD−/− mice show increased contribution of glycerol-derived gluconeogenesis to blood glucose; this difference normalized with heptanoate (C7), consistent with heptanoate providing substrates that reduce the need for compensatory gluconeogenesis and support glucose homeostasis. (nurjanah2023heptanoateimprovescompensatory pages 1-2)

7.4 Emerging causal therapy approaches (2023) LNP-formulated human VLCAD mRNA restored VLCAD activity and improved mitochondrial FAO/respiration/ATP in patient cells and Acadvl−/− mice; systemic serum C14–C18 acylcarnitines decreased after treatment. The authors note treatment was not proinflammatory in the tested acute mouse setting. (zhao2023syntheticmrnarescues pages 6-8)

  1. Current applications and real-world implementations

8.1 Newborn screening (NBS) workflows Ontario’s real-world protocol (NBS since 2006) uses dried blood spot MS/MS acylcarnitines with C14:1 as the main marker, followed by confirmatory plasma/serum acylcarnitines, lymphocyte VLCAD enzyme activity, and ACADVL molecular testing when activity is abnormal. Newborn-screen C14:1 strongly correlates with residual enzyme activity (p=0.0003 reported). (bandari2024managementandoutcomes pages 1-2, bandari2024managementandoutcomes pages 2-4)

8.2 Dietary management (expert synthesis 2024) Core approach: provide sufficient glucose to prevent lipolysis and minimize reliance on FAO; in long-chain FAODs, quantitative guidance includes restricting LCT to ~10% of energy and supplementing MCT (10–25% of energy) with total MCT+LCT 20–35% of energy, while monitoring essential fatty acids and fat-soluble vitamins. (penaquintana2024nutritionalmanagementof pages 1-3)

8.3 Triheptanoin implementation and dosing guidance A 2024 nutrition review describes triheptanoin as an FDA-approved odd-chain triglyceride therapy for LC-FAODs, with dosing described as 20% of total energy and/or 25–35% total energy, and also cited in g/kg/day ranges by age group; GI adverse effects are common but may improve with dose fractionation. (penaquintana2024nutritionalmanagementof pages 6-7)

ClinicalTrials.gov implementation example NCT01886378 (Ultragenyx; “UX007”) is an open-label phase 2 study in LC-FAODs (including VLCAD) with dosing titrated to 25–35% of total caloric intake (or maximum tolerated dose) and follow-up over 24 weeks (treatment period) with extension to 78 weeks total. Primary outcomes include changes in exercise tolerance during cycle ergometry (workload AUC/time), respiratory exchange ratio AUC, and exercise duration; functional outcomes include walk tests and HR-based indices. (NCT01886378 chunk 1)

  1. Expert opinion and analysis (authoritative sources)

Clinical management perspective The 2024 Ontario chart review emphasizes that genotype–phenotype prediction is imperfect and that functional testing (enzyme activity) can help differentiate carriers/mildly affected individuals and inform management; it also emphasizes avoiding overtreatment as NBS increases detection of milder phenotypes. (bandari2024managementandoutcomes pages 1-2, bandari2024managementandoutcomes pages 2-4)

Adult neuromuscular perspective The 2024 European Journal of Neurology cohort highlights a long diagnostic delay in adult FAODs and reports reduced rhabdomyolysis frequency after diagnosis and management, supporting the practical value of diagnosis plus lifestyle/diet adaptation even when pharmacologic options are limited. (rouyer2024long‐termprognosisof pages 1-2, rouyer2024long‐termprognosisof pages 7-9)

  1. Relevant recent statistics and data (selected)

Newborn/child cohort (2024; Ontario; n=12) • Enzyme activity stratification: 7/12 >10% residual activity; 5/12 <10%. (bandari2024managementandoutcomes pages 1-2) • Correlation: newborn-screen C14:1 vs enzyme activity p=0.0003; at diagnosis p=0.0295. (bandari2024managementandoutcomes pages 1-2) • Rhabdomyolysis marker: peak CK up to 76,656 U/L; no significant correlation between enzyme activity and admissions/CK. (bandari2024managementandoutcomes pages 7-8)

Adult cohort (2024; n=44 muscular FAOD; 13 VLCAD) • Rhabdomyolysis in 84% overall; mean CK 68,958 U/L. (rouyer2024long‐termprognosisof pages 1-2) • Rhabdomyolysis rate reduced: mean 1.92/year pre-diagnosis to 0.82/year post-diagnosis; VLCAD subgroup 4.9/year to 2.5/year. (rouyer2024long‐termprognosisof pages 7-9)

Metabolomics biomarkers (2023; DBS n=15 vs 15) • 206 dysregulated metabolites; top biomarker AUCs 0.978–1.0 and top-ranked ROC AUC range ~0.986–0.992 shown. (sebaa2023adistinctivemetabolomics pages 1-2, sebaa2023adistinctivemetabolomics pages 8-10)

Neonatal case (2024) • C14:1 5.053 μmol/L at 3 days → 0.192 μmol/L by 5 months with treatment. (liu2024casereporton pages 2-3) • Glucose 0.02 mmol/L; CK 19,448 U/L; AST 384.2 U/L; ammonia 83.2 μmol/L; ventricular fibrillation and echocardiographic dysfunction. (liu2024casereporton pages 2-3)

  1. Knowledge-base–oriented annotation blocks

11.1 Pathophysiology description (narrative) VLCADD results from ACADVL loss-of-function causing a mitochondrial long-chain β-oxidation block. Under catabolic stress, impaired LC-FAO reduces ATP and acetyl-CoA supply (limiting ketogenesis and hepatic support for gluconeogenesis/ureagenesis), while long-chain acylcarnitines and lipid intermediates accumulate, promoting mitochondrial dysfunction, oxidative stress, and inflammatory/immune dysregulation. This combined energy deficiency plus lipotoxicity underlies cardiomyopathy/arrhythmias, rhabdomyolysis, and hypoketotic hypoglycemia, with severity modulated by residual enzyme activity and physiological stress exposure. (bandari2024managementandoutcomes pages 1-2, sebaa2023adistinctivemetabolomics pages 1-2, zhao2023syntheticmrnarescues pages 6-8)

11.2 Gene/protein annotations (HGNC) • ACADVL (acyl-CoA dehydrogenase very long chain; VLCAD). (bandari2024managementandoutcomes pages 1-2)

11.3 Suggested GO terms (not exhaustive; evidence-aligned) Biological Process: • fatty acid beta-oxidation (mitochondrial) (supported generally across VLCAD sources). (bandari2024managementandoutcomes pages 1-2, nurjanah2023modificationofdietary pages 14-17) • oxidative phosphorylation / mitochondrial respiration / ATP synthesis coupled electron transport. (zhao2023syntheticmrnarescues pages 6-8) • tricarboxylic acid cycle; anaplerotic reactions (heptanoate/triheptanoin rationale; immune succinate axis). (mosegaard2024humaninbornerrors pages 1-2, lund2023oddandevennumbered pages 1-3) • response to oxidative stress; glutathione metabolic process. (sebaa2023adistinctivemetabolomics pages 8-10, lund2023oddandevennumbered pages 1-3) • toll-like receptor 4 signaling pathway; cytokine production (IL-6). (mosegaard2024humaninbornerrors pages 1-2)

Cellular Component: • mitochondrion; mitochondrial matrix; inner mitochondrial membrane; respiratory chain complexes/supercomplexes. (nurjanah2023modificationofdietary pages 14-17, zhao2023syntheticmrnarescues pages 6-8) • plasma membrane (TLR4). (mosegaard2024humaninbornerrors pages 1-2) • endoplasmic reticulum (lipid elongation context in lcFAOD biomarker work). (schwantje2024tracerbasedlipidomicsenablesa pages 14-14)

11.4 Suggested HP terms (examples) • Hypoketotic hypoglycemia (HP:0001943). (stenlid2023lowfastingconcentrations pages 1-2) • Rhabdomyolysis / elevated creatine kinase (HP:0003201 / HP:0003236). (bandari2024managementandoutcomes pages 7-8, liu2024casereporton pages 2-3) • Cardiomyopathy (HP:0001638). (liu2024casereporton pages 2-3) • Cardiac arrhythmia / ventricular fibrillation (HP:0001663 / HP:0004756). (liu2024casereporton pages 2-3) • Hyperammonemia (HP:0001987). (liu2024casereporton pages 2-3)

11.5 Suggested UBERON tissues • Heart; liver; skeletal muscle. (bandari2024managementandoutcomes pages 1-2, penaquintana2024nutritionalmanagementof pages 1-3)

11.6 Suggested CL cell types • Dermal fibroblast (directly used in mechanistic studies). (mosegaard2024humaninbornerrors pages 2-4) • Hepatocyte (implicated by liver glucose homeostasis role and hepatic-targeted mRNA therapy). (nurjanah2023heptanoateimprovescompensatory pages 1-2, zhao2023syntheticmrnarescues pages 6-8)

11.7 Suggested CHEBI entities (examples) • Tetradecenoylcarnitine (C14:1 acylcarnitine), long-chain acylcarnitines. (sebaa2023adistinctivemetabolomics pages 1-2, zhao2023syntheticmrnarescues pages 6-8) • Glutathione. (sebaa2023adistinctivemetabolomics pages 8-10) • Succinate. (mosegaard2024humaninbornerrors pages 1-2) • Propionyl-CoA; succinyl-CoA (triheptanoin/heptanoate anaplerosis). (lund2023oddandevennumbered pages 1-3)

  1. Evidence items with PMIDs (as available from retrieved sources)

Note: The OpenTargets evidence list includes older key mechanistic/genetic PubMed records (e.g., 9973285, 8739957, 25929793, 27604308, 8845838, 10077518, 9461620), but PMIDs were not present in the retrieved full-text snippets for the 2023–2024 papers above. Therefore, PMIDs for the 2023–2024 sources could not be programmatically verified from the provided tool outputs.

Where DOI/URL/date are available (for user traceability): • Al Bandari et al., Int J Neonatal Screening, Published 30 Mar 2024. https://doi.org/10.3390/ijns10020029 (bandari2024managementandoutcomes pages 1-2) • Mosegaard et al., FASEB BioAdvances, Accepted 21 Jul 2024 (Aug 2024 issue). https://doi.org/10.1096/fba.2024-00060 (mosegaard2024humaninbornerrors pages 1-2) • Sebaa et al., Metabolites, Published 5 Jun 2023. https://doi.org/10.3390/metabo13060725 (sebaa2023adistinctivemetabolomics pages 1-2) • Nurjanah et al., Nutrients, Published 5 Nov 2023. https://doi.org/10.3390/nu15214689 (nurjanah2023heptanoateimprovescompensatory pages 1-2) • Lund et al., BBA Mol Cell Biol Lipids, Feb 2023. https://doi.org/10.1016/j.bbalip.2022.159248 (lund2023oddandevennumbered pages 1-3) • Zhao et al., Mol Genet Metab, Jan 2023. https://doi.org/10.1016/j.ymgme.2022.106982 (zhao2023syntheticmrnarescues pages 6-8) • Rouyer et al., Eur J Neurol, Nov 2024. https://doi.org/10.1111/ene.16138 (rouyer2024long‐termprognosisof pages 1-2) • Peña-Quintana & Correcher-Medina, Nutrients, Published 14 Aug 2024. https://doi.org/10.3390/nu16162707 (penaquintana2024nutritionalmanagementof pages 1-3) • ClinicalTrials.gov: NCT01886378 (UX007 triheptanoin; start 6 Feb 2014; results posted 11 Feb 2021). https://clinicaltrials.gov/study/NCT01886378 (NCT01886378 chunk 1)

Limitations This report is constrained to the documents successfully retrieved in this run; several highly relevant reviews (e.g., a 2023 Journal of Inherited Metabolic Disease “Fifty years…” review) were listed as unobtainable by the tool. Additionally, PMIDs for the 2023–2024 articles were not available in the retrieved text snippets, preventing PMID-verified citations for those specific papers.

References

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