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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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Pathophysiology

7

ACADVL molecular function deficiency

Biallelic ACADVL pathogenic variants reduce very long-chain acyl-CoA dehydrogenase catalytic activity.

hepatocyte link cardiac muscle cell link skeletal muscle fiber link

ACADVL

fatty acid beta-oxidation link

very-long-chain fatty acyl-CoA dehydrogenase activity link

mitochondrion link

Downstream

Impaired very-long-chain fatty acid beta-oxidation Reduced ACADVL activity blocks initial dehydrogenation of C12-C20 acyl-CoAs.

VLCAD enzyme activity Biallelic ACADVL dysfunction is reflected by reduced measured VLCAD enzyme activity.

Show evidence (1 reference)

PMID:40149952 PARTIAL Human Clinical

"Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000."

Provides disease-level context for VLCADD as an FAO disorder, but only partially supports the specific catalytic-activity claim.

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 link fatty acid beta-oxidation link

Downstream

Tissue energy deficit in high-demand organs

Lipotoxic metabolite accumulation

Ketone bodies Impaired hepatic long-chain FAO limits ketogenesis, producing the hypoketotic biochemical state.

Tetradecenoylcarnitine (C14:1) Blocked long-chain beta-oxidation produces elevated C14:1 acylcarnitine, the principal diagnostic marker.

Long-chain acylcarnitines (C14, C16, C18 species) Impaired long-chain acyl-CoA oxidation leads to abnormal long-chain acylcarnitine profiles.

Glucagon FAO impairment is associated with reduced fasting glucagon concentrations in VLCAD patients.

Show evidence (1 reference)

PMID:40149952 SUPPORT Human Clinical

"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 link skeletal muscle fiber link

oxidative phosphorylation link gluconeogenesis link

heart link skeletal muscle tissue link liver link

Downstream

Hypoketotic hypoglycemia Energy failure and impaired hepatic ketogenesis produce hypoketotic hypoglycemia during fasting or catabolic stress.

Cardiomyopathy Myocardial energy deficit contributes to hypertrophic or dilated cardiomyopathy in severe VLCAD.

Rhabdomyolysis Skeletal muscle energy deficit during exercise or catabolic stress predisposes to rhabdomyolysis.

Hepatomegaly Hepatic energy deficit and impaired fatty acid handling contribute to hepatomegaly in hepatic VLCAD presentations.

Exercise intolerance Reduced skeletal muscle energy production causes exercise intolerance in the myopathic form.

Myalgia Skeletal muscle energy failure manifests as muscle cramps and pain during myopathic episodes.

Muscle weakness Recurrent skeletal muscle energy stress can be associated with persistent weakness.

Lethargy Acute substrate stress can precipitate lethargic metabolic decompensation.

Hyperammonemia Severe neonatal metabolic decompensation may include secondary hyperammonemia.

Lactic acidosis Severe metabolic decompensation may include lactic acidosis in early-childhood VLCAD presentations.

Muscular hypotonia Systemic and skeletal-muscle energy deficit contributes to hypotonia in severe early-onset disease.

Seizure Severe neurologic presentations in VLCAD can include status epilepticus and epileptic spasms.

Elevated creatine kinase Rhabdomyolysis from skeletal muscle energy failure raises serum creatine kinase.

Vomiting Vomiting can accompany severe infantile metabolic decompensation.

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.

Lipotoxic metabolite accumulation

Accumulating long-chain acylcarnitines (especially C14:1 and related C14-C18 species) and fatty acid intermediates may contribute directly to pathology through increased cellular permeability, inflammation, calcium signaling disruption, and arrhythmogenic potential.

lipid metabolic process link

mitochondrion link

Downstream

Secondary mitochondrial dysfunction and OXPHOS impairment

Cardiac arrhythmia Long-chain acylcarnitine accumulation is linked to arrhythmogenic cardiac involvement.

Long-chain carboxylic and dicarboxylic acids Lipotoxic substrate handling abnormalities include excess long-chain carboxylic and dicarboxylic acid intermediates.

Show evidence (1 reference)

PMID:37367883 SUPPORT Human Clinical

"Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns."

Demonstrates widespread metabolic disruption from accumulated toxic intermediates.

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 link

mitochondrial respiratory chain complex I link

Downstream

Oxidative stress and glutathione vulnerability

Show evidence (2 references)

PMID:40149952 SUPPORT Human Clinical

"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 Human Clinical

"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 link glutathione metabolic process link

Downstream

Immunometabolic dysregulation

Glutathione Oxidative stress in VLCAD deficiency is reflected by glutathione pathway vulnerability and altered glutathione levels.

Show evidence (1 reference)

PMID:37367883 SUPPORT Human Clinical

"Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns."

Metabolomics data consistent with oxidative stress in VLCADD newborns.

Immunometabolic dysregulation

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 link

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.

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Pathograph

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Phenotypes

15

Cardiovascular 2

Cardiomyopathy FREQUENT Cardiomyopathy (HP:0001638)

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 OCCASIONAL Arrhythmia (HP:0011675)

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 FREQUENT Hepatomegaly (HP:0002240)

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 FREQUENT Vomiting (HP:0002013)

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 VERY_FREQUENT Hypoketotic hypoglycemia (HP:0001985)

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 OCCASIONAL Hyperammonemia (HP:0001987)

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 OCCASIONAL Lactic acidosis (HP:0003128)

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 VERY_FREQUENT Elevated circulating creatine kinase concentration (HP:0003236)

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 FREQUENT Rhabdomyolysis (HP:0003201)

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 OCCASIONAL Muscle weakness (HP:0001324)

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 FREQUENT Hypotonia (HP:0001252)

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 FREQUENT Lethargy (HP:0001254)

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 OCCASIONAL Seizure (HP:0001250)

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 FREQUENT Exercise intolerance (HP:0003546)

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 FREQUENT Myalgia (HP:0003326)

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

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

ClinGen classifies the ACADVL-very long chain acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

9

Avoidance of fasting

Action: dietary intervention MAXO:0000088

Frequent feeding and fasting limitation to prevent catabolic stress is the cornerstone of VLCAD management. Maximum fasting duration is age-dependent and shorter than in healthy individuals.

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 intervention MAXO:0000088

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 intervention MAXO:0000088

Dietary restriction of long-chain triglycerides to approximately 10% of total energy intake, while ensuring adequate essential fatty acid supply and monitoring fat-soluble vitamins.

Mechanism Target:

MODULATES Lipotoxic 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 supplementation MAXO:0000106

FDA-approved odd-chain triglyceride therapy for long-chain FAODs. Triheptanoin provides anaplerotic substrates (propionyl-CoA) that support the TCA cycle and gluconeogenesis, dosed at approximately 20-35% of total energy intake. GI adverse effects may improve with dose fractionation.

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: Pharmacotherapy 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 intervention MAXO:0000088

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 reduces myopathic crises.

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 care MAXO:0000950

Standard cardiac management including pharmacotherapy for heart failure and arrhythmia monitoring 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.

Newborn screening

Action: disease screening MAXO:0000124

VLCAD deficiency is detectable by newborn screening via tandem mass spectrometry using C14:1 acylcarnitine as the primary marker, followed by confirmatory plasma/serum acylcarnitines, lymphocyte VLCAD enzyme activity assay, and ACADVL molecular testing.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, carrier testing, and prenatal diagnostic options.

Show evidence (1 reference)

PMID:20301763 SUPPORT Human Clinical

"VLCAD deficiency is inherited in an autosomal recessive manner."

Autosomal recessive inheritance supports the role of genetic counseling.

🔬

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 Lipotoxic 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 Lipotoxic 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.

{ }

Source YAML

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name: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
category: Mendelian
creation_date: '2026-02-23T23:04:38Z'
updated_date: '2026-05-19T18:50:51Z'
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 toxic 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. Prevalence is estimated at 1:30,000 to 1:100,000 births.

  '
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:
- notes: Estimated prevalence approximately 1:30,000 to 1:100,000 births, with regional variation. A 2024 clinical cohort review reports 1:30,000-1:100,000; immunometabolism studies cite 1:31,500-1:94,569 worldwide.
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
  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:40149952
    reference_title: "The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    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: Provides disease-level context for VLCADD as an FAO disorder, but only partially supports the specific catalytic-activity claim.
  downstream:
  - target: Impaired very-long-chain fatty acid beta-oxidation
    description: Reduced ACADVL activity blocks initial dehydrogenation of C12-C20 acyl-CoAs.
  - target: VLCAD enzyme activity
    description: Biallelic ACADVL dysfunction is reflected by reduced measured VLCAD enzyme activity.
    causal_link_type: DIRECT
    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 reduced VLCAD enzyme activity measurements.
- name: Impaired very-long-chain fatty acid beta-oxidation
  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: HUMAN_CLINICAL
    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
  - target: Lipotoxic metabolite accumulation
  - 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: Tetradecenoylcarnitine (C14:1)
    description: Blocked long-chain beta-oxidation produces elevated C14:1 acylcarnitine, the principal diagnostic marker.
    causal_link_type: DIRECT
    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 data link C14:1 elevation at newborn screening to low VLCAD enzyme activity.
  - 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.
  - target: Glucagon
    description: FAO impairment is associated with reduced fasting glucagon concentrations in VLCAD patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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 reduced fasting glucagon downstream of VLCAD deficiency.
- name: Tissue energy deficit in high-demand organs
  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.
  downstream:
  - target: Hypoketotic hypoglycemia
    description: Energy failure and impaired hepatic ketogenesis produce hypoketotic hypoglycemia during fasting or catabolic stress.
    causal_link_type: DIRECT
    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: Hypoketotic hypoglycemia is a feared clinical complication and the treatment focuses on avoiding hypoglycemia.
      explanation: Patient-focused clinical study supports hypoketotic hypoglycemia as an energy-balance complication.
  - target: Cardiomyopathy
    description: Myocardial energy deficit contributes to hypertrophic or dilated cardiomyopathy in severe VLCAD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Myocardial ATP deficit
    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: GeneReviews supports cardiomyopathy in the severe energy-demand-organ phenotype.
  - target: Rhabdomyolysis
    description: Skeletal muscle energy deficit during exercise or catabolic stress predisposes to rhabdomyolysis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Exercise-induced muscle energy failure
    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
      explanation: GeneReviews supports exercise-provoked rhabdomyolysis in VLCAD.
  - target: Hepatomegaly
    description: Hepatic energy deficit and impaired fatty acid handling contribute to hepatomegaly in hepatic VLCAD presentations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatic metabolic decompensation
    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
      explanation: GeneReviews supports hepatomegaly in the hepatic VLCAD phenotype.
  - target: Exercise intolerance
    description: Reduced skeletal muscle energy production causes exercise intolerance in the myopathic form.
    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 later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance.
      explanation: GeneReviews supports exercise intolerance in the myopathic form.
  - target: Myalgia
    description: Skeletal muscle energy failure manifests as muscle cramps and pain during myopathic episodes.
    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 later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance.
      explanation: GeneReviews supports muscle pain in the myopathic VLCAD form.
  - target: Muscle weakness
    description: Recurrent skeletal muscle energy stress can be associated with persistent weakness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: Adult FAOD cohort evidence supports muscle weakness associated with myopathic manifestations.
  - target: Lethargy
    description: Acute substrate stress can precipitate lethargic metabolic decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolic decompensation
    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 decompensation after long-chain fat loading.
  - target: Hyperammonemia
    description: Severe neonatal metabolic decompensation may include secondary hyperammonemia.
    causal_link_type: UNKNOWN
    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 during early VLCAD disease.
  - target: Lactic acidosis
    description: Severe metabolic decompensation may include lactic acidosis in early-childhood VLCAD presentations.
    causal_link_type: UNKNOWN
    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.
  - target: Muscular hypotonia
    description: Systemic and skeletal-muscle energy deficit contributes to hypotonia in severe early-onset disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Skeletal muscle energy deficit
    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, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia.
      explanation: GeneReviews supports hypotonia in severe early-onset VLCAD.
  - target: Seizure
    description: Severe neurologic presentations in VLCAD can include status epilepticus and epileptic spasms.
    causal_link_type: UNKNOWN
    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 status epilepticus and infantile epileptic spasms secondary to VLCAD deficiency.
  - target: Elevated creatine kinase
    description: Rhabdomyolysis from skeletal muscle energy failure raises serum creatine kinase.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Rhabdomyolysis
    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.
  - target: Vomiting
    description: Vomiting can accompany severe infantile metabolic decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolic decompensation
    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 decompensation after long-chain fat loading.
- name: Lipotoxic metabolite accumulation
  description: 'Accumulating long-chain acylcarnitines (especially C14:1 and related C14-C18 species) and fatty acid intermediates may contribute directly to pathology through increased cellular permeability, inflammation, calcium signaling disruption, and arrhythmogenic potential.

    '
  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: Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns.
    explanation: Demonstrates widespread metabolic disruption from accumulated toxic intermediates.
  downstream:
  - target: Secondary mitochondrial dysfunction and OXPHOS impairment
  - target: Cardiac arrhythmia
    description: Long-chain acylcarnitine accumulation is linked to arrhythmogenic cardiac involvement.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cardiac lipotoxicity
    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, pericardial effusion, and arrhythmias
      explanation: GeneReviews supports arrhythmias as part of severe cardiac VLCAD.
  - target: Long-chain carboxylic and dicarboxylic acids
    description: Lipotoxic substrate handling abnormalities include excess long-chain carboxylic and dicarboxylic acid intermediates.
    causal_link_type: UNKNOWN
    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 long-chain carboxylic and dicarboxylic acid accumulation in VLCAD.
- name: Secondary mitochondrial dysfunction and OXPHOS impairment
  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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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.
  downstream:
  - target: Oxidative stress and glutathione vulnerability
- name: Oxidative stress and glutathione vulnerability
  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: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: Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns.
    explanation: Metabolomics data consistent with oxidative stress in VLCADD newborns.
  downstream:
  - target: Immunometabolic dysregulation
  - 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: Immunometabolic dysregulation
  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
    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
  frequency: VERY_FREQUENT
  description: 'Hypoglycemia with inadequate ketone production during fasting or catabolic stress. A feared complication across all VLCAD subtypes.

    '
  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
  frequency: FREQUENT
  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
  frequency: FREQUENT
  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
  frequency: FREQUENT
  description: 'Liver enlargement during acute metabolic decompensation, associated with hepatic steatosis from impaired fatty acid oxidation.

    '
  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
  frequency: FREQUENT
  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
  frequency: FREQUENT
  description: 'Muscle pain is a common symptom, particularly in the later-onset myopathic form, and may occur independently of rhabdomyolysis episodes.

    '
  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
  frequency: OCCASIONAL
  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
  frequency: OCCASIONAL
  description: 'Arrhythmias including ventricular fibrillation may occur in the severe neonatal form and are related to lipotoxic effects of accumulated long-chain acylcarnitines on cardiac conduction.

    '
  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
  frequency: FREQUENT
  description: 'Low energy and reduced responsiveness during metabolic crises, associated with hypoglycemia and energy failure.

    '
  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
  frequency: OCCASIONAL
  description: 'Secondary hyperammonemia during metabolic decompensation, resulting from impaired hepatic FAO support for ureagenesis.

    '
  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
  frequency: OCCASIONAL
  description: 'Elevated lactate during metabolic crises, reflecting impaired mitochondrial energy metabolism and compensatory anaerobic glycolysis.

    '
  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
  frequency: FREQUENT
  description: 'Generalized hypotonia, particularly in the severe neonatal form, reflecting systemic energy deficit in skeletal muscle.

    '
  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
  frequency: OCCASIONAL
  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
  frequency: VERY_FREQUENT
  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.
- name: Vomiting
  frequency: FREQUENT
  description: 'Vomiting associated with fasting intolerance and metabolic decompensation episodes.

    '
  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: Lipotoxic 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: Lipotoxic 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
  gene_term:
    preferred_term: ACADVL
    term:
      id: hgnc:92
      label: ACADVL
  inheritance:
  - name: Autosomal recessive
    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.
  variants:
  - name: Over 400 pathogenic ACADVL variants described
    description: 'Biallelic pathogenic variants in ACADVL cause VLCAD deficiency. The mutation spectrum includes missense, nonsense, splice-site, and small insertions/deletions. Genotype-phenotype correlations are imperfect; functional testing of residual enzyme activity provides better prognostic information than genotype alone.

      '
    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 C14:1 result at diagnosis is the value that has been guiding our initial clinical management in asymptomatic diagnosed newborns.
      explanation: Supports that functional markers better guide management than genotype alone.
  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.
treatments:
- name: Avoidance of fasting
  description: 'Frequent feeding and fasting limitation to prevent catabolic stress is the cornerstone of VLCAD management. Maximum fasting duration is age-dependent and shorter than in healthy individuals.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      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.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      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 ensuring adequate essential fatty acid supply and monitoring fat-soluble vitamins.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Lipotoxic 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: 'FDA-approved odd-chain triglyceride therapy for long-chain FAODs. Triheptanoin provides anaplerotic substrates (propionyl-CoA) that support the TCA cycle and gluconeogenesis, dosed at approximately 20-35% of total energy intake. GI adverse effects may improve with dose fractionation.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  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.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      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 reduces myopathic crises.
    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 cardiac management including pharmacotherapy for heart failure and arrhythmia monitoring for patients with cardiac involvement.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      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: Newborn screening
  description: 'VLCAD deficiency is detectable by newborn screening via tandem mass spectrometry using C14:1 acylcarnitine as the primary marker, followed by confirmatory plasma/serum acylcarnitines, lymphocyte VLCAD enzyme activity assay, and ACADVL molecular testing.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
- 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: MAXO:0000079
      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.
progression:
- notes: 'Disease progression follows a cascade: catabolic triggers (fasting, illness, exercise) increase fatty acid mobilization and FAO demand. The VLCAD block reduces acetyl-CoA and ATP generation, impairing ketogenesis and causing hypoketotic hypoglycemia. Simultaneously, long-chain acylcarnitines and lipid intermediates accumulate, causing cellular toxicity. Secondary mitochondrial defects (ETC supercomplex disruption, oxidative stress) worsen bioenergetics. Tissue-level failure manifests as cardiomyopathy, rhabdomyolysis, and hepatic dysfunction. After diagnosis and management, rhabdomyolysis frequency decreases significantly (4.9 to 2.5 episodes per year in VLCAD).'
notes: 'Genotype-phenotype prediction in VLCAD deficiency is imperfect. Functional testing (residual enzyme activity) provides better prognostic information than genotype alone. With expanded newborn screening, milder phenotypes are increasingly detected, and overtreatment should be avoided. mRNA therapy approaches are in preclinical development and have shown promise in restoring VLCAD activity in patient fibroblasts and mouse models.

  '
references:
- reference: PMID:20301763
  title: "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:20301763

Very Long-Chain Acyl-Coenzyme A 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.

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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

(sebaa2023adistinctivemetabolomics pages 1-2): Rajaa Sebaa, Reem H. AlMalki, Wafaa Alseraty, and Anas M. Abdel Rahman. A distinctive metabolomics profile and potential biomarkers for very long acylcarnitine dehydrogenase deficiency (vlcadd) diagnosis in newborns. Metabolites, 13:725, Jun 2023. URL: https://doi.org/10.3390/metabo13060725, doi:10.3390/metabo13060725. This article has 13 citations.
(bandari2024managementandoutcomes pages 1-2): Maria Al Bandari, Laura Nagy, Vivian Cruz, Stacy Hewson, Alomgir Hossain, and Michal Inbar-Feigenberg. Management and outcomes of very long-chain acyl-coa dehydrogenase deficiency (vlcad deficiency): a retrospective chart review. International Journal of Neonatal Screening, 10:29, Mar 2024. URL: https://doi.org/10.3390/ijns10020029, doi:10.3390/ijns10020029. This article has 11 citations.
(nurjanah2023modificationofdietary pages 14-17): Modification of dietary substrates impacts glucose homeostasis in very long-chain Acyl-CoA dehydrogenase deficient (VLCAD-/-) mice This article has 0 citations.
(mosegaard2024humaninbornerrors pages 1-2): Signe Mosegaard, Krishna S. Twayana, Simone W. Denis, Jeffrey Kroon, Bauke V. Schomakers, Michel van Weeghel, Riekelt H. Houtkooper, Rikke K. J. Olsen, and Christian K. Holm. Human inborn errors of long‐chain fatty acid oxidation show impaired inflammatory responses to tlr4‐ligand lps. FASEB BioAdvances, 6:337-350, Aug 2024. URL: https://doi.org/10.1096/fba.2024-00060, doi:10.1096/fba.2024-00060. This article has 5 citations.
(li2024fournovelvariants pages 1-2): Lulu Li, Yueling Tang, Jin-qi Zhao, L. Gong, N. Yang, Shunan Wang, Hai-he Yang, and Yuanyuan Kong. Four novel variants identified in the acadvl gene causing very-long-chain acyl-coenzyme a dehydrogenase deficiency in four unrelated chinese families. Frontiers in Genetics, Aug 2024. URL: https://doi.org/10.3389/fgene.2024.1433160, doi:10.3389/fgene.2024.1433160. This article has 3 citations and is from a peer-reviewed journal.
(penaquintana2024nutritionalmanagementof pages 1-3): Luis Peña-Quintana and Patricia Correcher-Medina. Nutritional management of patients with fatty acid oxidation disorders. Nutrients, 16:2707, Aug 2024. URL: https://doi.org/10.3390/nu16162707, doi:10.3390/nu16162707. This article has 7 citations.
(zhao2023syntheticmrnarescues pages 6-8): Xue-Jun Zhao, AI-Walid Mohsen, Stephanie Mihalik, Keaton Solo, Ermal Aliu, Huifang Shi, Shakuntala Basu, Catherine Kochersperger, Clinton Van’t Land, Anuradha Karunanidhi, Kimberly A. Coughlan, Summar Siddiqui, Lisa M. Rice, Shawn Hillier, Eleonora Guadagnin, Paloma H. Giangrande, Paolo G.V. Martini, and Jerry Vockley. Synthetic mrna rescues very long-chain acyl-coa dehydrogenase deficiency in patient fibroblasts and a murine model. Molecular Genetics and Metabolism, 138(1):106982, Jan 2023. URL: https://doi.org/10.1016/j.ymgme.2022.106982, doi:10.1016/j.ymgme.2022.106982. This article has 16 citations and is from a peer-reviewed journal.
(lund2023oddandevennumbered pages 1-3): Martin Lund, Robert Heaton, Iain P. Hargreaves, Niels Gregersen, and Rikke K.J. Olsen. Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-coa dehydrogenase deficiency. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1868(2):159248, Feb 2023. URL: https://doi.org/10.1016/j.bbalip.2022.159248, doi:10.1016/j.bbalip.2022.159248. This article has 6 citations and is from a peer-reviewed journal.
(sebaa2023adistinctivemetabolomics pages 8-10): Rajaa Sebaa, Reem H. AlMalki, Wafaa Alseraty, and Anas M. Abdel Rahman. A distinctive metabolomics profile and potential biomarkers for very long acylcarnitine dehydrogenase deficiency (vlcadd) diagnosis in newborns. Metabolites, 13:725, Jun 2023. URL: https://doi.org/10.3390/metabo13060725, doi:10.3390/metabo13060725. This article has 13 citations.
(mosegaard2024humaninbornerrors pages 2-4): Signe Mosegaard, Krishna S. Twayana, Simone W. Denis, Jeffrey Kroon, Bauke V. Schomakers, Michel van Weeghel, Riekelt H. Houtkooper, Rikke K. J. Olsen, and Christian K. Holm. Human inborn errors of long‐chain fatty acid oxidation show impaired inflammatory responses to tlr4‐ligand lps. FASEB BioAdvances, 6:337-350, Aug 2024. URL: https://doi.org/10.1096/fba.2024-00060, doi:10.1096/fba.2024-00060. This article has 5 citations.
(nurjanah2023heptanoateimprovescompensatory pages 1-2): Siti Nurjanah, Albert Gerding, Marcel A. Vieira-Lara, Bernard Evers, Miriam Langelaar-Makkinje, Ute Spiekerkoetter, Barbara M. Bakker, and Sara Tucci. Heptanoate improves compensatory mechanism of glucose homeostasis in mitochondrial long-chain fatty acid oxidation defect. Nutrients, 15:4689, Nov 2023. URL: https://doi.org/10.3390/nu15214689, doi:10.3390/nu15214689. This article has 5 citations.
(NCT01886378 chunk 1): A Study of UX007 (Triheptanoin) in Participants With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD). Ultragenyx Pharmaceutical Inc. 2014. ClinicalTrials.gov Identifier: NCT01886378
(liu2024casereporton pages 2-3): R Liu, J Nie, Q Cao, S Cui, X Miao, J Pan, and X Chen. Case report on very long chain acyl-coa dehydrogenase deficiency in a term neonate. Journal of Case Reports and Medical Images, Dec 2024. URL: https://doi.org/10.52768/jcaserepclinimages/1159, doi:10.52768/jcaserepclinimages/1159. This article has 0 citations.
(rouyer2024long‐termprognosisof pages 7-9): Alice Rouyer, Céline Tard, Anne‐Frédérique Dessein, Marco Spinazzi, Anne‐Laure Bédat‐Millet, Dalia Dimitri‐Boulos, Aleksandra Nadaj‐Pakleza, Jean‐Baptiste Chanson, Guillaume Nicolas, Claire Douillard, and Pascal Laforêt. Long‐term prognosis of fatty‐acid oxidation disorders in adults: optimism despite the limited effective therapies available. European Journal of Neurology, Nov 2024. URL: https://doi.org/10.1111/ene.16138, doi:10.1111/ene.16138. This article has 11 citations and is from a domain leading peer-reviewed journal.
(schwantje2024tracerbasedlipidomicsenablesa pages 14-14): M Schwantje and S Mosegaard. Tracer-based lipidomics enables the discovery of disease-specific candidate biomarkers in mitochondrial β-oxidation disorders. Unknown journal, 2024.
(rouyer2024long‐termprognosisof pages 11-12): Alice Rouyer, Céline Tard, Anne‐Frédérique Dessein, Marco Spinazzi, Anne‐Laure Bédat‐Millet, Dalia Dimitri‐Boulos, Aleksandra Nadaj‐Pakleza, Jean‐Baptiste Chanson, Guillaume Nicolas, Claire Douillard, and Pascal Laforêt. Long‐term prognosis of fatty‐acid oxidation disorders in adults: optimism despite the limited effective therapies available. European Journal of Neurology, Nov 2024. URL: https://doi.org/10.1111/ene.16138, doi:10.1111/ene.16138. This article has 11 citations and is from a domain leading peer-reviewed journal.
(stenlid2023lowfastingconcentrations pages 1-2): Rasmus Stenlid, Hannes Manell, Rikard Seth, Sara Y. Cerenius, Azazul Chowdhury, Camilla Roa Cortés, Isabelle Nyqvist, Thomas Lundqvist, Maria Halldin, and Peter Bergsten. Low fasting concentrations of glucagon in patients with very long-chain acyl-coa dehydrogenase deficiency. Metabolites, 13:780, Jun 2023. URL: https://doi.org/10.3390/metabo13070780, doi:10.3390/metabo13070780. This article has 3 citations.
(bandari2024managementandoutcomes pages 7-8): Maria Al Bandari, Laura Nagy, Vivian Cruz, Stacy Hewson, Alomgir Hossain, and Michal Inbar-Feigenberg. Management and outcomes of very long-chain acyl-coa dehydrogenase deficiency (vlcad deficiency): a retrospective chart review. International Journal of Neonatal Screening, 10:29, Mar 2024. URL: https://doi.org/10.3390/ijns10020029, doi:10.3390/ijns10020029. This article has 11 citations.
(rouyer2024long‐termprognosisof pages 1-2): Alice Rouyer, Céline Tard, Anne‐Frédérique Dessein, Marco Spinazzi, Anne‐Laure Bédat‐Millet, Dalia Dimitri‐Boulos, Aleksandra Nadaj‐Pakleza, Jean‐Baptiste Chanson, Guillaume Nicolas, Claire Douillard, and Pascal Laforêt. Long‐term prognosis of fatty‐acid oxidation disorders in adults: optimism despite the limited effective therapies available. European Journal of Neurology, Nov 2024. URL: https://doi.org/10.1111/ene.16138, doi:10.1111/ene.16138. This article has 11 citations and is from a domain leading peer-reviewed journal.
(sebaa2023adistinctivemetabolomics media cf95c180): Rajaa Sebaa, Reem H. AlMalki, Wafaa Alseraty, and Anas M. Abdel Rahman. A distinctive metabolomics profile and potential biomarkers for very long acylcarnitine dehydrogenase deficiency (vlcadd) diagnosis in newborns. Metabolites, 13:725, Jun 2023. URL: https://doi.org/10.3390/metabo13060725, doi:10.3390/metabo13060725. This article has 13 citations.
(sebaa2023adistinctivemetabolomics media f4e325fd): Rajaa Sebaa, Reem H. AlMalki, Wafaa Alseraty, and Anas M. Abdel Rahman. A distinctive metabolomics profile and potential biomarkers for very long acylcarnitine dehydrogenase deficiency (vlcadd) diagnosis in newborns. Metabolites, 13:725, Jun 2023. URL: https://doi.org/10.3390/metabo13060725, doi:10.3390/metabo13060725. This article has 13 citations.
(bandari2024managementandoutcomes pages 2-4): Maria Al Bandari, Laura Nagy, Vivian Cruz, Stacy Hewson, Alomgir Hossain, and Michal Inbar-Feigenberg. Management and outcomes of very long-chain acyl-coa dehydrogenase deficiency (vlcad deficiency): a retrospective chart review. International Journal of Neonatal Screening, 10:29, Mar 2024. URL: https://doi.org/10.3390/ijns10020029, doi:10.3390/ijns10020029. This article has 11 citations.
(penaquintana2024nutritionalmanagementof pages 6-7): Luis Peña-Quintana and Patricia Correcher-Medina. Nutritional management of patients with fatty acid oxidation disorders. Nutrients, 16:2707, Aug 2024. URL: https://doi.org/10.3390/nu16162707, doi:10.3390/nu16162707. This article has 7 citations.

Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

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