RARE DISEASE
Very long chain acyl-CoA dehydrogenase deficiency
Very long chain acyl-CoA dehydrogenase deficiency
Very long chain acyl-CoA dehydrogenase deficiency
Synonyms: VLCAD deficiency, VLCADD
Synonyms: VLCAD deficiency, VLCADD
Synonyms: VLCAD deficiency, VLCADD
Drug discovery
2
drugs
With orphan designations
Overview
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder caused by mutations in the ACADVL gene, impairing mitochondrial β-oxidation of long-chain fatty acids. Clinical presentation varies by age: severe infantile forms feature cardiomyopathy, hypoglycemia, and liver dysfunction; childhood-onset types present with hepatic and metabolic crises; and adult myopathic forms manifest as exercise-induced rhabdomyolysis. Diagnosis involves elevated C14:1 acylcarnitines on newborn screening, genetic testing, and enzyme assays. Management prioritizes fasting avoidance, low long-chain fat diets with medium-chain triglyceride (MCT) supplementation, and emergency glucose protocols during metabolic stress [1][2][7][12].
Burden
High mortality risk in untreated infantile forms due to cardiac/liver complications [1][7].
Chronic morbidity includes recurrent rhabdomyolysis, cardiomyopathy, and hepatopathy [6][12][19].
Caregivers report financial strain, limited access to specialized nutrition, and psychosocial stress [2][10][14].
Therapies
Dietary: Strict long-chain fat restriction, MCT supplementation, and avoidance of prolonged fasting [1][8][16].
Emergency care: Intravenous glucose during metabolic crises to prevent hypoglycemia and rhabdomyolysis [5][19].
Pharmacological: Bezafibrate (PPAR-agonist) and triheptanoin (experimental) show promise in improving β-oxidation and clinical outcomes [3][17].
Categories: rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
183 drug discovery papers about Very long chain acyl-CoA dehydrogenase deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
183 drug discovery papers about Very long chain acyl-CoA dehydrogenase deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-01 | A25-23 A 34-Year-Old Woman With Hyperammonemia, Rhabdomyolysis, and Recurrent Tachyarrhythmias
Abstract Introduction While rare, inborn errors of metabolism occasionally evade detection during childhood. These diagnoses can lead to sudden onset of life-threatening multi-system organ failure requiring treatment in adult ICUs. Early recognition of patterns of abnormalities that can suggest an undiagnosed genetic disorder provides an opportunity to obtain rapid whole genome sequencing, which can facilitate diagnosis and the initiation of lifesaving treatment. Case Report A 34-year-old woman with a history of endometriosis and “fatty liver disease” was found unresponsive on the floor of her home after one day of nausea, vomiting, and confusion. She was intubated by EMS due to altered mental status. Initial pre-hospital glucose was 30 mg/dL, requiring D10 administration prior to hospital arrival. Admission labs were notable for mild anemia, elevated lactate (6.2), hyperammonemia (175), elevated CPK (3131), and profound acidemia (pH 7.08). Urine drug screen was negative. A broad infectious workup was negative. CT chest, abdomen, and pelvis was unrevealing. She was admitted to the ICU, where she was found to be in distributive shock requiring initiation of norepinephrine. A few hours later, she experienced a precipitous increase in pressor requirements followed by a ventricular-fibrillation cardiac arrest, which lasted 7 minutes. Her post-arrest labs were notable for hyperkalemia, prompting initiation of continuous renal replacement therapy. A similar decompensation including a second ventricular-fibrillation arrest occurred the following day, requiring 30 minutes of ACLS. The underlying etiology of the second arrest was unclear, as patient was on CRRT with normal potassium at this time. Given the lack of a unifying diagnosis and her constellation of laboratory abnormalities including persistent elevation in lactic acid, triglycerides, CK, and ammonia, concern was raised for a possible inborn error of metabolism. Rapid trio whole exome sequencing was performed, and was diagnostic for Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency. The patient was treated with triheptanoin. After an extended ICU and inpatient rehab course, she was discharged home with excellent functional status. Discussion Adult-onset episodic myopathic form of VLCAD deficiency is an inborn error of metabolism that is most frequently diagnosed in childhood; however, in some cases the diagnosis may be missed during early life. In adults, this condition presents with intermittent rhabdomyolysis, sometimes provoked by exercise; however, it can occur without a clear precipitant. This case demonstrates the utility of whole exome sequencing in the adult ICU, which can be a cost-effective test in appropriately selected patients. This abstract is funded by: None
2026-01-28 | Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.
2025-12-05 | Perioperative Management of a Patient With Very Long Chain Acyl-CoA Dehydrogenase Deficiency Undergoing Laparoscopic Sleeve Gastrectomy: First Report of Bariatric Surgery in VLCADD.
Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is a rare inherited disorder of mitochondrial fatty acid β-oxidation that predisposes patients to metabolic crises, rhabdomyolysis, and cardiomyopathy. Surgical stress, fasting, and anaesthesia may precipitate metabolic decompensation. We present the case of a 65-year-old female with late-onset VLCADD, multiple comorbidities, and chronic kidney disease (CKD) stage 3 who underwent laparoscopic sleeve gastrectomy. Despite perioperative glucose infusion, normothermia, and careful anaesthetic planning, she developed postoperative rhabdomyolysis. This case highlights perioperative challenges in VLCADD, provides practical strategies for anaesthetic and nutritional management, and, to our knowledge, represents the first report of bariatric surgery in a patient with VLCADD. Long-term follow-up demonstrated sustained weight loss, improved cardiometabolic profile, and stable muscle and renal function.
2026-05-01 | A25-23 A 34-Year-Old Woman With Hyperammonemia, Rhabdomyolysis, and Recurrent Tachyarrhythmias
Abstract Introduction While rare, inborn errors of metabolism occasionally evade detection during childhood. These diagnoses can lead to sudden onset of life-threatening multi-system organ failure requiring treatment in adult ICUs. Early recognition of patterns of abnormalities that can suggest an undiagnosed genetic disorder provides an opportunity to obtain rapid whole genome sequencing, which can facilitate diagnosis and the initiation of lifesaving treatment. Case Report A 34-year-old woman with a history of endometriosis and “fatty liver disease” was found unresponsive on the floor of her home after one day of nausea, vomiting, and confusion. She was intubated by EMS due to altered mental status. Initial pre-hospital glucose was 30 mg/dL, requiring D10 administration prior to hospital arrival. Admission labs were notable for mild anemia, elevated lactate (6.2), hyperammonemia (175), elevated CPK (3131), and profound acidemia (pH 7.08). Urine drug screen was negative. A broad infectious workup was negative. CT chest, abdomen, and pelvis was unrevealing. She was admitted to the ICU, where she was found to be in distributive shock requiring initiation of norepinephrine. A few hours later, she experienced a precipitous increase in pressor requirements followed by a ventricular-fibrillation cardiac arrest, which lasted 7 minutes. Her post-arrest labs were notable for hyperkalemia, prompting initiation of continuous renal replacement therapy. A similar decompensation including a second ventricular-fibrillation arrest occurred the following day, requiring 30 minutes of ACLS. The underlying etiology of the second arrest was unclear, as patient was on CRRT with normal potassium at this time. Given the lack of a unifying diagnosis and her constellation of laboratory abnormalities including persistent elevation in lactic acid, triglycerides, CK, and ammonia, concern was raised for a possible inborn error of metabolism. Rapid trio whole exome sequencing was performed, and was diagnostic for Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency. The patient was treated with triheptanoin. After an extended ICU and inpatient rehab course, she was discharged home with excellent functional status. Discussion Adult-onset episodic myopathic form of VLCAD deficiency is an inborn error of metabolism that is most frequently diagnosed in childhood; however, in some cases the diagnosis may be missed during early life. In adults, this condition presents with intermittent rhabdomyolysis, sometimes provoked by exercise; however, it can occur without a clear precipitant. This case demonstrates the utility of whole exome sequencing in the adult ICU, which can be a cost-effective test in appropriately selected patients. This abstract is funded by: None
2026-01-28 | Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.
2025-12-05 | Perioperative Management of a Patient With Very Long Chain Acyl-CoA Dehydrogenase Deficiency Undergoing Laparoscopic Sleeve Gastrectomy: First Report of Bariatric Surgery in VLCADD.
Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is a rare inherited disorder of mitochondrial fatty acid β-oxidation that predisposes patients to metabolic crises, rhabdomyolysis, and cardiomyopathy. Surgical stress, fasting, and anaesthesia may precipitate metabolic decompensation. We present the case of a 65-year-old female with late-onset VLCADD, multiple comorbidities, and chronic kidney disease (CKD) stage 3 who underwent laparoscopic sleeve gastrectomy. Despite perioperative glucose infusion, normothermia, and careful anaesthetic planning, she developed postoperative rhabdomyolysis. This case highlights perioperative challenges in VLCADD, provides practical strategies for anaesthetic and nutritional management, and, to our knowledge, represents the first report of bariatric surgery in a patient with VLCADD. Long-term follow-up demonstrated sustained weight loss, improved cardiometabolic profile, and stable muscle and renal function.
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Drug Discovery Landscape
2 orphan drug designations for Very long chain acyl-CoA dehydrogenase deficiency.
2 orphan drug designations for Very long chain acyl-CoA dehydrogenase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Triheptanoin | small molecules | EMA | 2015-06-19 | — | Ultragenyx Netherlands B.V. |
Triheptanoin | small molecules | EMA | 2012-12-06 | — | B. Braun Melsungen AG |
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