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:
categories:
Small molecules
proteins
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.
2001-05-01 | Conversion of ?-butyrobetaine to L -carnitine by Achromobacter cycloclast
-Carnitine is an ubiquitous substance that plays a major role in the transportation of long-chain fatty acids. We investigated crucial factors that influence microbial conversion of γ-butyrobetaine to L-carnitine using an Achromobacter cycloclast strain. Two-stage culture results showed that γ-butyrobetaine induced enzymes essential for the conversion, which suggests that the precursor should be present in the initial cell growth stage. The addition of yeast extract enhanced L-carnitine production whereas inorganic nitrogen sources inhibited it. Under nitrogen-limiting conditions, the cells accumulated poly-β-hydroxybutyrate instead of L-carnitine. Among the trace elements tested, nickel addition enhanced L-carnitine production by almost twice that of the control and copper strongly inhibited the conversion. L-Carnitine production was reduced when the medium contained inorganic salts of sodium, potassium, and calcium at a concentration greater than 2 g l−1. A higher L-carnitine yield was achieved when cells were incubated in a lower culture volume. The optimal pH for L-carnitine production was 5 to 5.5, whereas that of growth was 7.0, indicating that a pH shift was required. Under optimal conditions, L-carnitine concentrations as high as 15 g l−1 were obtained in 62 h with a 45% molar conversion yield. Journal of Industrial Microbiology & Biotechnology (2001) 26, 309–315.
1986-05-01 | Effect of growth hormone on fatty acid oxidation: Growth hormone increases the activity of 2,4-dienoyl-CoA reductase in mitochondria
The effect of growth hormone on the β-oxidation of saturated and unsaturated fatty acids was studied with mitochondria isolated from control rats, hypophysectomized rats, and hypophysectomized rats treated with growth hormone. Rates of respiration supported by polyunsaturated fatty acylcarnitines, in contrast to rates observed with palmitoylcarnitine or oleoylcarnitine, were slightly lower in hypophysectomized rats than in normal rats, but were higher in hypophysectomized rats treated with growth hormone. The effects were most pronounced with docosahexaenoylcarnitine, the substrate with the highest degree of unsaturation. Since uncoupling of mitochondria with 2,4-dinitrophenol resulted in lower rates of docosahexaenoylcarnitine-supported respiration, while substitution of ATP for ADP yielded higher rates, it appears that energy is required for the effective oxidation of polyunsaturated fatty acids. Growth hormone treatment of hypophysectomized rats caused a threefold increase in the activity of 2,4-dienoyl-CoA reductase or 4-enoyl-CoA reductase (EC 1.3.1.34) in mitochondria, but not in peroxisomes. The activities of other β-oxidation enzymes remained virtually unchanged. Rates of acetoacetate formation from linolenoylcarnitine, but not from palmitoylcarnitine, were stimulated by glutamate in mitochondria from hypophysectomized rats and hypophysectomized rats treated with growth hormone. All data together lead to the conclusion that the mitochondrial oxidation of highly polyunsaturated fatty acids is limited by the availability of NADPH and the activity of 2,4-dienoyl-CoA reductase which is induced by growth hormone treatment.
1965-08-01 | The effect of treatment of rats with pituitary growth hormone on the activities of some enzymes involved in fatty acid degradation and synthesis
1. Measurements have been made of the activities of acyl-CoA dehydrogenase, enoyl-CoA hydratase, beta-hydroxyacyl-CoA dehydrogenase and ketothiolase in the livers of rats treated for either 12hr. or 3 days with pituitary growth hormone. 2. There was a significant increase in the activity of acyl-CoA dehydrogenase in rats treated with the hormone for 3 days. 3. Measurements were also made of the lipogenic enzymes acetyl-CoA carboxylase and palmitate synthase in the livers of similarly treated animals. 4. There was a depression of the activity of both enzymes after 12hr. treatment and a further decline after 3 days. 5. The results are discussed in relation to the known increase in the rate of fatty acid oxidation and inhibition of fatty acid synthesis in rats treated with growth hormone.
small molecules
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
2025-11-12 | Long-Chain Fatty Acid Beta-Oxidation Defects: A Case Series and Literature Review.
Fatty acid beta-oxidation defects (FAOD) are a subgroup of lipid myopathies with heterogeneous presentations. Clinical presentation may manifest as muscular weakness, cramps, postexercise myalgias, and episodic rhabdomyolysis in children or adults. Our objective was to describe the clinical manifestations, biochemical, anatomopathological, and molecular results in a series of adult patients diagnosed with FAOD during adolescence or adulthood at five centers in Argentina. A total of seven patients with carnitine palmitoyltransferase-2 (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency were reported. The definite diagnosis of metabolic myopathies due to FAOD requires an understanding of clinical, biochemical, neurophysiological, and muscular imaging/biopsy patterns. All patients in this series consulted pediatricians, general practitioners, rheumatologists, and orthopedists for years, underscoring the need to disseminate these presentation patterns across various medical specialties. Early diagnosis and treatment using traditional diets and new pharmacological strategies not only enhance the quality of life, but also improve survival in these patients.
2025-03-26 | Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.
Mitochondria, also known as the powerhouse of cells, have an important role in cellular metabolism and energy production. However, during Mitochondrial Dysfunction (MD), it is known to generate reactive oxidative species and induce cellular apoptosis. A number of research findings have linked MD to various diseases, highlighting its critical role in maintaining health and contributing to disease development. In this regard, recent research has revealed that disruptions in lipid metabolism, especially in fatty acid oxidation, are significant contributors to MD. However, the precise mechanisms by which these defects lead to disease remain poorly understood. This review explores how disruptions in lipid metabolism are responsible for triggering oxidative stress, inflammation, and cellular damage, leading to impaired mitochondrial function. By examining specific fatty acid oxidation disorders, such as carnitine palmitoyltransferase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency, this review aims to uncover the underlying molecular pathways connecting lipid metabolism to mitochondrial dysfunction. Furthermore, MD is a common underlying mechanism in a wide array of diseases, including neurodegenerative disorders and metabolic syndromes. Understanding the mechanisms behind mitochondrial malfunction may aid in the development of tailored therapies to restore mitochondrial health and treat intricate health conditions.
2023-12-14 | 18 Months of Treatment with Triheptanoin in 2 Patients with Long Chain Fatty Acid Oxidation Disorders.
Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD. Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP. Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed. In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment.
2023-11-05 | Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect
Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin—a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone—can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD−/−) mice with 13C3-glycerol in the presence and absence of heptanoate (C7). The incorporation of 13C3-glycerol into blood glucose was higher in VLCAD−/− mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with 13C enrichment of liver metabolites in VLCAD−/− mice. In contrast, the C7 bolus significantly decreased the 13C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD−/− mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.
gene therapies
2025-03-17 | P019: Comparison of treatment efficacy of very long chain acyl-CoA (VLCAD) deficiency with an AAV9.hVLCAD vector, synthetic VLCAD mRNA, and triheptanoin
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is the most prevalent long chain fatty acid oxidation disorder, characterized by hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. Previously we have reported the creation of a robust muscle specific long chain acyl-CoA dehydrogenase on a complete VLCAD deficient background (mAcadl-/-:Acadvl-/-; MDKO) mouse model exhibiting the major clinical manifestations in adolescents and adults, recurrent e rhabdomyolysis and progressive cardiomyopathy.
2024-08-06 | Newborn screening for long-chain fatty acid oxidation disorders
Long-chain fatty acid oxidation disorders (lcFAOD) are a group of metabolic disorders where the body cannot properly use dietary long-chain fatty acids (LCFAs) for energy. LCFAs are crucial energy sources, particularly during fasting, fever, or exercise. Genetic variants in the proteins or enzymes involved in the long-chain fatty acid oxidation pathway can cause lcFAOD, leading to the accumulation of specific long-chain acyl-CoAs and their carnitine derivatives, known as long-chain acylcarnitines. Symptoms of lcFAOD include hypoglycemia, myopathy, rhabdomyolysis, exercise intolerance, cardiomyopathy, and arrhythmia, which typically manifest during metabolic stress. Mitochondrial trifunctional protein (MTP) disorders uniquely present with pigmentary retinopathy and peripheral neuropathy. Newborn screening (NBS) aims to promptly diagnose conditions that can cause irreversible harm early in life, preventing severe outcomes through early treatment. Mass spectrometry allows for the detection of multiple metabolites in dried blood spots, enabling the inclusion of numerous disorders in NBS programs worldwide. In 2007, the Netherlands included two lcFAOD, very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), in their NBS program, showing benefits in preventing severe hypoglycemia. Despite its benefits, NBS also presents several challenges. Utilizing a wide variety of methods, including in vitro experiments, innovative monitoring techniques, testing protocols, questionnaires, and retrospective chart research, the research described in this thesis aimed to identify and clarify some of the challenges introduced by NBS with a focus on lcFAOD. One of the discussed challenges is the risk of over- and underdiagnosis. Sensitive methods detect minor biochemical abnormalities, potentially identifying mildly affected or asymptomatic individuals, raising questions about the benefits of NBS for these cases. Conversely, some patients, particularly those with thermo-sensitive lcFAOD may be missed due to the absence of characteristic acylcarnitine abnormalities at normal temperatures. To enhance early recognition, genetic screening may be beneficial. Predicting prognosis after NBS diagnosis is crucial to balance early disease detection and avoiding unnecessary treatment, but remains difficult. Studies identified candidate biomarkers for disease severity, such as C18:2-carnitine for VLCADD, which can predict severe phenotypes, and lysophosphatidylcholine (LPC)(14:1), a potential severity marker for VLCADD. For LCHADD, a novel lipid class, S-(3-hydroxyacyl)cysteamines, was discovered as a specific biomarker. Understanding the natural history of NBS-diagnosed lcFAOD patients is vital for prognosis and personalized treatment. Research involving exercise tests and quantitative MRI (qMRI) in adolescent lcFAOD patients revealed variable exercise capacities and potential disease markers. These insights may help tailor monitoring and treatment strategies, though long-term monitoring remains necessary to understand the disease course and develop evidence-based guidelines. Current treatments, such as dietary management and preventing catabolism, do not completely prevent symptoms in all lcFAOD patients. Future approaches may involve gene therapy, aiming to correct the genetic root cause of the disorders. The ultimate goal is personalized treatment and early disease stratification to provide optimal care while minimizing unnecessary interventions and burden.
2019-04-17 | AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency
Abstract Very‐long chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD −/− ), and (2) to determine if AAV9‐mediated gene therapy improves respiratory function. For the first aim, VLCAD −/− and wild‐type (WT) mice underwent an exercise/fast “stress protocol” and awake spontaneous breathing was evaluated using whole‐body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO 2 : 0.21; FiCO 2 : 0.07; nitrogen balance). During hypercapnia, VLCAD −/− mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD −/− animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9‐VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno‐staining with anti‐human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD −/− mice and a single injection with AAV9‐VLCAD gene therapy ameliorates breathing.
2012-03-06 | Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy
Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 1012 vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD−/− mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD−/− mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD−/− mice maintained euglycemia, whereas untreated VLCAD−/− mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans.
2010-06-07 | Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models
Abstract Mouse models have been designed for a number of fatty acid oxidation defects. Studies in these mouse models have demonstrated that different pathogenetic mechanisms play a role in the pathophysiology of defects of fatty acid oxidation. Supplementation with L‐carnitine does not prevent low tissue carnitine levels and induces acylcarnitine production having potentially toxic effects, as presented in very‐long‐chain acyl‐CoA dehydrogenase (VLCAD)‐deficient mice. Energy deficiency appears to be an important mechanism in the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation defects and is also the underlying mechanism of cold intolerance. Hypoglycemia as one major clinical sign in all fatty acid oxidation defects occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake rather than to transcriptional changes that are also observed simultaneously, as presented in medium‐chain acyl‐CoA dehydrogenase (MCAD)‐deficient mice. There are reports that an impaired fatty acid oxidation also plays a role in intrauterine life. The embryonic loss demonstrated for some enzyme defects in the mouse supports this hypothesis. However, the exact mechanisms are unknown. This observation correlates to maternal hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, as observed in pregnancies carrying a long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD)‐deficient fetus. Synergistic heterozygosity has been shown in isolated patients and in mouse models to be associated with clinical phenotypes common to fatty acid oxidation disorders. Synergistic mutations may also modulate severity of the clinical phenotype and explain in part clinical heterogeneity of fatty acid oxidation defects. In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies.
oligonucleotides
2023-01-27 | Synthetic mRNA rescues very long-chain acyl-CoA dehydrogenase deficiency in patient fibroblasts and a murine model.
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of long chain fatty acid β-oxidation (FAO) with limited treatment options. Patients present with heterogeneous clinical phenotypes affecting predominantly heart, liver, and skeletal muscle. While VLCAD deficiency is a systemic disease, restoration of liver FAO has the potential to improve symptoms more broadly due to increased total body ATP production and reduced accumulation of potentially toxic metabolites. We explored the use of synthetic human VLCAD (hVLCAD) mRNA and lipid nanoparticle encapsulated hVLCAD mRNA (LNP-VLCAD) to generate functional VLCAD enzyme in patient fibroblasts derived from VLCAD deficient patients, mouse embryonic fibroblasts, hepatocytes isolated from VLCAD knockout (Acadvl-/-) mice, and Acadvl-/- mice to reverse the metabolic effects of the deficiency. Transfection of all cell types with hVLCAD mRNA resulted in high level expression of protein that localized to mitochondria with increased enzyme activity. Intravenous administration of LNP-VLCAD to Acadvl-/- mice produced a significant amount of VLCAD protein in liver, which declined over a week. Treated Acadvl-/- mice showed reduced hepatic steatosis, were more resistant to cold stress, and accumulated less toxic metabolites in blood than untreated animals. Results from this study support the potential for hVLCAD mRNA for treatment of VLCAD deficiency.
proteins
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.
2001-05-01 | Conversion of ?-butyrobetaine to L -carnitine by Achromobacter cycloclast
-Carnitine is an ubiquitous substance that plays a major role in the transportation of long-chain fatty acids. We investigated crucial factors that influence microbial conversion of γ-butyrobetaine to L-carnitine using an Achromobacter cycloclast strain. Two-stage culture results showed that γ-butyrobetaine induced enzymes essential for the conversion, which suggests that the precursor should be present in the initial cell growth stage. The addition of yeast extract enhanced L-carnitine production whereas inorganic nitrogen sources inhibited it. Under nitrogen-limiting conditions, the cells accumulated poly-β-hydroxybutyrate instead of L-carnitine. Among the trace elements tested, nickel addition enhanced L-carnitine production by almost twice that of the control and copper strongly inhibited the conversion. L-Carnitine production was reduced when the medium contained inorganic salts of sodium, potassium, and calcium at a concentration greater than 2 g l−1. A higher L-carnitine yield was achieved when cells were incubated in a lower culture volume. The optimal pH for L-carnitine production was 5 to 5.5, whereas that of growth was 7.0, indicating that a pH shift was required. Under optimal conditions, L-carnitine concentrations as high as 15 g l−1 were obtained in 62 h with a 45% molar conversion yield. Journal of Industrial Microbiology & Biotechnology (2001) 26, 309–315.
1986-05-01 | Effect of growth hormone on fatty acid oxidation: Growth hormone increases the activity of 2,4-dienoyl-CoA reductase in mitochondria
The effect of growth hormone on the β-oxidation of saturated and unsaturated fatty acids was studied with mitochondria isolated from control rats, hypophysectomized rats, and hypophysectomized rats treated with growth hormone. Rates of respiration supported by polyunsaturated fatty acylcarnitines, in contrast to rates observed with palmitoylcarnitine or oleoylcarnitine, were slightly lower in hypophysectomized rats than in normal rats, but were higher in hypophysectomized rats treated with growth hormone. The effects were most pronounced with docosahexaenoylcarnitine, the substrate with the highest degree of unsaturation. Since uncoupling of mitochondria with 2,4-dinitrophenol resulted in lower rates of docosahexaenoylcarnitine-supported respiration, while substitution of ATP for ADP yielded higher rates, it appears that energy is required for the effective oxidation of polyunsaturated fatty acids. Growth hormone treatment of hypophysectomized rats caused a threefold increase in the activity of 2,4-dienoyl-CoA reductase or 4-enoyl-CoA reductase (EC 1.3.1.34) in mitochondria, but not in peroxisomes. The activities of other β-oxidation enzymes remained virtually unchanged. Rates of acetoacetate formation from linolenoylcarnitine, but not from palmitoylcarnitine, were stimulated by glutamate in mitochondria from hypophysectomized rats and hypophysectomized rats treated with growth hormone. All data together lead to the conclusion that the mitochondrial oxidation of highly polyunsaturated fatty acids is limited by the availability of NADPH and the activity of 2,4-dienoyl-CoA reductase which is induced by growth hormone treatment.
1965-08-01 | The effect of treatment of rats with pituitary growth hormone on the activities of some enzymes involved in fatty acid degradation and synthesis
1. Measurements have been made of the activities of acyl-CoA dehydrogenase, enoyl-CoA hydratase, beta-hydroxyacyl-CoA dehydrogenase and ketothiolase in the livers of rats treated for either 12hr. or 3 days with pituitary growth hormone. 2. There was a significant increase in the activity of acyl-CoA dehydrogenase in rats treated with the hormone for 3 days. 3. Measurements were also made of the lipogenic enzymes acetyl-CoA carboxylase and palmitate synthase in the livers of similarly treated animals. 4. There was a depression of the activity of both enzymes after 12hr. treatment and a further decline after 3 days. 5. The results are discussed in relation to the known increase in the rate of fatty acid oxidation and inhibition of fatty acid synthesis in rats treated with growth hormone.
small molecules
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
2025-11-12 | Long-Chain Fatty Acid Beta-Oxidation Defects: A Case Series and Literature Review.
Fatty acid beta-oxidation defects (FAOD) are a subgroup of lipid myopathies with heterogeneous presentations. Clinical presentation may manifest as muscular weakness, cramps, postexercise myalgias, and episodic rhabdomyolysis in children or adults. Our objective was to describe the clinical manifestations, biochemical, anatomopathological, and molecular results in a series of adult patients diagnosed with FAOD during adolescence or adulthood at five centers in Argentina. A total of seven patients with carnitine palmitoyltransferase-2 (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency were reported. The definite diagnosis of metabolic myopathies due to FAOD requires an understanding of clinical, biochemical, neurophysiological, and muscular imaging/biopsy patterns. All patients in this series consulted pediatricians, general practitioners, rheumatologists, and orthopedists for years, underscoring the need to disseminate these presentation patterns across various medical specialties. Early diagnosis and treatment using traditional diets and new pharmacological strategies not only enhance the quality of life, but also improve survival in these patients.
2025-03-26 | Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.
Mitochondria, also known as the powerhouse of cells, have an important role in cellular metabolism and energy production. However, during Mitochondrial Dysfunction (MD), it is known to generate reactive oxidative species and induce cellular apoptosis. A number of research findings have linked MD to various diseases, highlighting its critical role in maintaining health and contributing to disease development. In this regard, recent research has revealed that disruptions in lipid metabolism, especially in fatty acid oxidation, are significant contributors to MD. However, the precise mechanisms by which these defects lead to disease remain poorly understood. This review explores how disruptions in lipid metabolism are responsible for triggering oxidative stress, inflammation, and cellular damage, leading to impaired mitochondrial function. By examining specific fatty acid oxidation disorders, such as carnitine palmitoyltransferase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency, this review aims to uncover the underlying molecular pathways connecting lipid metabolism to mitochondrial dysfunction. Furthermore, MD is a common underlying mechanism in a wide array of diseases, including neurodegenerative disorders and metabolic syndromes. Understanding the mechanisms behind mitochondrial malfunction may aid in the development of tailored therapies to restore mitochondrial health and treat intricate health conditions.
2023-12-14 | 18 Months of Treatment with Triheptanoin in 2 Patients with Long Chain Fatty Acid Oxidation Disorders.
Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD. Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP. Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed. In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment.
2023-11-05 | Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect
Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin—a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone—can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD−/−) mice with 13C3-glycerol in the presence and absence of heptanoate (C7). The incorporation of 13C3-glycerol into blood glucose was higher in VLCAD−/− mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with 13C enrichment of liver metabolites in VLCAD−/− mice. In contrast, the C7 bolus significantly decreased the 13C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD−/− mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.
gene therapies
2025-03-17 | P019: Comparison of treatment efficacy of very long chain acyl-CoA (VLCAD) deficiency with an AAV9.hVLCAD vector, synthetic VLCAD mRNA, and triheptanoin
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is the most prevalent long chain fatty acid oxidation disorder, characterized by hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. Previously we have reported the creation of a robust muscle specific long chain acyl-CoA dehydrogenase on a complete VLCAD deficient background (mAcadl-/-:Acadvl-/-; MDKO) mouse model exhibiting the major clinical manifestations in adolescents and adults, recurrent e rhabdomyolysis and progressive cardiomyopathy.
2024-08-06 | Newborn screening for long-chain fatty acid oxidation disorders
Long-chain fatty acid oxidation disorders (lcFAOD) are a group of metabolic disorders where the body cannot properly use dietary long-chain fatty acids (LCFAs) for energy. LCFAs are crucial energy sources, particularly during fasting, fever, or exercise. Genetic variants in the proteins or enzymes involved in the long-chain fatty acid oxidation pathway can cause lcFAOD, leading to the accumulation of specific long-chain acyl-CoAs and their carnitine derivatives, known as long-chain acylcarnitines. Symptoms of lcFAOD include hypoglycemia, myopathy, rhabdomyolysis, exercise intolerance, cardiomyopathy, and arrhythmia, which typically manifest during metabolic stress. Mitochondrial trifunctional protein (MTP) disorders uniquely present with pigmentary retinopathy and peripheral neuropathy. Newborn screening (NBS) aims to promptly diagnose conditions that can cause irreversible harm early in life, preventing severe outcomes through early treatment. Mass spectrometry allows for the detection of multiple metabolites in dried blood spots, enabling the inclusion of numerous disorders in NBS programs worldwide. In 2007, the Netherlands included two lcFAOD, very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), in their NBS program, showing benefits in preventing severe hypoglycemia. Despite its benefits, NBS also presents several challenges. Utilizing a wide variety of methods, including in vitro experiments, innovative monitoring techniques, testing protocols, questionnaires, and retrospective chart research, the research described in this thesis aimed to identify and clarify some of the challenges introduced by NBS with a focus on lcFAOD. One of the discussed challenges is the risk of over- and underdiagnosis. Sensitive methods detect minor biochemical abnormalities, potentially identifying mildly affected or asymptomatic individuals, raising questions about the benefits of NBS for these cases. Conversely, some patients, particularly those with thermo-sensitive lcFAOD may be missed due to the absence of characteristic acylcarnitine abnormalities at normal temperatures. To enhance early recognition, genetic screening may be beneficial. Predicting prognosis after NBS diagnosis is crucial to balance early disease detection and avoiding unnecessary treatment, but remains difficult. Studies identified candidate biomarkers for disease severity, such as C18:2-carnitine for VLCADD, which can predict severe phenotypes, and lysophosphatidylcholine (LPC)(14:1), a potential severity marker for VLCADD. For LCHADD, a novel lipid class, S-(3-hydroxyacyl)cysteamines, was discovered as a specific biomarker. Understanding the natural history of NBS-diagnosed lcFAOD patients is vital for prognosis and personalized treatment. Research involving exercise tests and quantitative MRI (qMRI) in adolescent lcFAOD patients revealed variable exercise capacities and potential disease markers. These insights may help tailor monitoring and treatment strategies, though long-term monitoring remains necessary to understand the disease course and develop evidence-based guidelines. Current treatments, such as dietary management and preventing catabolism, do not completely prevent symptoms in all lcFAOD patients. Future approaches may involve gene therapy, aiming to correct the genetic root cause of the disorders. The ultimate goal is personalized treatment and early disease stratification to provide optimal care while minimizing unnecessary interventions and burden.
2019-04-17 | AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency
Abstract Very‐long chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD −/− ), and (2) to determine if AAV9‐mediated gene therapy improves respiratory function. For the first aim, VLCAD −/− and wild‐type (WT) mice underwent an exercise/fast “stress protocol” and awake spontaneous breathing was evaluated using whole‐body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO 2 : 0.21; FiCO 2 : 0.07; nitrogen balance). During hypercapnia, VLCAD −/− mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD −/− animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9‐VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno‐staining with anti‐human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD −/− mice and a single injection with AAV9‐VLCAD gene therapy ameliorates breathing.
2012-03-06 | Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy
Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 1012 vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD−/− mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD−/− mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD−/− mice maintained euglycemia, whereas untreated VLCAD−/− mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans.
2010-06-07 | Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models
Abstract Mouse models have been designed for a number of fatty acid oxidation defects. Studies in these mouse models have demonstrated that different pathogenetic mechanisms play a role in the pathophysiology of defects of fatty acid oxidation. Supplementation with L‐carnitine does not prevent low tissue carnitine levels and induces acylcarnitine production having potentially toxic effects, as presented in very‐long‐chain acyl‐CoA dehydrogenase (VLCAD)‐deficient mice. Energy deficiency appears to be an important mechanism in the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation defects and is also the underlying mechanism of cold intolerance. Hypoglycemia as one major clinical sign in all fatty acid oxidation defects occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake rather than to transcriptional changes that are also observed simultaneously, as presented in medium‐chain acyl‐CoA dehydrogenase (MCAD)‐deficient mice. There are reports that an impaired fatty acid oxidation also plays a role in intrauterine life. The embryonic loss demonstrated for some enzyme defects in the mouse supports this hypothesis. However, the exact mechanisms are unknown. This observation correlates to maternal hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, as observed in pregnancies carrying a long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD)‐deficient fetus. Synergistic heterozygosity has been shown in isolated patients and in mouse models to be associated with clinical phenotypes common to fatty acid oxidation disorders. Synergistic mutations may also modulate severity of the clinical phenotype and explain in part clinical heterogeneity of fatty acid oxidation defects. In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies.
oligonucleotides
2023-01-27 | Synthetic mRNA rescues very long-chain acyl-CoA dehydrogenase deficiency in patient fibroblasts and a murine model.
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of long chain fatty acid β-oxidation (FAO) with limited treatment options. Patients present with heterogeneous clinical phenotypes affecting predominantly heart, liver, and skeletal muscle. While VLCAD deficiency is a systemic disease, restoration of liver FAO has the potential to improve symptoms more broadly due to increased total body ATP production and reduced accumulation of potentially toxic metabolites. We explored the use of synthetic human VLCAD (hVLCAD) mRNA and lipid nanoparticle encapsulated hVLCAD mRNA (LNP-VLCAD) to generate functional VLCAD enzyme in patient fibroblasts derived from VLCAD deficient patients, mouse embryonic fibroblasts, hepatocytes isolated from VLCAD knockout (Acadvl-/-) mice, and Acadvl-/- mice to reverse the metabolic effects of the deficiency. Transfection of all cell types with hVLCAD mRNA resulted in high level expression of protein that localized to mitochondria with increased enzyme activity. Intravenous administration of LNP-VLCAD to Acadvl-/- mice produced a significant amount of VLCAD protein in liver, which declined over a week. Treated Acadvl-/- mice showed reduced hepatic steatosis, were more resistant to cold stress, and accumulated less toxic metabolites in blood than untreated animals. Results from this study support the potential for hVLCAD mRNA for treatment of VLCAD deficiency.
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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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