RARE DISEASE
Medium chain acyl-CoA dehydrogenase deficiency
Medium chain acyl-CoA dehydrogenase deficiency
Medium chain acyl-CoA dehydrogenase deficiency
Synonyms: ACADM deficiency, Carnitine deficiency secondary to medium-chain acyl-CoA dehydrogenase deficiency, MCAD deficiency, MCADD, Medium chain acyl-coenzyme A dehydrogenase deficiency
Synonyms: ACADM deficiency, Carnitine deficiency secondary to medium-chain acyl-CoA dehydrogenase deficiency, MCAD deficiency, MCADD, Medium chain acyl-coenzyme A dehydrogenase deficiency
Synonyms: ACADM deficiency, Carnitine deficiency secondary to medium-chain acyl-CoA dehydrogenase deficiency, MCAD deficiency, MCADD, Medium chain acyl-coenzyme A dehydrogenase deficiency
Drug discovery
1
drug
With orphan designation
Overview
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder impairing mitochondrial fatty acid β-oxidation, leading to hypoketotic hypoglycemia, lethargy, hepatomegaly, and metabolic crises during fasting or illness. Caused by ACADM gene mutations, it is included in newborn screening. Early diagnosis allows preventive strategies, including avoidance of fasting and emergency glucose management, significantly reducing mortality and morbidity risks. Untreated, it can cause seizures, coma, or sudden death [1][2][9].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
102 drug discovery papers about Medium chain acyl-CoA dehydrogenase deficiency, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
102 drug discovery papers about Medium chain acyl-CoA dehydrogenase deficiency, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-28 | Gymnema sylvestre Extract for Alternative Glucose Metabolism Pathway Activation
Gymnemic acids in Gymnema sylvestre activate FOXO1-mediated gluconeogenesis through G6PC and PCK1 upregulation while enhancing glycogen synthesis via GSK3β inhibition, providing glucose-based energy production to compensate for impaired fatty acid β-oxidation in MCADD patients
2026-04-28 | Bezafibrate-MCT Oil Combination Therapy for Enhanced Alternative Energy Metabolism
Bezafibrate activates PPARα to upregulate medium-chain acyl-CoA dehydrogenase (MCAD) and short-chain acyl-CoA dehydrogenase (SCAD) expression. Combined with medium-chain triglyceride oil, this bypasses the LCHAD deficiency by providing readily oxidizable medium-chain fatty acids while enhancing the enzymatic capacity for their metabolism through peroxisome proliferator response elements.
2026-04-28 | Bezafibrate-Riboflavin Combination Therapy for MCADD Metabolic Rescue
Bezafibrate acts as a PPAR-α agonist upregulating ACADM gene expression and residual enzyme activity, while riboflavin (vitamin B2) stabilizes the FAD cofactor binding domain of mutant ACADM proteins, preventing protein misfolding and enhancing catalytic efficiency
2026-02-07 | Energetic stress in combination with impaired fatty acid oxidation induces sequestration of CoA and adaptation of CoA metabolism.
Coenzyme A (CoA) is a vital cofactor involved in 8-10% of all metabolic reactions in human cells. Different inherited enzyme deficiencies in which the oxidation of acyl-CoAs is hampered have been hypothesised to share a phenotype characterised by toxic accumulation of acyl-CoA and a concomitant decline in free CoA (CoASH) levels, whereby CoASH becomes limiting for other metabolic reactions. This is referred to as CoASH sequestration. There is, however, limited experimental evidence for this hypothesis. Using a combination of approaches, we test this hypothesis in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common deficiency of mitochondrial fatty acid oxidation (mFAO), under energetic stress. Both in vitro MCAD-knockout (KO) HepG2 cells and a kinetic model of mFAO showed decreased CoASH, elevated medium-chain acyl-CoA, and decreased long-chain acyl-CoA levels. MCAD-KO mice exposed to fasting and cold as energetic stressors had a significantly increased total CoA pool and increased expression of CoA biosynthetic enzymes in the liver, indicative of an upregulated CoA biosynthesis. Expression of carnitine acyltransferases and acyl-CoA thioesterases, enzymes that liberate CoASH from acyl-CoAs, was also upregulated, suggesting an adaptive response of CoA metabolism to decreased CoASH. Finally, computational model simulations showed that a combination of elevated total CoA and thioesterase activity led to normalisation of both CoASH and medium-chain acyl-CoA levels. Together, the results provide the first evidence for the CoA sequestration hypothesis in MCADD. The observed adaptation of CoA metabolism under energetic stress may act as a compensatory response that counteracts CoASH depletion and accumulation of toxic medium-chain acyl-CoAs.
2026-01-30 | Tachycardiomyopathy-like presentation in neonatal MCAD deficiency: A novel cardiac phenotype.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia, while neonatal presentations are less common. Although the disorder classically manifests with metabolic decompensation, atypical cardiac involvement has occasionally been reported but remains exceedingly rare. MCADD is included in many newborn screening programs, enabling early detection and timely management. We report a full-term female neonate who, at 3 days of life, developed severe metabolic decompensation with refractory supraventricular tachyarrhythmias, severe systolic dysfunction, and biventricular dilation requiring maximal inotropic support. Expanded newborn screening revealed a profile consistent with MCADD, and genetic testing identified a homozygous variant in the ACADM gene, described according to HGVS nomenclature as ACADM(NM_000016.6):c.985A > C p.(Lys329Gln). Disease-specific management, including high-rate intravenous glucose administration, carnitine supplementation, and a tailored low-fat diet, resulted in complete normalization of cardiac function within 48 hours. This case represents a tachycardiomyopathy-like presentation of neonatal-onset MCADD, a novel and rarely described cardiac phenotype. It emphasizes the importance of considering fatty acid oxidation disorders in the differential diagnosis of unexplained arrhythmias and cardiomyopathy in neonates, particularly before newborn screening results are available. Early diagnosis and prompt initiation of metabolic treatment are essential to reverse potentially life-threatening cardiac manifestations in MCADD. This report highlights a novel phenotype and expands the clinical spectrum of neonatal-onset MCADD.
proteins
2026-08-17 | [Screening and genetic variation analysis of fatty acid oxidation disorder in neonates in Qingdao City].
To investigate the incidence, genetic mutation characteristics, and prognosis of fatty acid oxidation disorder (FAOD) in neonates in Qingdao. Clinical data of neonates diagnosed with FAOD from 2014 to 2023 at the Qingdao Neonatal Disease Screening Center were collected and analyzed to determine the incidence, genotype, and prognosis. Among 562 225 neonates screened, 42 were diagnosed with FAOD across six types, yielding an overall incidence of 1/13 386. Primary carnitine deficiency was the most common (20 cases, 48%), with one case showing growth retardation during follow-up. Medium-chain acyl-CoA dehydrogenase deficiency was identified in 6 cases, all of whom demonstrated normal development during follow-up. Short-chain acyl-CoA dehydrogenase deficiency was diagnosed in 5 cases, with one case exhibiting skin erythema, papules, scaling, and dryness during follow-up. Very-long-chain acyl-CoA dehydrogenase deficiency was diagnosed in 5 cases; during follow-up, one patient died and another experienced recurrent rhabdomyolysis. Short/branched-chain acyl-CoA dehydrogenase deficiency was found in 4 cases, with one case showing language regression during follow-up. Multiple acyl-CoA dehydrogenase deficiency was detected in 2 cases; during follow-up, one patient died and one exhibited delayed motor development. Genetic testing performed on 37 of the 42 patients with FAOD identified a hotspot mutation, c.1400C>G, in the SLC22A5 gene among those with primary carnitine deficiency, whereas no predominant hotspot mutations were detected in other FAOD subtypes. In Qingdao, primary carnitine deficiency is the most prevalent subtypes of FAOD in neonates, characterized by the hotspot mutation c.1400C>G in the SLC22A5 gene. Except for very-long-chain acyl-CoA dehydrogenase deficiency and multiple acyl-CoA dehydrogenase deficiency, most children with other FAOD subtypes have a favorable prognosis.
2026-08-11 | Medium Chain Acyl-CoA Dehydrogenase Deficiency; an Unexpected Cause of Neonatal Ketoacidosis.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) classically presents with hypoketotic hypoglycaemia; however, this presentation is now rare following the introduction of newborn screening. While children with MCADD may produce some ketones, severe ketoacidosis has not been previously described. Here we report two patients with MCADD presenting with severe ketoacidosis in the neonatal period prior to results of newborn screening. Patient 1 presented on Day 5 with hypoglycaemia, profound ketoacidosis and circulatory shock, and developed refractory ventricular tachycardia requiring extra-corporeal membrane oxygenation. Patient 2 presented on Day 4 with severe ketoacidosis, but only borderline hypoglycaemia. The diagnosis of MCADD was rapidly confirmed in both by analysis of acylcarnitines and urine organic acids, with subsequent genetic confirmation of ACADM mutations. We conclude that MCADD should be included in the differential diagnosis of neonatal ketoacidosis, with or without hypoglycaemia.
2026-03-24 | The role of neonatal screening in the diagnosis of a rare inherited metabolic disease (case study)
Hereditary metabolic diseases occur in all populations, but are usually rare. However, they have severe and in many cases fatal manifestations and outcomes. Objective of the study: to show the importance of neonatal screening in the diagnosis of familial cases of hereditary metabolic diseases using a clinical example of medium-chain acyl-CoA dehydrogenase deficiency. A family with three children was under observation. In child V., born in 2023, the following was revealed as part of the extended neonatal screening: “Medium-chain acyl-CoA dehydrogenase deficiency of fatty acids”. In the girl’s brother, a boy P., born in 2022, clinical symptoms debuted at the age of 1 year 11 months, which also indicated a metabolic disorder in the child. Given the hereditary nature of the disease, previously diagnosed in the boy’s sister, the child underwent a genetic examination aimed at finding this hereditary disease. The study confirmed the deficiency of medium-chain acyl-CoA dehydrogenase of fatty acids. Taking into account the anamnesis, pedigree, clinical picture, laboratory tests, molecular genetic examination, a conclusion was made about the familial nature of the disease. Considering that many patients do not have symptoms of this disease throughout their lives, the older brother of the children, boy A., born in 2012, and parents were also examined for mitochondrial fatty acid oxidation disorder. Boy A. and parents were determined to be heterozygous carriers. Conducting neonatal screening provides not only the opportunity to detect metabolic disorders at the preclinical stage of the disease, but also to verify a complex rare nosology in the family, selectively in older children suffering from unclear polymorphic symptoms. In addition, when conducting extended neonatal screening, the final stage includes a molecular genetic examination, which allows confirming the diagnosis of a hereditary disease, but also identifying heterozygous carriers of the mutant gene in the family and forming contingents that require systematic medical and genetic monitoring.
2026-03-02 | Exploring Deleterious Nonsynonymous SNPs in the ACADM Gene: Insights Into Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) via In Silico Analysis.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), a potentially lethal metabolic disorder, is often associated with single-nucleotide polymorphisms (SNPs) in the acyl-CoA dehydrogenase, medium-chain (ACADM) gene. The current research investigates the structural and functional implications of these genetic variants through diverse bioinformatics techniques. A range of in silico techniques were utilized to thoroughly evaluate the effect of nonsynonymous SNPs. Molecular docking and molecular dynamics simulation evaluation comprehensively validated the mutational impact on protein's stability. Gene interaction analysis demonstrated that ACADM is involved in several cellular pathways and co-expression networks. Two nsSNPs, rs121434282 and rs200724875, were found to have a significant impact on the composition and functionality of ACADM. This research lays the foundation for precision medicine advancements, specifically against metabolic disorders. Thorough validation of the proposed nsSNPs, supported by animal models, is crucial for understanding their role in MCADD.
2025-09-30 | Clinical, Biochemical and Molecular Characterisation of Newborns With Fatty Acid β-Oxidation Disorders: Novel Variants in the ACADM , ACADVL and SLC22A5 Genes.
In this study, we aimed to assess clinical, laboratory and molecular features of newborns with clinical suspicion for systemic primary carnitine deficiency (CUD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). The implementation of newborn screening programs for fatty acid β-oxidation disorders (FAODs) has changed the natural course of these diseases, facilitating the initiation of preventive or therapeutic measures for affected newborns shortly after birth. This study included 94 newborns who were admitted between 2016 and 2023 because of biochemical signs of CUD, MCADD and VLCADD, and provided clinical, biochemical and genotypic data. Definitive molecular diagnosis confirmed that 16/94 newborns (17%) were true positives of the NBS, and 17 novel variants were detected in SLC22A5, ACADM and ACADVL genes. We assessed the clinical evolution of patients over time. This study expands the genotypic spectrum of SLC22A5, ACADM and ACADVL and highlights the role of genetics in identifying and correctly characterising FAODs.
oligonucleotides
2023-07-07 | Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
small molecules
2026-04-28 | Gymnema sylvestre Extract for Alternative Glucose Metabolism Pathway Activation
Gymnemic acids in Gymnema sylvestre activate FOXO1-mediated gluconeogenesis through G6PC and PCK1 upregulation while enhancing glycogen synthesis via GSK3β inhibition, providing glucose-based energy production to compensate for impaired fatty acid β-oxidation in MCADD patients
2026-04-28 | Bezafibrate-MCT Oil Combination Therapy for Enhanced Alternative Energy Metabolism
Bezafibrate activates PPARα to upregulate medium-chain acyl-CoA dehydrogenase (MCAD) and short-chain acyl-CoA dehydrogenase (SCAD) expression. Combined with medium-chain triglyceride oil, this bypasses the LCHAD deficiency by providing readily oxidizable medium-chain fatty acids while enhancing the enzymatic capacity for their metabolism through peroxisome proliferator response elements.
2026-04-28 | Bezafibrate-Riboflavin Combination Therapy for MCADD Metabolic Rescue
Bezafibrate acts as a PPAR-α agonist upregulating ACADM gene expression and residual enzyme activity, while riboflavin (vitamin B2) stabilizes the FAD cofactor binding domain of mutant ACADM proteins, preventing protein misfolding and enhancing catalytic efficiency
2026-02-07 | Energetic stress in combination with impaired fatty acid oxidation induces sequestration of CoA and adaptation of CoA metabolism.
Coenzyme A (CoA) is a vital cofactor involved in 8-10% of all metabolic reactions in human cells. Different inherited enzyme deficiencies in which the oxidation of acyl-CoAs is hampered have been hypothesised to share a phenotype characterised by toxic accumulation of acyl-CoA and a concomitant decline in free CoA (CoASH) levels, whereby CoASH becomes limiting for other metabolic reactions. This is referred to as CoASH sequestration. There is, however, limited experimental evidence for this hypothesis. Using a combination of approaches, we test this hypothesis in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common deficiency of mitochondrial fatty acid oxidation (mFAO), under energetic stress. Both in vitro MCAD-knockout (KO) HepG2 cells and a kinetic model of mFAO showed decreased CoASH, elevated medium-chain acyl-CoA, and decreased long-chain acyl-CoA levels. MCAD-KO mice exposed to fasting and cold as energetic stressors had a significantly increased total CoA pool and increased expression of CoA biosynthetic enzymes in the liver, indicative of an upregulated CoA biosynthesis. Expression of carnitine acyltransferases and acyl-CoA thioesterases, enzymes that liberate CoASH from acyl-CoAs, was also upregulated, suggesting an adaptive response of CoA metabolism to decreased CoASH. Finally, computational model simulations showed that a combination of elevated total CoA and thioesterase activity led to normalisation of both CoASH and medium-chain acyl-CoA levels. Together, the results provide the first evidence for the CoA sequestration hypothesis in MCADD. The observed adaptation of CoA metabolism under energetic stress may act as a compensatory response that counteracts CoASH depletion and accumulation of toxic medium-chain acyl-CoAs.
2026-01-30 | Tachycardiomyopathy-like presentation in neonatal MCAD deficiency: A novel cardiac phenotype.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia, while neonatal presentations are less common. Although the disorder classically manifests with metabolic decompensation, atypical cardiac involvement has occasionally been reported but remains exceedingly rare. MCADD is included in many newborn screening programs, enabling early detection and timely management. We report a full-term female neonate who, at 3 days of life, developed severe metabolic decompensation with refractory supraventricular tachyarrhythmias, severe systolic dysfunction, and biventricular dilation requiring maximal inotropic support. Expanded newborn screening revealed a profile consistent with MCADD, and genetic testing identified a homozygous variant in the ACADM gene, described according to HGVS nomenclature as ACADM(NM_000016.6):c.985A > C p.(Lys329Gln). Disease-specific management, including high-rate intravenous glucose administration, carnitine supplementation, and a tailored low-fat diet, resulted in complete normalization of cardiac function within 48 hours. This case represents a tachycardiomyopathy-like presentation of neonatal-onset MCADD, a novel and rarely described cardiac phenotype. It emphasizes the importance of considering fatty acid oxidation disorders in the differential diagnosis of unexplained arrhythmias and cardiomyopathy in neonates, particularly before newborn screening results are available. Early diagnosis and prompt initiation of metabolic treatment are essential to reverse potentially life-threatening cardiac manifestations in MCADD. This report highlights a novel phenotype and expands the clinical spectrum of neonatal-onset MCADD.
proteins
2026-08-17 | [Screening and genetic variation analysis of fatty acid oxidation disorder in neonates in Qingdao City].
To investigate the incidence, genetic mutation characteristics, and prognosis of fatty acid oxidation disorder (FAOD) in neonates in Qingdao. Clinical data of neonates diagnosed with FAOD from 2014 to 2023 at the Qingdao Neonatal Disease Screening Center were collected and analyzed to determine the incidence, genotype, and prognosis. Among 562 225 neonates screened, 42 were diagnosed with FAOD across six types, yielding an overall incidence of 1/13 386. Primary carnitine deficiency was the most common (20 cases, 48%), with one case showing growth retardation during follow-up. Medium-chain acyl-CoA dehydrogenase deficiency was identified in 6 cases, all of whom demonstrated normal development during follow-up. Short-chain acyl-CoA dehydrogenase deficiency was diagnosed in 5 cases, with one case exhibiting skin erythema, papules, scaling, and dryness during follow-up. Very-long-chain acyl-CoA dehydrogenase deficiency was diagnosed in 5 cases; during follow-up, one patient died and another experienced recurrent rhabdomyolysis. Short/branched-chain acyl-CoA dehydrogenase deficiency was found in 4 cases, with one case showing language regression during follow-up. Multiple acyl-CoA dehydrogenase deficiency was detected in 2 cases; during follow-up, one patient died and one exhibited delayed motor development. Genetic testing performed on 37 of the 42 patients with FAOD identified a hotspot mutation, c.1400C>G, in the SLC22A5 gene among those with primary carnitine deficiency, whereas no predominant hotspot mutations were detected in other FAOD subtypes. In Qingdao, primary carnitine deficiency is the most prevalent subtypes of FAOD in neonates, characterized by the hotspot mutation c.1400C>G in the SLC22A5 gene. Except for very-long-chain acyl-CoA dehydrogenase deficiency and multiple acyl-CoA dehydrogenase deficiency, most children with other FAOD subtypes have a favorable prognosis.
2026-08-11 | Medium Chain Acyl-CoA Dehydrogenase Deficiency; an Unexpected Cause of Neonatal Ketoacidosis.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) classically presents with hypoketotic hypoglycaemia; however, this presentation is now rare following the introduction of newborn screening. While children with MCADD may produce some ketones, severe ketoacidosis has not been previously described. Here we report two patients with MCADD presenting with severe ketoacidosis in the neonatal period prior to results of newborn screening. Patient 1 presented on Day 5 with hypoglycaemia, profound ketoacidosis and circulatory shock, and developed refractory ventricular tachycardia requiring extra-corporeal membrane oxygenation. Patient 2 presented on Day 4 with severe ketoacidosis, but only borderline hypoglycaemia. The diagnosis of MCADD was rapidly confirmed in both by analysis of acylcarnitines and urine organic acids, with subsequent genetic confirmation of ACADM mutations. We conclude that MCADD should be included in the differential diagnosis of neonatal ketoacidosis, with or without hypoglycaemia.
2026-03-24 | The role of neonatal screening in the diagnosis of a rare inherited metabolic disease (case study)
Hereditary metabolic diseases occur in all populations, but are usually rare. However, they have severe and in many cases fatal manifestations and outcomes. Objective of the study: to show the importance of neonatal screening in the diagnosis of familial cases of hereditary metabolic diseases using a clinical example of medium-chain acyl-CoA dehydrogenase deficiency. A family with three children was under observation. In child V., born in 2023, the following was revealed as part of the extended neonatal screening: “Medium-chain acyl-CoA dehydrogenase deficiency of fatty acids”. In the girl’s brother, a boy P., born in 2022, clinical symptoms debuted at the age of 1 year 11 months, which also indicated a metabolic disorder in the child. Given the hereditary nature of the disease, previously diagnosed in the boy’s sister, the child underwent a genetic examination aimed at finding this hereditary disease. The study confirmed the deficiency of medium-chain acyl-CoA dehydrogenase of fatty acids. Taking into account the anamnesis, pedigree, clinical picture, laboratory tests, molecular genetic examination, a conclusion was made about the familial nature of the disease. Considering that many patients do not have symptoms of this disease throughout their lives, the older brother of the children, boy A., born in 2012, and parents were also examined for mitochondrial fatty acid oxidation disorder. Boy A. and parents were determined to be heterozygous carriers. Conducting neonatal screening provides not only the opportunity to detect metabolic disorders at the preclinical stage of the disease, but also to verify a complex rare nosology in the family, selectively in older children suffering from unclear polymorphic symptoms. In addition, when conducting extended neonatal screening, the final stage includes a molecular genetic examination, which allows confirming the diagnosis of a hereditary disease, but also identifying heterozygous carriers of the mutant gene in the family and forming contingents that require systematic medical and genetic monitoring.
2026-03-02 | Exploring Deleterious Nonsynonymous SNPs in the ACADM Gene: Insights Into Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) via In Silico Analysis.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), a potentially lethal metabolic disorder, is often associated with single-nucleotide polymorphisms (SNPs) in the acyl-CoA dehydrogenase, medium-chain (ACADM) gene. The current research investigates the structural and functional implications of these genetic variants through diverse bioinformatics techniques. A range of in silico techniques were utilized to thoroughly evaluate the effect of nonsynonymous SNPs. Molecular docking and molecular dynamics simulation evaluation comprehensively validated the mutational impact on protein's stability. Gene interaction analysis demonstrated that ACADM is involved in several cellular pathways and co-expression networks. Two nsSNPs, rs121434282 and rs200724875, were found to have a significant impact on the composition and functionality of ACADM. This research lays the foundation for precision medicine advancements, specifically against metabolic disorders. Thorough validation of the proposed nsSNPs, supported by animal models, is crucial for understanding their role in MCADD.
2025-09-30 | Clinical, Biochemical and Molecular Characterisation of Newborns With Fatty Acid β-Oxidation Disorders: Novel Variants in the ACADM , ACADVL and SLC22A5 Genes.
In this study, we aimed to assess clinical, laboratory and molecular features of newborns with clinical suspicion for systemic primary carnitine deficiency (CUD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). The implementation of newborn screening programs for fatty acid β-oxidation disorders (FAODs) has changed the natural course of these diseases, facilitating the initiation of preventive or therapeutic measures for affected newborns shortly after birth. This study included 94 newborns who were admitted between 2016 and 2023 because of biochemical signs of CUD, MCADD and VLCADD, and provided clinical, biochemical and genotypic data. Definitive molecular diagnosis confirmed that 16/94 newborns (17%) were true positives of the NBS, and 17 novel variants were detected in SLC22A5, ACADM and ACADVL genes. We assessed the clinical evolution of patients over time. This study expands the genotypic spectrum of SLC22A5, ACADM and ACADVL and highlights the role of genetics in identifying and correctly characterising FAODs.
oligonucleotides
2023-07-07 | Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Medium chain acyl-CoA dehydrogenase deficiency.
1 orphan drug designation for Medium chain acyl-CoA dehydrogenase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Riboflavin | small molecules | EMA | 2023-11-08 | — | iniuva GmbH |
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