Materiały źródłowe

• #1 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #2 Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency – The Medical Biochemistry Page

  https://themedicalbiochemistrypage.org/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency/

  Deficiency in MCAD is the most common defect observed in the process of mitochondrial -oxidation of fatty acids. […] MCAD deficiency (MCADD) is an autosomal recessive disorder that satisfies the criteria for newborn screening and is in fact one of the diseases that is screened for in the US in all newborns. […] At least 340 mutations in the ACADM gene have been identified. […] By far, the most prevalent mutation (89%) found in MCAD deficiency patients is a single nucleotide substitution at position 985. This substitution is an A for G change that converts amino acid 329 from a lysine to a glutamic acid (K329E). This mutation alters the -helical domain of the C-terminal portion of the enzyme. […] The defect in fatty acid oxidation leads to the presence, in the plasma and urine, of toxic metabolic intermediates such as dicarboxylic acids as well as medium-chain acylcarnitines.

• #3 Orphanet: Medium chain acyl-CoA dehydrogenase deficiency

  https://www.orpha.net/en/disease/detail/42

  Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inborn error of mitochondrial fatty acid oxidation characterized by a rapidly progressive metabolic crisis, often presenting as hypoketotic hypoglycemia, lethargy, vomiting, seizures and coma, which can be fatal in the absence of emergency medical intervention. […] MCADD is caused by mutations in the ACADM gene (1p31) which encodes the mitochondrial MCAD protein. The most prevalent mutation, c.985AG, (K329E), p.(Lys329Glu), accounted for about 80% of clinical disease prior to newborn screening programs but many more individuals are now being identified with other ACADM mutations. […] Diagnosis is through the identification of a characteristic abnormal pattern in dried blood spots or plasma of acylcarnitines species (increased C6, C8 and increased ratio of C8/C10 with abnormal urine organic acid findings of C6 to C10 dicarboxylic acids, hexanoylglycine and suberylglycine). Final confirmation is by mutation analysis. MCADD is now included in newborn screening programs in many European countries such as the UK, Germany, the Netherlands, Portugal and Spain. […] MCADD is inherited autosomal recessively. Genetic counseling is possible. […] The prognosis is excellent in diagnosed patients who avoid fasting and who are managed appropriately during an intercurrent illness/ metabolic crisis.

• #4 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder characterized by mitochondrial fatty acid -oxidation impairment, leading to severe metabolic consequences. The inability to provide energy to tissues during glycogen depletion results in hypoketotic hypoglycemia, the hallmark presentation in young children. […] Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.

• #5 Orphanet: Medium chain acyl-CoA dehydrogenase deficiency

  https://www.orpha.net/en/disease/detail/42

  Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inborn error of mitochondrial fatty acid oxidation characterized by a rapidly progressive metabolic crisis, often presenting as hypoketotic hypoglycemia, lethargy, vomiting, seizures and coma, which can be fatal in the absence of emergency medical intervention. […] MCADD is caused by mutations in the ACADM gene (1p31) which encodes the mitochondrial MCAD protein. The most prevalent mutation, c.985AG, (K329E), p.(Lys329Glu), accounted for about 80% of clinical disease prior to newborn screening programs but many more individuals are now being identified with other ACADM mutations. […] Diagnosis is through the identification of a characteristic abnormal pattern in dried blood spots or plasma of acylcarnitines species (increased C6, C8 and increased ratio of C8/C10 with abnormal urine organic acid findings of C6 to C10 dicarboxylic acids, hexanoylglycine and suberylglycine). Final confirmation is by mutation analysis. MCADD is now included in newborn screening programs in many European countries such as the UK, Germany, the Netherlands, Portugal and Spain. […] MCADD is inherited autosomal recessively. Genetic counseling is possible. […] The prognosis is excellent in diagnosed patients who avoid fasting and who are managed appropriately during an intercurrent illness/ metabolic crisis.

• #6 Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency – The Medical Biochemistry Page

  https://themedicalbiochemistrypage.org/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency/

  Deficiency in MCAD is the most common defect observed in the process of mitochondrial -oxidation of fatty acids. […] MCAD deficiency (MCADD) is an autosomal recessive disorder that satisfies the criteria for newborn screening and is in fact one of the diseases that is screened for in the US in all newborns. […] At least 340 mutations in the ACADM gene have been identified. […] By far, the most prevalent mutation (89%) found in MCAD deficiency patients is a single nucleotide substitution at position 985. This substitution is an A for G change that converts amino acid 329 from a lysine to a glutamic acid (K329E). This mutation alters the -helical domain of the C-terminal portion of the enzyme. […] The defect in fatty acid oxidation leads to the presence, in the plasma and urine, of toxic metabolic intermediates such as dicarboxylic acids as well as medium-chain acylcarnitines.

• #7

  https://omim.org/entry/607008?search=acadm&highlight=acadm

  Matsubara et al. (1986) stated that 5 acyl-CoA dehydrogenases had been reported: short-chain (606885), medium-chain (EC 1.3.99.3), and long-chain (609576) acyl-CoA dehydrogenases; isovaleryl-CoA dehydrogenase (243500); and 2-methyl branched-chain acyl-CoA dehydrogenase. The first 3 catalyze the initial reaction in the beta-oxidation of fatty acids, while the last 2 catalyze the dehydrogenation of branched short-chain acyl-CoAs in the metabolism of the branched-chain amino acids. All 5 may have evolved from a common ancestral gene. […] Medium-chain acyl-CoA dehydrogenase catalyzes the initial reaction in the beta-oxidation of C4 to C12 straight-chain acyl-CoAs (Matsubara et al., 1986). […] In 9 patients with MCAD deficiency, Matsubara et al. (1990) identified a homozygous 985A-G transition in the MCAD gene, which resulted in a lys304-to-glu substitution (K304E; 607008.0001) in the mature protein. These patients were unrelated, suggesting a high incidence of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles.

• #8

  https://omim.org/entry/607008

  Matsubara et al. (1986) stated that 5 acyl-CoA dehydrogenases had been reported: short-chain (606885), medium-chain (EC 1.3.99.3), and long-chain (609576) acyl-CoA dehydrogenases; isovaleryl-CoA dehydrogenase (243500); and 2-methyl branched-chain acyl-CoA dehydrogenase. The first 3 catalyze the initial reaction in the beta-oxidation of fatty acids, while the last 2 catalyze the dehydrogenation of branched short-chain acyl-CoAs in the metabolism of the branched-chain amino acids. All 5 may have evolved from a common ancestral gene. […] Medium-chain acyl-CoA dehydrogenase catalyzes the initial reaction in the beta-oxidation of C4 to C12 straight-chain acyl-CoAs (Matsubara et al., 1986). […] In 9 patients with MCAD deficiency, Matsubara et al. (1990) identified a homozygous 985A-G transition in the MCAD gene, which resulted in a lys304-to-glu substitution (K304E; 607008.0001) in the mature protein. These patients were unrelated, suggesting a high incidence of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles.

• #9 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/24897

  Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease. MCAD dysfunction disrupts the dehydrogenation step of β-oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. The body attempts to compensate by maximizing gluconeogenesis; however, when glycogen stores are depleted, rapid progression to hypoketotic hypoglycemia occurs. MCAD dysfunction also results in the accumulation of medium-length fatty acyl-CoAs in the mitochondrial matrix. They, in turn, bind to mitochondrial carnitine, resulting in the formation of acylcarnitines. These formed medium-length acylcarnitines, C6 to C12, are then eliminated from the mitochondrial matrix and released into circulation. These acylcarnitines are used as a serum biomarker to detect MCAD dysfunction, forming the basis of NBS and confirmatory diagnostic tests. The accumulated medium-length acyl-CoAs can also be converted to acylglycines by conjugation with glycine. Acylglycines, including hexonylglycine (C6) and suberylglycine (C8), are subsequently excreted in the urine. These urinary organic acids can be measured and are used as diagnostic biomarkers for MCADD. MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.

• #10

  https://omim.org/entry/607008

  Tajima et al. (2016) sequenced the ACADM gene in a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of MCAD deficiency. The most prevalent mutation was a 4-bp deletion (c.449_452delCTGA; 607008.0016) identified in 25 ACADM alleles of 22 subjects from 19 families. Other prevalent mutations in this cohort included R17H, G362E, R53C, and R281S. These 5 mutations accounted for 60% of the mutations identified in this patient cohort.

• #11 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110

  Newborns with elevated octanoyl-carnitine levels in the newborn screen go generally for genetic tests and additionally enzymatic activity measurements. […] Before newborn screening when MCAD was identified on the basis of clinical findings, c.985AG was identified as the most prevalent mutation in the ACADM gene where approximately 80% of patients exhibited homozygosity for this change. […] With the advent of newborn screening, where many newborns are identified in the absence of a clinical presentation, a second prevalent mutation was identified c.199TC (allele frequency approximately 6%). […] This mutation however, has never been conclusively linked to clinical symptoms. […] The distinction between patients at risk of symptomatic disease and individuals who may never develop symptomatic disease in the long term is very important.

• #12

  https://omim.org/entry/607008?search=acadm&highlight=acadm

  Maier et al. (2009) concluded that protein misfolding with loss-of-function is the common molecular basis in MCAD deficiency. […] The distinction between 'normal’ and 'disease’ in MCAD deficiency is blurred into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing. […] Tajima et al. (2016) found that the most prevalent mutation was a 4-bp deletion (c.449_452delCTGA) in the ACADM gene, predicted to result in a frameshift and premature termination (Thr150Argfs). The mutation, which was found by direct sequencing of the gene, was identified in 25 ACADM alleles of 22 individuals from 19 families. Analyses in patient lymphocytes showed that the mutation resulted in abolished ACADM enzyme activity.

• #13 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder characterized by mitochondrial fatty acid -oxidation impairment, leading to severe metabolic consequences. The inability to provide energy to tissues during glycogen depletion results in hypoketotic hypoglycemia, the hallmark presentation in young children. […] Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.

• #14 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #15 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #16 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood.

• #17 Medium-Chain Acyl-CoA Dehydrogenase Deficiency | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/24897

  Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme. The most prevalent mutation is c.985AG, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function. This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease. MCAD dysfunction disrupts the dehydrogenation step of β-oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. The body attempts to compensate by maximizing gluconeogenesis; however, when glycogen stores are depleted, rapid progression to hypoketotic hypoglycemia occurs. MCAD dysfunction also results in the accumulation of medium-length fatty acyl-CoAs in the mitochondrial matrix. They, in turn, bind to mitochondrial carnitine, resulting in the formation of acylcarnitines. These formed medium-length acylcarnitines, C6 to C12, are then eliminated from the mitochondrial matrix and released into circulation. These acylcarnitines are used as a serum biomarker to detect MCAD dysfunction, forming the basis of NBS and confirmatory diagnostic tests. The accumulated medium-length acyl-CoAs can also be converted to acylglycines by conjugation with glycine. Acylglycines, including hexonylglycine (C6) and suberylglycine (C8), are subsequently excreted in the urine. These urinary organic acids can be measured and are used as diagnostic biomarkers for MCADD. MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.

• #18 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder characterized by mitochondrial fatty acid -oxidation impairment, leading to severe metabolic consequences. The inability to provide energy to tissues during glycogen depletion results in hypoketotic hypoglycemia, the hallmark presentation in young children. […] Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length. Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria’s first step of medium-chain fatty acid oxidation. MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene. […] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.

• #19 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #20 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/946755-overview

  The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated. […] Finally, gluconeogenesis is effectively disabled in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.

• #21 MCAD deficiency | Student Doctor Network

  https://forums.studentdoctor.net/threads/mcad-deficiency.936218/

  What’s the mechanism of the decreased glucose in MCAD deficiency? We’d get decreased acetyl-CoA, but that’s normally used to make ketones or is merely processed through the TCA cycle. I wouldn’t think glucose should be particularly affected, unless the lack of monoacyl glycerol produced (because beta-oxidation is impaired) is significant enough such that gluconeogenesis, based on this substrate alone, decreases. […] As far as I understand the problem with the acyl-CoA dehydrogenase deficiencies are when there is prolonged fasting, but not in between meals if they are spaced out correctly. So any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. End result being severe hypoglycemia and hypoketonuria. So after we used up all our glucose and try to create more through gluconeogenesis, we can’t because gluconeogenesis depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. End result being that gluconeogenesis can’t compensate for the continued consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.

• #22 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #23 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/946755-overview

  The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape. […] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. A 2016 study has suggested that metabolic stress causing flooding of the -oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation. […] The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step.

• #24 Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders | BMC Biology | Full Text

  https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0327-5

  The absence of the one enzyme-one reaction relationship and the resulting substrate competition has a major impact on the systemic properties of lipid and polymer metabolism in general. […] In this study, we took a systems-biology approach to investigate whether and how substrate competition is involved in the characteristic features of mFAO disorders, and particularly in the loss of metabolic robustness in these patients. […] Here we provide evidence that (1) substrate competition in mFAO a mechanism inherent to the repetitive metabolism of fatty acids renders the pathway vulnerable to substrate overload, particularly in the absence of MCAD; […] We hypothesized that this was caused by the competition among CoA esters of different chain lengths for a limited set of acyl-CoA dehydrogenases.

• #25 Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders | BMC Biology | Full Text

  https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0327-5

  In the absence of MCAD, it appeared that, instead, molecular competition an intrinsic biochemical feature of the pathway topology was the cause of the pathways susceptibility to becoming overloaded and losing its capability to maintain flux at high substrate concentrations. […] We conclude that substrate competition is the main mechanism that helps to explain the acylcarnitine profiles seen in MADD patients, and that a computational model that includes substrate competition may explain the severity of the disease phenotype in these patients.

• #26 Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency – The Medical Biochemistry Page

  https://themedicalbiochemistrypage.org/medium-chain-acyl-coa-dehydrogenase-mcad-deficiency/

  The mechanism that leads to the accumulation of medium-chain acylcarnitines in MCAD deficiency stems from the need for the mitochondria to replenish the CoASH pool for continued oxidation of long-chain fatty acids. […] This mechanism results in the accumulation of the medium-chain acylcarnitines typically seen in MCAD deficient patient.

• #27 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #28 Loss of the Mitochondrial Fatty Acid β-Oxidation Protein Medium-Chain Acyl-Coenzyme A Dehydrogenase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function | Scientific Reports

  https://www.nature.com/articles/s41598-017-18530-4

  Medium-chain acyl-Coenzyme A dehydrogenase (MCAD) is involved in the initial step of mitochondrial fatty acid -oxidation (FAO). Loss of function results in MCAD deficiency, a disorder that usually presents in childhood with hypoketotic hypoglycemia, vomiting and lethargy. While the disruption of mitochondrial fatty acid metabolism is the primary metabolic defect, secondary defects in mitochondrial oxidative phosphorylation (OXPHOS) may also contribute to disease pathogenesis. […] Overall, our findings suggest that the loss of MCAD is associated with a reduction in steady-state OXPHOS complex levels, resulting in secondary defects in OXPHOS function which may contribute to the pathology of MCAD deficiency. […] One possible pathogenic mechanism may involve the direct effects of MCAD deficiency on mitochondrial oxidative phosphorylation (OXPHOS). MCAD was previously shown to associate with the OXPHOS supercomplex, a high-molecular weight structure that contains OXPHOS complexes I, III and IV. Furthermore, this complex was able to oxidize palmitoyl-CoA and octanoyl-CoA, providing evidence for a physical association between MCAD (as well as other FAO enzymes) with the OXPHOS supercomplex.

• #29 Loss of the Mitochondrial Fatty Acid β-Oxidation Protein Medium-Chain Acyl-Coenzyme A Dehydrogenase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function | Scientific Reports

  https://www.nature.com/articles/s41598-017-18530-4

  These findings support the concept of an additional pathogenic mechanism in MCAD deficiency, whereby the loss of MCAD may directly disrupt the OXPHOS supercomplex, resulting in secondary OXPHOS defects and mitochondrial respiratory dysfunction. […] Our results suggest that the loss of MCAD is associated with OXPHOS complex instability and dysfunction which may contribute to the pathogenesis of MCAD deficiency. […] The loss of OXPHOS supercomplex stability in MCAD-deficient cells may also play a role in ROS generation. The formation of the OXPHOS supercomplex has been shown to limit the production of ROS, whereas OXPHOS supercomplex destabilization has been shown to increase basal ROS generation in Barth Syndrome patient lymphoblasts. […] In summary, our results describe a new role for MCAD in OXPHOS complex biogenesis. While it remains to be determined exactly how MCAD interacts with the OXPHOS complexes and/or the OXPHOS supercomplex, it is clear that the loss of MCAD has a detrimental effect on OXPHOS complex stability and activity. These findings have implications for our understanding of MCAD deficiency, where OXPHOS dysfunction may contribute to disease pathogenesis.

• #30 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #31 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD) Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/946755-clinical

  Because medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive trait, other affected members of a family pedigree are unlikely to be historically available to assist in diagnosis. […] The gene has been mapped to locus 1p31; more than 80 allelic variations have been reported. […] The most common mutation is 985AG, which refers to a substitution of a guanine nucleotide for an adenine nucleotide at the 985th residue. […] Acute hepatic failure in a previously healthy gravid female who is homozygous for the 985AG mutation has been reported, thus confirming the potential for later onset, as well as the severity of complications with this specific mutation. […] Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. […] Medium-chain fatty acids accumulating in MCAD deficiency elicit lipid and protein oxidative damage and decrease non-enzymatic antioxidant defenses in rat brain.

• #32 SciELO Brazil – Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies

  https://www.scielo.br/j/jiems/a/Qcm3gjH4smdjmkBZ6mcbcjb/?lang=en

  Taken together, the available data strongly indicate that the major fatty acids accumulating in MCAD and LCHAD deficiencies probably contribute to the pathogenesis and perhaps symptomatology of affected patients, by disrupting mitochondrial homeostasis, especially during catabolic situations in which their concentrations significantly increase in blood and other tissues due to accelerated lipolysis. […] Growing evidence obtained from human and animal studies revealed that disturbance of mitochondrial functions associated with oxidative stress at least partly caused by accumulating fatty acids is involved in the pathophysiology of MCAD and LCHAD deficiencies.

• #33 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #34 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/946755-overview

  The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated. […] Finally, gluconeogenesis is effectively disabled in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.

• #35 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood.

• #36 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood.

• #37 Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045110

  Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450) is the most common inherited disorder of fatty acid metabolism presenting with hypoglycaemia, hepatopathy and Reye-like symptoms during catabolism. […] In order to identify functional effects of these mutant genotypes we correlated residual MCAD (OMIM 607008) activities as measured by octanoyl-CoA oxidation in lymphocytes with both genotype and relevant medical reports in 65 newborns harbouring mutant alleles. […] This demonstrates a correlation between the octanoyl-CoA oxidation rate in lymphocytes and the clinical outcome. […] The octanoyl-CoA oxidation rate, therefore, allows a risk assessment at birth and the identification of new ACADM genotypes associated with asymptomatic disease variants. […] The clinical phenotype is generally induced by catabolism. Increased energy demand beyond the availability of glucose, prolonged fasting, illness or childhood immunization may induce metabolic derangement with clinical symptoms such as hypoketotic hypoglycemia, hepatic dysfunction and neurological impairment.

• #38 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023

  Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid -oxidation in humans. […] The pathogenesis of the wide range of metabolic disturbances in MCAD deficiency is poorly understood and certain aspects of patient management are controversial. An animal model for MCAD deficiency is essential to better understand the pathogenesis of MCAD deficiency and to develop better management regimens for human patients. […] Successfully targeting Acadm produced a mouse model for MCAD deficiency with features that mimic the clinical, biochemical, and pathologic phenotype found in human patients. […] A high degree of neonatal mortality in MCAD/ mice was a striking observation and appears to be analogous to the patterns of clinical episodes and mortality in MCAD-deficient patients.

• #39 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023

  Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid -oxidation in humans. […] The pathogenesis of the wide range of metabolic disturbances in MCAD deficiency is poorly understood and certain aspects of patient management are controversial. An animal model for MCAD deficiency is essential to better understand the pathogenesis of MCAD deficiency and to develop better management regimens for human patients. […] Successfully targeting Acadm produced a mouse model for MCAD deficiency with features that mimic the clinical, biochemical, and pathologic phenotype found in human patients. […] A high degree of neonatal mortality in MCAD/ mice was a striking observation and appears to be analogous to the patterns of clinical episodes and mortality in MCAD-deficient patients.

• #40 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023

  The microvesicular and macrovesicular hepatic steatosis seen in fasted MCAD/ mice is consistent with the primary pathological finding seen in human MCAD patients with fasting stress. […] Sporadic cardiac lesions in MCAD/ mice, however, were an interesting and unexpected finding. The diffuse cardiomyopathy with multifocal myocyte degeneration and necrosis observed in MCAD/ mice has not been reported in human MCAD patients, however, cardiac arrhythmias and dysfunction have been reported in MCAD-deficient patients. […] The MCAD-deficient mouse offers new insights into the pathogenesis of mitochondrial -oxidation deficiencies and will provide a robust tool to better understand the role of fatty acids in other relevant diseases.

• #41 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023

  The microvesicular and macrovesicular hepatic steatosis seen in fasted MCAD/ mice is consistent with the primary pathological finding seen in human MCAD patients with fasting stress. […] Sporadic cardiac lesions in MCAD/ mice, however, were an interesting and unexpected finding. The diffuse cardiomyopathy with multifocal myocyte degeneration and necrosis observed in MCAD/ mice has not been reported in human MCAD patients, however, cardiac arrhythmias and dysfunction have been reported in MCAD-deficient patients. […] The MCAD-deficient mouse offers new insights into the pathogenesis of mitochondrial -oxidation deficiencies and will provide a robust tool to better understand the role of fatty acids in other relevant diseases.

• #42 Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010023

  The microvesicular and macrovesicular hepatic steatosis seen in fasted MCAD/ mice is consistent with the primary pathological finding seen in human MCAD patients with fasting stress. […] Sporadic cardiac lesions in MCAD/ mice, however, were an interesting and unexpected finding. The diffuse cardiomyopathy with multifocal myocyte degeneration and necrosis observed in MCAD/ mice has not been reported in human MCAD patients, however, cardiac arrhythmias and dysfunction have been reported in MCAD-deficient patients. […] The MCAD-deficient mouse offers new insights into the pathogenesis of mitochondrial -oxidation deficiencies and will provide a robust tool to better understand the role of fatty acids in other relevant diseases.

• #43 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1424/

  Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. […] Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage. […] Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency. […] Loss of function.

• #44

  https://omim.org/entry/607008?search=acadm&highlight=acadm

  Maier et al. (2009) concluded that protein misfolding with loss-of-function is the common molecular basis in MCAD deficiency. […] The distinction between 'normal’ and 'disease’ in MCAD deficiency is blurred into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing. […] Tajima et al. (2016) found that the most prevalent mutation was a 4-bp deletion (c.449_452delCTGA) in the ACADM gene, predicted to result in a frameshift and premature termination (Thr150Argfs). The mutation, which was found by direct sequencing of the gene, was identified in 25 ACADM alleles of 22 individuals from 19 families. Analyses in patient lymphocytes showed that the mutation resulted in abolished ACADM enzyme activity.

• #45 Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders | BMC Biology | Full Text

  https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0327-5

  In the absence of MCAD, it appeared that, instead, molecular competition an intrinsic biochemical feature of the pathway topology was the cause of the pathways susceptibility to becoming overloaded and losing its capability to maintain flux at high substrate concentrations. […] We conclude that substrate competition is the main mechanism that helps to explain the acylcarnitine profiles seen in MADD patients, and that a computational model that includes substrate competition may explain the severity of the disease phenotype in these patients.

• #46 Loss of the Mitochondrial Fatty Acid β-Oxidation Protein Medium-Chain Acyl-Coenzyme A Dehydrogenase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function | Scientific Reports

  https://www.nature.com/articles/s41598-017-18530-4

  These findings support the concept of an additional pathogenic mechanism in MCAD deficiency, whereby the loss of MCAD may directly disrupt the OXPHOS supercomplex, resulting in secondary OXPHOS defects and mitochondrial respiratory dysfunction. […] Our results suggest that the loss of MCAD is associated with OXPHOS complex instability and dysfunction which may contribute to the pathogenesis of MCAD deficiency. […] The loss of OXPHOS supercomplex stability in MCAD-deficient cells may also play a role in ROS generation. The formation of the OXPHOS supercomplex has been shown to limit the production of ROS, whereas OXPHOS supercomplex destabilization has been shown to increase basal ROS generation in Barth Syndrome patient lymphoblasts. […] In summary, our results describe a new role for MCAD in OXPHOS complex biogenesis. While it remains to be determined exactly how MCAD interacts with the OXPHOS complexes and/or the OXPHOS supercomplex, it is clear that the loss of MCAD has a detrimental effect on OXPHOS complex stability and activity. These findings have implications for our understanding of MCAD deficiency, where OXPHOS dysfunction may contribute to disease pathogenesis.

• #47 SciELO Brazil – Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies

  https://www.scielo.br/j/jiems/a/Qcm3gjH4smdjmkBZ6mcbcjb/?lang=en

  Taken together, the available data strongly indicate that the major fatty acids accumulating in MCAD and LCHAD deficiencies probably contribute to the pathogenesis and perhaps symptomatology of affected patients, by disrupting mitochondrial homeostasis, especially during catabolic situations in which their concentrations significantly increase in blood and other tissues due to accelerated lipolysis. […] Growing evidence obtained from human and animal studies revealed that disturbance of mitochondrial functions associated with oxidative stress at least partly caused by accumulating fatty acids is involved in the pathophysiology of MCAD and LCHAD deficiencies.

• #48 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (MCADD): Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/946755-overview

  The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated. […] Finally, gluconeogenesis is effectively disabled in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.

• #49 Medium-Chain Acyl-CoA Dehydrogenase Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560837/

  MCAD dysfunction disrupts the dehydrogenation step of -oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. […] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients. […] MCADD is considered a „conformational disorder;” however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood.

• #50 The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update | Genetics in Medicine

  https://www.nature.com/articles/gim200638

  Children with MCADD detected through screening can be expected to have a lower average risk for developing symptomatic disease because they are less likely to have genotypes associated with clinical symptoms. […] The association is likely dependent on a variety of genetic and environmental factors. […] The high specificity of a diagnostic acylcarnitine profile obtained using MS/MS had led to decreased use of enzyme assays for confirmation in the clinical setting. […] Not all individuals with MCADD develop such a clinical presentation, whether a severe metabolic crisis or milder symptoms. […] Use of variable diagnostic criteria for MCADD complicates comparison of data from multiple sources. […] The presence of two severe mutations on the ACADM gene, that is, missense or stop mutations resulting in no residual enzymatic activity, is considered diagnostic.

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