RARE DISEASE
Short chain acyl-CoA dehydrogenase deficiency
Short chain acyl-CoA dehydrogenase deficiency
Short chain acyl-CoA dehydrogenase deficiency
Synonyms: ACADS deficiency, SCAD deficiency, SCADD
Synonyms: ACADS deficiency, SCAD deficiency, SCADD
Synonyms: ACADS deficiency, SCAD deficiency, SCADD
Drug discovery
0
drugs
With orphan designations
Overview
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive disorder disrupting mitochondrial β-oxidation of short-chain fatty acids. Most patients remain asymptomatic, though symptomatic cases may present with hypoglycemia, developmental delay, seizures, hypotonia, or metabolic crises triggered by fasting/illness. Diagnosis involves elevated plasma C4-carnitine, urinary ethylmalonic acid, and ACADS gene variants/mutations. Management focuses on preventive strategies; pharmacotherapy evidence remains limited [1][5][6][8].
Burden
Clinical: 25–30% of symptomatic cases report neurodevelopmental delays; 20–30% exhibit failure to thrive [1][5][10].
Economic: Reduced morbidity/mortality with newborn screening; most require minimal intervention [5][12][14].
Genetic: Over 35 ACADS mutations identified; Ashkenazi Jewish variant (p.R171W) is common [3][6][9].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
30 drug discovery papers about Short chain acyl-CoA dehydrogenase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
30 drug discovery papers about Short chain acyl-CoA dehydrogenase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-04-27 | Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review
Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.
2026-03-27 | Short-chain acyl-CoA dehydrogenase initiates mtDNA demethylation and leakage to fuel antitumor immunity in colorectal cancer.
Reprogramming of lipid metabolism and cyclic GMP‒AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling is associated with cancer development. However, whether and how fatty acid metabolism regulates the cGAS‒STING pathway in colorectal cancer (CRC) remains to be elucidated. In this study, we found that short-chain acyl-CoA dehydrogenase (ACADS) is aberrantly deficient in CRC cells and is associated with cancer progression in human patients. We further revealed that ablation of ACADS promoted CRC progression by orchestrating the cGAS‒STING signaling-dependent immunosuppressive tumor microenvironment (TME) in mouse xenografts and AOM/DSS-induced CRC models. Mechanistically, ACADS deficiency suppressed cGAS‒STING signaling by inhibiting mtDNA leakage in a nonmetabolic manner. ACADS binds to and inhibits mitochondrial DNMT1 (mito-DNMT1)-dependent mtDNA methylation, thereby stabilizing mtDNA and inhibiting its leakage. Genetic and pharmacological modulation of mito-DNMT1 restored ACADS-regulated mtDNA leakage, cGAS‒STING signaling, and CRC progression. Importantly, strong correlations between ACADS, mito-DNMT1, and STING signaling and the immune TME were found in patients with CRC. Furthermore, we screened and identified an old drug, hypericin, as an ACADS-binding compound that upregulates ACADS expression. Hypericin treatment can mimic ACADS overexpression-regulated pathways, ultimately improving the immune TME and suppressing CRC growth. These findings highlight a previously undiscovered ACADS/mito-DNMT1 complex that links fatty acid metabolism reprogramming to mtDNA methylation and cGAS‒STING signaling-dependent antitumor immunity.
2023-07-24 | Riboflavin ameliorates pathological cardiac hypertrophy and fibrosis through the activation of short-chain acyl-CoA dehydrogenase.
Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. FAD, a coenzyme of SCAD, participates in the electron transfer of SCAD-catalyzed fatty acid β-oxidation, which plays a crucial role in maintaining the balance of myocardial energy metabolism. Insufficient riboflavin intake can lead to symptoms similar to short-chain acyl-CoA dehydrogenase (SCAD) deficiency or flavin adenine dinucleotide (FAD) gene abnormality, which can be alleviated by riboflavin supplementation. However, whether riboflavin can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of riboflavin on pathological cardiac hypertrophy and fibrosis. In vitro experiments, riboflavin increased SCAD expression and the content of ATP, decreased the free fatty acids content and improved PE-induced cardiomyocytes hypertrophy and AngⅡ-induced cardiac fibroblasts proliferation by increasing the content of FAD, which were attenuated by knocking down the expression of SCAD using small interfering RNA. In vivo experiments, riboflavin significantly increased the expression of SCAD and the energy metabolism of the heart to improve TAC induced pathological myocardial hypertrophy and fibrosis in mice. The results demonstrate that riboflavin improves pathological cardiac hypertrophy and fibrosis by increasing the content of FAD to activate SCAD, which may be a new strategy for treating pathological cardiac hypertrophy and fibrosis.
2020-06-08 | Deficiency in the short-chain acyl-CoA dehydrogenase protects mice against diet-induced obesity and insulin resistance.
Acyl-CoA dehydrogenases (CADs) participate in mitochondrial fatty acid oxidation; abnormal fatty acid oxidation is associated with obesity and related metabolic disorders. We decipher the impact of short-chain CAD (SCAD) on adiposity and insulin resistance. BALB/cBy strain mice derived from BALB/c strain are deficient in SCAD activity because of a spontaneous deletion in the acyl-CoA dehydrogenases (Acads) gene. Adiposity, lipogenesis, and insulin sensitivity were compared in BALB/c and BALB/cBy mice subjected to high-fat diets (HFDs). A whole hepatic transcriptome profiling experiment with microarrays was performed to evaluate the mechanisms by which SCAD deficiency protects against insulin resistance. Acads-deficient mice were significantly resistant to HFD-induced obesity and insulin resistance as compared with control mice. Reduced obesity results from decreased triglyceride content due to activation of AMPK in liver that would reduce hepatic content of malonyl-CoA, resulting in decreased hepatic de novo lipogenesis. Improved insulin sensitivity was associated with reduced diacylglycerol content commensurate with reduced PKC-ε activity and increased protein kinase B (AKT) activation in liver and skeletal muscle. Additionally, Acads-deficient mice displayed significantly higher expression of the endoplasmic chaperone 78-kDa glucose-regulated protein, which was further associated with the AKT activation in the primary hepatocytes. Modulation of SCAD expression may therefore be a novel therapeutic approach to manage and prevent obesity and related metabolic diseases, such as diabetes.-Chen, Y., Chen, J., Zhang, C., Yang, S., Zhang, X., Liu, Y., Su, Z. Deficiency in the short-chain acyl-CoA dehydrogenase protects mice against diet-induced obesity and insulin resistance.
proteins
2025-11-15 | Short-chain Acyl-CoA Dehydrogenase Deficiency in a Child: A Case Report
Short-chain 3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) enzyme deficiency is an autosomal recessive inborn error of metabolism affecting mitochondrial Fatty Acid Oxidation (FAO). In this condition, the body fails to produce energy from fats during times of stress. Effective energy production relies on the mitochondrial β-oxidation of fatty acids, which is especially crucial during periods of fasting, infections, and other metabolic stressors. Children with this deficiency often present with transient and nonspecific symptoms. Here, we present the case of a five-year-old male child with a recurrent history of seizures, persistent hypoglycaemia, metabolic acidosis with hypotension requiring inotropic support, and a deteriorating Glasgow Coma Scale score necessitating mechanical ventilation. Upon evaluation, he was found to have hypoinsulinemia, and his electroencephalogram suggested encephalopathy. After ruling out sepsis, hyperinsulinaemia, and meningoencephalitis, inborn errors of metabolism were suspected, with a fatty acid oxidation defect being the most likely diagnosis. The patient was ultimately diagnosed with SCHAD deficiency using Gas Chromatography-Mass Spectrometry Tandem Mass Spectrometry (GCMS-TMS). The potential for rapid deterioration associated with SCHAD deficiency underscores the need for prompt evaluation and intervention, which are essential for early diagnosis and favourable outcomes to prevent morbidity and mortality. The serious complications associated with this condition also highlight the necessity for newborn screening for inborn errors of metabolism.
2025-02-20 | Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies.
This study aims to characterize the metabolic alterations in patients with inherited mitochondrial enzymopathies. We focused on wide-coverage targeted metabolomic, organic acid and lipidomic analyses of patients with TMEM70 deficiency (TMEM70d), short-chain acyl-CoA dehydrogenase deficiency (SCADd), and individuals with both deficiencies (TMEM70d-SCADd). Serum and urine samples were collected from patients with TMEM70d (n = 13), SCADd (n = 11), TMEM70d-SCADd (n = 3), and controls (n = 38). Analyses were conducted using high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Univariate and multivariate statistical evaluation was performed to identify significant metabolic differences between patient groups and controls. Distinct metabolic profiles were observed in urine and serum samples of patients with TMEM70d, SCADd, and TMEM70d-SCADd compared to controls. Urinary metabolomics revealed significant elevations in butyrylcarnitine and metabolites related to branched-chain amino acid degradation in SCADd and TMEM70d-SCADd patients. Serum metabolomic analysis indicated alterations in pyruvate metabolism, citric acid cycle intermediates, and acylcarnitine metabolism in TMEM70d and TMEM70d-SCADd patients. Lipidomic analysis showed decreased levels of glycerophospholipids and sphingolipids across all patient groups. Patients with TMEM70d, SCADd, and TMEM70d-SCADd exhibit distinct metabolic signatures characterized by disturbances in energy metabolism, amino acid degradation, and lipid homeostasis. The combination of TMEM70d and SCADd leads to synergistic metabolic effects, emphasizing the importance of comprehensive metabolic profiling in understanding complex mitochondrial disorders and identifying potential biomarkers for diagnosis and treatment monitoring.
2020-02-27 | Protein Misfolding Diseases and Therapeutic Approaches.
Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.
2007-04-26 | Handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins in transgenic mice
To investigate the in vivo handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins, three transgenic mouse lines were produced by pronuclear injection of cDNA encoding the wild-type, hSCAD-wt, and two disease causing folding variants hSCAD-319C>T and hSCAD-625G>A. The transgenic mice were mated with an SCAD-deficient mouse strain (BALB/cByJ) and, in the second generation, three mouse lines were obtained without endogenous SCAD expression but harboring hSCAD-wt, hSCAD-319C>T, and hSCAD-625G>A transgenes, respectively. All three lines had expression of the transgene at the RNA level in liver, muscle or brain tissues. Expression at the protein level was detected only in the brain tissue of hSCAD-wt mice, but here it was significantly higher than the level of endogenous SCAD protein in control mouse brains--in correlation with expression at the RNA level. The results may indicate that the two hSCAD folding variants are degraded by the mouse mitochondrial protein quality control system. Indeed, pulse-chase studies with isolated mitochondria revealed that soluble variant hSCAD protein was rapidly eliminated. This is in agreement with the fact that no disease phenotype developed for any of the lines transgenic for the hSCAD folding variants. The indicated remarkable efficiency of the mouse protein quality control system in the degradation of SCAD folding variants should be further substantiated and investigated, since it might indicate ways to prevent disease-causing effects.
2001-01-11 | Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders.
Many disease-causing point mutations do not seriously compromise synthesis of the affected polypeptide but rather exert their effects by impairing subsequent protein folding or stability of the folded protein. This often results in rapid degradation of the affected protein. The concepts of such 'conformational disease' are illustrated by reference to cystic fibrosis, phenylketonuria and short-chain acyl-CoA dehydrogenase deficiency. Other cellular components such as chaperones and proteases, as well as environmental factors, may combine to modulate the phenotype of such disorders and this may open up new therapeutic approaches.
small molecules
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.
2026-04-27 | Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review
Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.
2026-03-27 | Short-chain acyl-CoA dehydrogenase initiates mtDNA demethylation and leakage to fuel antitumor immunity in colorectal cancer.
Reprogramming of lipid metabolism and cyclic GMP‒AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling is associated with cancer development. However, whether and how fatty acid metabolism regulates the cGAS‒STING pathway in colorectal cancer (CRC) remains to be elucidated. In this study, we found that short-chain acyl-CoA dehydrogenase (ACADS) is aberrantly deficient in CRC cells and is associated with cancer progression in human patients. We further revealed that ablation of ACADS promoted CRC progression by orchestrating the cGAS‒STING signaling-dependent immunosuppressive tumor microenvironment (TME) in mouse xenografts and AOM/DSS-induced CRC models. Mechanistically, ACADS deficiency suppressed cGAS‒STING signaling by inhibiting mtDNA leakage in a nonmetabolic manner. ACADS binds to and inhibits mitochondrial DNMT1 (mito-DNMT1)-dependent mtDNA methylation, thereby stabilizing mtDNA and inhibiting its leakage. Genetic and pharmacological modulation of mito-DNMT1 restored ACADS-regulated mtDNA leakage, cGAS‒STING signaling, and CRC progression. Importantly, strong correlations between ACADS, mito-DNMT1, and STING signaling and the immune TME were found in patients with CRC. Furthermore, we screened and identified an old drug, hypericin, as an ACADS-binding compound that upregulates ACADS expression. Hypericin treatment can mimic ACADS overexpression-regulated pathways, ultimately improving the immune TME and suppressing CRC growth. These findings highlight a previously undiscovered ACADS/mito-DNMT1 complex that links fatty acid metabolism reprogramming to mtDNA methylation and cGAS‒STING signaling-dependent antitumor immunity.
2023-07-24 | Riboflavin ameliorates pathological cardiac hypertrophy and fibrosis through the activation of short-chain acyl-CoA dehydrogenase.
Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. FAD, a coenzyme of SCAD, participates in the electron transfer of SCAD-catalyzed fatty acid β-oxidation, which plays a crucial role in maintaining the balance of myocardial energy metabolism. Insufficient riboflavin intake can lead to symptoms similar to short-chain acyl-CoA dehydrogenase (SCAD) deficiency or flavin adenine dinucleotide (FAD) gene abnormality, which can be alleviated by riboflavin supplementation. However, whether riboflavin can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of riboflavin on pathological cardiac hypertrophy and fibrosis. In vitro experiments, riboflavin increased SCAD expression and the content of ATP, decreased the free fatty acids content and improved PE-induced cardiomyocytes hypertrophy and AngⅡ-induced cardiac fibroblasts proliferation by increasing the content of FAD, which were attenuated by knocking down the expression of SCAD using small interfering RNA. In vivo experiments, riboflavin significantly increased the expression of SCAD and the energy metabolism of the heart to improve TAC induced pathological myocardial hypertrophy and fibrosis in mice. The results demonstrate that riboflavin improves pathological cardiac hypertrophy and fibrosis by increasing the content of FAD to activate SCAD, which may be a new strategy for treating pathological cardiac hypertrophy and fibrosis.
2020-06-08 | Deficiency in the short-chain acyl-CoA dehydrogenase protects mice against diet-induced obesity and insulin resistance.
Acyl-CoA dehydrogenases (CADs) participate in mitochondrial fatty acid oxidation; abnormal fatty acid oxidation is associated with obesity and related metabolic disorders. We decipher the impact of short-chain CAD (SCAD) on adiposity and insulin resistance. BALB/cBy strain mice derived from BALB/c strain are deficient in SCAD activity because of a spontaneous deletion in the acyl-CoA dehydrogenases (Acads) gene. Adiposity, lipogenesis, and insulin sensitivity were compared in BALB/c and BALB/cBy mice subjected to high-fat diets (HFDs). A whole hepatic transcriptome profiling experiment with microarrays was performed to evaluate the mechanisms by which SCAD deficiency protects against insulin resistance. Acads-deficient mice were significantly resistant to HFD-induced obesity and insulin resistance as compared with control mice. Reduced obesity results from decreased triglyceride content due to activation of AMPK in liver that would reduce hepatic content of malonyl-CoA, resulting in decreased hepatic de novo lipogenesis. Improved insulin sensitivity was associated with reduced diacylglycerol content commensurate with reduced PKC-ε activity and increased protein kinase B (AKT) activation in liver and skeletal muscle. Additionally, Acads-deficient mice displayed significantly higher expression of the endoplasmic chaperone 78-kDa glucose-regulated protein, which was further associated with the AKT activation in the primary hepatocytes. Modulation of SCAD expression may therefore be a novel therapeutic approach to manage and prevent obesity and related metabolic diseases, such as diabetes.-Chen, Y., Chen, J., Zhang, C., Yang, S., Zhang, X., Liu, Y., Su, Z. Deficiency in the short-chain acyl-CoA dehydrogenase protects mice against diet-induced obesity and insulin resistance.
proteins
2025-11-15 | Short-chain Acyl-CoA Dehydrogenase Deficiency in a Child: A Case Report
Short-chain 3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) enzyme deficiency is an autosomal recessive inborn error of metabolism affecting mitochondrial Fatty Acid Oxidation (FAO). In this condition, the body fails to produce energy from fats during times of stress. Effective energy production relies on the mitochondrial β-oxidation of fatty acids, which is especially crucial during periods of fasting, infections, and other metabolic stressors. Children with this deficiency often present with transient and nonspecific symptoms. Here, we present the case of a five-year-old male child with a recurrent history of seizures, persistent hypoglycaemia, metabolic acidosis with hypotension requiring inotropic support, and a deteriorating Glasgow Coma Scale score necessitating mechanical ventilation. Upon evaluation, he was found to have hypoinsulinemia, and his electroencephalogram suggested encephalopathy. After ruling out sepsis, hyperinsulinaemia, and meningoencephalitis, inborn errors of metabolism were suspected, with a fatty acid oxidation defect being the most likely diagnosis. The patient was ultimately diagnosed with SCHAD deficiency using Gas Chromatography-Mass Spectrometry Tandem Mass Spectrometry (GCMS-TMS). The potential for rapid deterioration associated with SCHAD deficiency underscores the need for prompt evaluation and intervention, which are essential for early diagnosis and favourable outcomes to prevent morbidity and mortality. The serious complications associated with this condition also highlight the necessity for newborn screening for inborn errors of metabolism.
2025-02-20 | Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies.
This study aims to characterize the metabolic alterations in patients with inherited mitochondrial enzymopathies. We focused on wide-coverage targeted metabolomic, organic acid and lipidomic analyses of patients with TMEM70 deficiency (TMEM70d), short-chain acyl-CoA dehydrogenase deficiency (SCADd), and individuals with both deficiencies (TMEM70d-SCADd). Serum and urine samples were collected from patients with TMEM70d (n = 13), SCADd (n = 11), TMEM70d-SCADd (n = 3), and controls (n = 38). Analyses were conducted using high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Univariate and multivariate statistical evaluation was performed to identify significant metabolic differences between patient groups and controls. Distinct metabolic profiles were observed in urine and serum samples of patients with TMEM70d, SCADd, and TMEM70d-SCADd compared to controls. Urinary metabolomics revealed significant elevations in butyrylcarnitine and metabolites related to branched-chain amino acid degradation in SCADd and TMEM70d-SCADd patients. Serum metabolomic analysis indicated alterations in pyruvate metabolism, citric acid cycle intermediates, and acylcarnitine metabolism in TMEM70d and TMEM70d-SCADd patients. Lipidomic analysis showed decreased levels of glycerophospholipids and sphingolipids across all patient groups. Patients with TMEM70d, SCADd, and TMEM70d-SCADd exhibit distinct metabolic signatures characterized by disturbances in energy metabolism, amino acid degradation, and lipid homeostasis. The combination of TMEM70d and SCADd leads to synergistic metabolic effects, emphasizing the importance of comprehensive metabolic profiling in understanding complex mitochondrial disorders and identifying potential biomarkers for diagnosis and treatment monitoring.
2020-02-27 | Protein Misfolding Diseases and Therapeutic Approaches.
Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.
2007-04-26 | Handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins in transgenic mice
To investigate the in vivo handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins, three transgenic mouse lines were produced by pronuclear injection of cDNA encoding the wild-type, hSCAD-wt, and two disease causing folding variants hSCAD-319C>T and hSCAD-625G>A. The transgenic mice were mated with an SCAD-deficient mouse strain (BALB/cByJ) and, in the second generation, three mouse lines were obtained without endogenous SCAD expression but harboring hSCAD-wt, hSCAD-319C>T, and hSCAD-625G>A transgenes, respectively. All three lines had expression of the transgene at the RNA level in liver, muscle or brain tissues. Expression at the protein level was detected only in the brain tissue of hSCAD-wt mice, but here it was significantly higher than the level of endogenous SCAD protein in control mouse brains--in correlation with expression at the RNA level. The results may indicate that the two hSCAD folding variants are degraded by the mouse mitochondrial protein quality control system. Indeed, pulse-chase studies with isolated mitochondria revealed that soluble variant hSCAD protein was rapidly eliminated. This is in agreement with the fact that no disease phenotype developed for any of the lines transgenic for the hSCAD folding variants. The indicated remarkable efficiency of the mouse protein quality control system in the degradation of SCAD folding variants should be further substantiated and investigated, since it might indicate ways to prevent disease-causing effects.
2001-01-11 | Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders.
Many disease-causing point mutations do not seriously compromise synthesis of the affected polypeptide but rather exert their effects by impairing subsequent protein folding or stability of the folded protein. This often results in rapid degradation of the affected protein. The concepts of such 'conformational disease' are illustrated by reference to cystic fibrosis, phenylketonuria and short-chain acyl-CoA dehydrogenase deficiency. Other cellular components such as chaperones and proteases, as well as environmental factors, may combine to modulate the phenotype of such disorders and this may open up new therapeutic approaches.
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