RARE DISEASE
Succinyl-CoA:3-oxoacid CoA transferase deficiency
Succinyl-CoA:3-oxoacid CoA transferase deficiency
Succinyl-CoA:3-oxoacid CoA transferase deficiency
Synonyms: OXCT1 deficiency, SCOT deficiency, Succinyl-CoA acetoacetate transferase deficiency, Succinyl-CoA:3-ketoacid CoA transferase deficiency
Synonyms: OXCT1 deficiency, SCOT deficiency, Succinyl-CoA acetoacetate transferase deficiency, Succinyl-CoA:3-ketoacid CoA transferase deficiency
Synonyms: OXCT1 deficiency, SCOT deficiency, Succinyl-CoA acetoacetate transferase deficiency, Succinyl-CoA:3-ketoacid CoA transferase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Succinyl-CoA:3-oxoacid CoA transferase deficiency (SCOTD) is a rare autosomal recessive disorder of ketone body metabolism caused by OXCT1 mutations, leading to impaired mitochondrial ketolysis. Patients experience recurrent life-threatening ketoacidosis triggered by catabolic stressors (e.g., fasting, infections). Neonatal or infantile onset is common, with episodic vomiting, lethargy, tachypnea, and coma. Persistent ketosis is pathognomonic, though inconsistent in mild variants [1][4][14]. Treatment focuses on acute crisis management and long-term metabolic control.
Burden
Highest mortality risk in infancy due to severe ketoacidosis. Frequency/severity decline after age 10 [1][14].
Neurodevelopmental outcomes are generally normal with timely intervention [14][16], though rare cases report ADHD/cognitive delays [4][14]. Requires lifelong vigilance against metabolic decompensation.
Therapies
Acute: IV fluids with glucose (6–8 mg/kg/min) to suppress ketogenesis, cautious sodium bicarbonate use [1][4][16].
Chronic: Avoid fasting >4 hours, low-fat diet, home ketone monitoring [2][7][17]. Protein restriction not routinely recommended [1][14].
Pregnancy: Close monitoring due to heightened metabolic risks [2][14].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
20 drug discovery papers about Succinyl-CoA:3-oxoacid CoA transferase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
20 drug discovery papers about Succinyl-CoA:3-oxoacid CoA transferase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-10-28 | Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.
The heart uses various nutrient sources for energy production, primarily favoring fatty acid oxidation. Although ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging. To investigate the functional significance of ketone use in the heart, we employed a mouse model with impaired ketolysis in the heart. In addition, we administered a ketogenic diet to evaluate the effects of exogenous ketone supplementation on cardiac ketone metabolism and function in this model. The cardiac expression of SCOT (succinyl-CoA:3-ketoacid CoA transferase), a rate-limiting enzyme in ketolysis, decreases with age in mice. SCOT cardiomyocyte-specific knockout mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cardiomyocyte-specific knockout mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.
2025-05-23 | Pancrelipase as Adjunctive Therapy in Severe SCOT Deficiency: A Case of a Novel OXCT1 Gene Deletion.
Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) deficiency is a rare autosomal recessive disorder caused by biallelic sequence variants in the OXCT1 gene. This deficiency disrupts ketone body utilization, resulting in ketone accumulation and ketoacidosis. Clinical manifestations typically include respiratory distress, vomiting, lethargy, and, in severe cases, coma. This case presents the first known instance of severe SCOT deficiency resulting from a novel homozygous four-exon deletion (exons 4-7) in the OXCT1 gene. The proband presented at the age of 3 months with severe metabolic acidosis that was refractory to conventional management. Despite high doses of bicarbonate therapy and cornstarch, he remained dependent on intravenous glucose for weeks. Repeated attempts to discontinue intravenous glucose led to severe acidosis within 12-24 h. The introduction of pancreatic enzyme replacement therapy (Creon) significantly enhanced starch digestion and absorption, stabilizing his metabolic condition and enabling discharge within 3 days. This case highlights the therapeutic potential of combining pancreatic enzyme replacement with cornstarch in infants under 12 months of age, given their limited pancreatic amylase activity. It underscores a potential management strategy for infants with severe forms of inherited metabolic disorders, such as SCOT deficiency and glycogen storage disease type I, where cornstarch is a cornerstone of therapy.
2024-01-19 | AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation
Abstract Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a crucial energy sensor that regulates lipid and glucose metabolism. However, whether AMPK regulates ketone metabolism in whole body is unclear even though AMPK regulates ketogenesis in liver. Prolonged resulted in a significant increase in blood and urine levels of ketone bodies in wild-type (WT) mice. Interestingly, fasting AMPKα2 –/– and AMPKα1 –/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. BHB tolerance assays revealed that both AMPKα2 –/– and AMPKα1 –/– mice exhibited slower ketone consumption compared to WT mice, as indicated by higher blood BHB or urine BHB levels in the AMPKα2 –/– and AMPKα1 –/– mice even after the peak. Interestingly, fasting AMPKα2 –/– and AMPKα1 –/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. . Specifically, AMPKα2 ΔMusc mice showed approximately a twofold increase in blood BHB levels, and AMPKα2 ΔMyo mice exhibited a 1.5-fold increase compared to their WT littermates after a 48-h fasting. However, blood BHB levels in AMPKα1 ΔMusc and AMPKα1 ΔMyo mice were as same as in WT mice. Notably, AMPKα2 ΔMusc mice demonstrated a slower rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1 ΔMusc mice did not show such an effect. Declining rates of body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis, decreased in skeletal muscle of AMPKα2 –/– mice. Moreover, SCOT protein ubiquitination increased in C2C12 cells either transfected with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition. AMPKα2 physiologically binds and stabilizes SCOT, which is dependent on AMPKα2 activity.
2021-09-14 | Clinical variability and outcome of succinyl-CoA:3-ketoacid CoA transferase deficiency caused by a single OXCT1 mutation: Report of 17 cases.
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inherited metabolic disease caused by mutated OXCT1 gene resulting in recurrent ketoacidosis. Analysis of longitudinal data in such an ultra-rare disease is warranted to delineate genotype-phenotype correlations and management outcome. A retrospective analysis of 17 patients, from nine unrelated families, with SCOT deficiency who were followed up in the Medical Genetics Clinic at King Faisal Specialist Hospital and Research Centre was conducted. All the patients were homozygous for p.R468C in OXCT1 gene. Most of the patients (n = 15, 88.2%) were symptomatic presenting with recurrent ketoacidosis, the onset of which ranged from 6 months to 4 years (median 2 years). A striking inter- and intrafamilial variability that ranged from being entirely asymptomatic to death during the first episode. All patients were instructed to avoid fasting, restrict protein in diet, and receive carnitine supplementation. However, there was no correlation between following instructions of chronic management and outcome. Most of the patients had their crises resolved and all of them had normal neurodevelopmental outcome. Our data suggest that SCOT deficiency caused by homozygous p.R468C has variable clinical presentation and incomplete penetrance. The apparent lack of correlation between protein restriction +/- carnitine supplementation and outcome suggests that chronic dietary restriction may not be warranted. However, a longer follow-up on larger and heterogenous cohort of cases is needed before a clear conclusion on the long-term management can be reached.
2021-08-01 | On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate
d-β-hydroxybutyrate (d-3HB), a monomer of microbial polyhydroxybutyrate (PHB), is also a natural ketone body produced during carbohydrate deprivation to provide energy to the body cells, heart, and brain. In recent years, increasing evidence demonstrates that d-3HB can induce pleiotropic effects on the human body which are highly beneficial for improving physical and metabolic health. Conventional ketogenic diet (KD) or exogenous ketone salts (KS) and esters (KE) have been used to increase serum d-3HB level. However, strict adaptation to the KD was often associated with poor patient compliance, while the ingestion of KS caused gastrointestinal distresses due to excessive consumption of minerals. As for ingestion of KE, subsequent degradation is required before releasing d-3HB for absorption, making these methods somewhat inferior. This review provides novel insights into a biologically synthesized d-3HB (d-3-hydroxybutyric acid) which can induce a faster increase in plasma d-3HB compared to the use of KD, KS, or KE. It also emphasizes on the most recent applications of d-3HB in different fields, including its use in improving exercise performance and in treating metabolic or age-related diseases. Ketones may become a fourth micro-nutrient that is necessary to the human body along with carbohydrates, proteins, and fats. Indeed, d-3HB being a small molecule with multiple signaling pathways within the body exhibits paramount importance in mitigating metabolic and age-related diseases. Nevertheless, specific dose–response relationships and safety margins of using d-3HB remain to be elucidated with more research. • d-3HB induces pleiotropic effects on physical and metabolic health. • Exogenous ketone supplements are more effective than ketogenic diet. • d-3HB as a ketone supplement has long-term healthy impact.
small molecules
2025-10-28 | Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.
The heart uses various nutrient sources for energy production, primarily favoring fatty acid oxidation. Although ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging. To investigate the functional significance of ketone use in the heart, we employed a mouse model with impaired ketolysis in the heart. In addition, we administered a ketogenic diet to evaluate the effects of exogenous ketone supplementation on cardiac ketone metabolism and function in this model. The cardiac expression of SCOT (succinyl-CoA:3-ketoacid CoA transferase), a rate-limiting enzyme in ketolysis, decreases with age in mice. SCOT cardiomyocyte-specific knockout mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cardiomyocyte-specific knockout mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.
2025-05-23 | Pancrelipase as Adjunctive Therapy in Severe SCOT Deficiency: A Case of a Novel OXCT1 Gene Deletion.
Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) deficiency is a rare autosomal recessive disorder caused by biallelic sequence variants in the OXCT1 gene. This deficiency disrupts ketone body utilization, resulting in ketone accumulation and ketoacidosis. Clinical manifestations typically include respiratory distress, vomiting, lethargy, and, in severe cases, coma. This case presents the first known instance of severe SCOT deficiency resulting from a novel homozygous four-exon deletion (exons 4-7) in the OXCT1 gene. The proband presented at the age of 3 months with severe metabolic acidosis that was refractory to conventional management. Despite high doses of bicarbonate therapy and cornstarch, he remained dependent on intravenous glucose for weeks. Repeated attempts to discontinue intravenous glucose led to severe acidosis within 12-24 h. The introduction of pancreatic enzyme replacement therapy (Creon) significantly enhanced starch digestion and absorption, stabilizing his metabolic condition and enabling discharge within 3 days. This case highlights the therapeutic potential of combining pancreatic enzyme replacement with cornstarch in infants under 12 months of age, given their limited pancreatic amylase activity. It underscores a potential management strategy for infants with severe forms of inherited metabolic disorders, such as SCOT deficiency and glycogen storage disease type I, where cornstarch is a cornerstone of therapy.
2024-01-19 | AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation
Abstract Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a crucial energy sensor that regulates lipid and glucose metabolism. However, whether AMPK regulates ketone metabolism in whole body is unclear even though AMPK regulates ketogenesis in liver. Prolonged resulted in a significant increase in blood and urine levels of ketone bodies in wild-type (WT) mice. Interestingly, fasting AMPKα2 –/– and AMPKα1 –/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. BHB tolerance assays revealed that both AMPKα2 –/– and AMPKα1 –/– mice exhibited slower ketone consumption compared to WT mice, as indicated by higher blood BHB or urine BHB levels in the AMPKα2 –/– and AMPKα1 –/– mice even after the peak. Interestingly, fasting AMPKα2 –/– and AMPKα1 –/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. . Specifically, AMPKα2 ΔMusc mice showed approximately a twofold increase in blood BHB levels, and AMPKα2 ΔMyo mice exhibited a 1.5-fold increase compared to their WT littermates after a 48-h fasting. However, blood BHB levels in AMPKα1 ΔMusc and AMPKα1 ΔMyo mice were as same as in WT mice. Notably, AMPKα2 ΔMusc mice demonstrated a slower rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1 ΔMusc mice did not show such an effect. Declining rates of body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis, decreased in skeletal muscle of AMPKα2 –/– mice. Moreover, SCOT protein ubiquitination increased in C2C12 cells either transfected with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition. AMPKα2 physiologically binds and stabilizes SCOT, which is dependent on AMPKα2 activity.
2021-09-14 | Clinical variability and outcome of succinyl-CoA:3-ketoacid CoA transferase deficiency caused by a single OXCT1 mutation: Report of 17 cases.
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inherited metabolic disease caused by mutated OXCT1 gene resulting in recurrent ketoacidosis. Analysis of longitudinal data in such an ultra-rare disease is warranted to delineate genotype-phenotype correlations and management outcome. A retrospective analysis of 17 patients, from nine unrelated families, with SCOT deficiency who were followed up in the Medical Genetics Clinic at King Faisal Specialist Hospital and Research Centre was conducted. All the patients were homozygous for p.R468C in OXCT1 gene. Most of the patients (n = 15, 88.2%) were symptomatic presenting with recurrent ketoacidosis, the onset of which ranged from 6 months to 4 years (median 2 years). A striking inter- and intrafamilial variability that ranged from being entirely asymptomatic to death during the first episode. All patients were instructed to avoid fasting, restrict protein in diet, and receive carnitine supplementation. However, there was no correlation between following instructions of chronic management and outcome. Most of the patients had their crises resolved and all of them had normal neurodevelopmental outcome. Our data suggest that SCOT deficiency caused by homozygous p.R468C has variable clinical presentation and incomplete penetrance. The apparent lack of correlation between protein restriction +/- carnitine supplementation and outcome suggests that chronic dietary restriction may not be warranted. However, a longer follow-up on larger and heterogenous cohort of cases is needed before a clear conclusion on the long-term management can be reached.
2021-08-01 | On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate
d-β-hydroxybutyrate (d-3HB), a monomer of microbial polyhydroxybutyrate (PHB), is also a natural ketone body produced during carbohydrate deprivation to provide energy to the body cells, heart, and brain. In recent years, increasing evidence demonstrates that d-3HB can induce pleiotropic effects on the human body which are highly beneficial for improving physical and metabolic health. Conventional ketogenic diet (KD) or exogenous ketone salts (KS) and esters (KE) have been used to increase serum d-3HB level. However, strict adaptation to the KD was often associated with poor patient compliance, while the ingestion of KS caused gastrointestinal distresses due to excessive consumption of minerals. As for ingestion of KE, subsequent degradation is required before releasing d-3HB for absorption, making these methods somewhat inferior. This review provides novel insights into a biologically synthesized d-3HB (d-3-hydroxybutyric acid) which can induce a faster increase in plasma d-3HB compared to the use of KD, KS, or KE. It also emphasizes on the most recent applications of d-3HB in different fields, including its use in improving exercise performance and in treating metabolic or age-related diseases. Ketones may become a fourth micro-nutrient that is necessary to the human body along with carbohydrates, proteins, and fats. Indeed, d-3HB being a small molecule with multiple signaling pathways within the body exhibits paramount importance in mitigating metabolic and age-related diseases. Nevertheless, specific dose–response relationships and safety margins of using d-3HB remain to be elucidated with more research. • d-3HB induces pleiotropic effects on physical and metabolic health. • Exogenous ketone supplements are more effective than ketogenic diet. • d-3HB as a ketone supplement has long-term healthy impact.
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