RARE DISEASE
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
Synonyms: Crotonase deficiency, ECHS1D
Synonyms: Crotonase deficiency, ECHS1D
Synonyms: Crotonase deficiency, ECHS1D
Drug discovery
28
papers
On emerging therapies
Overview
Mitochondrial short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a rare autosomal recessive disorder disrupting valine metabolism and mitochondrial fatty acid oxidation. It manifests as Leigh-like syndrome with severe neurological features, including developmental regression, hypotonia, nystagmus, and basal ganglia lesions on MRI. Elevated lactate and valine-derived metabolites (e.g., methacrylyl-CoA) contribute to secondary pyruvate dehydrogenase complex inhibition and mitochondrial dysfunction. Most patients present in infancy with progressive encephalopathy and cardiorespiratory failure [2][6][16].
Therapies
Metabolic support: Triheptanoin (C7 oil) to replenish TCA cycle intermediates, showing modest motor improvements in case studies [3][12].
Valine restriction: Low-valine diets aim to reduce toxic metabolite accumulation [8][9].
Supportive care: Management of seizures, dystonia, and respiratory insufficiency [2][6].
Investigational approaches: AAV9-based gene therapy trials in preclinical stages [8].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
28 drug discovery papers about Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
28 drug discovery papers about Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-02 | Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming.
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of Echs1 in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, Echs1 deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator Atf4, acquire H3K9cr. Atf4 then upregulates fatty acid synthase (Fasn), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting Fasn can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or Atf4 inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an Echs1-H3K9cr-Atf4-Fasn axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.
2025-06-14 | Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China.
To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations. This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS). Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3-60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, n = 18; SPI, n = 13; LP, n = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS < 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (p < 0.05). In terms of genetics, all patients were compound heterozygous variants in the ECHS1 gene, with 21 novel variants identified. The most common variant was the c.489G > A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes. This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G > A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.
2025-05-31 | Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
Deficiency in the short-chain enoyl-CoA hydratase 1 (ECHS1) gene causes Leigh syndrome (LS), a rare inherited metabolic disorder. Despite LS that arises as a result of inborn errors of energy metabolism, the specific contributions of ECHS1 deficiency to energy metabolism processes, developmental delay, and its mediated signaling mechanism remain unclear. Here, we identify a novel compound heterozygous variant [c.724G > A (p.Glu242Lys) and c.865G > A (Asp289Asn)] in the ECHS1 gene from a family of Han Chinese descent, with the affected individual displaying typical LS symptoms. The ECHS1 variants exhibit reduced 2-enoyl-CoA hydratase activity, resulting in a restricted ATP production rate, but the cellular ATP levels remains unchanged. ECHS1 deficiency also decreases cell viability and proliferation. Mechanistically, ECHS1 interacts with ADRB2, and its variants suppress the ADRB2/protein kinase A (PKA) signaling. Treatment with PKA signaling agonists or overexpression of PKA subunits in ECHS1-deficient cells can rescue the ATP production rate and restore cell viability. Additionally, the mitochondrial E3 ligase MUL1 mediates the ubiquitylation and degradation of ECHS1 protein variants. In conclusion, our study suggests that ECHS1 deficiency impairs mitochondrial respiratory efficiency, thereby lowering the ATP production rate, and reveals a promising therapeutic approach by targeting ADRB2/PKA signaling to combat ECHS1 deficiency-induced LS.
2025-04-07 | Expanding the Clinical and Genetic Spectrum of Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency: Insights From Two Unrelated Chinese Families.
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare autosomal recessive disorder affecting valine metabolism, with clinical severity ranging from neonatal death to survival into adulthood. Despite advances in understanding ECHS1D, the genetic basis remains underexplored, particularly in underrepresented populations. This study aimed to investigate the clinical and genetic characteristics of ECHS1D in two unrelated Chinese families and identify novel pathogenic variants. Clinical and genetic data were collected, and whole-genome sequencing was performed to identify pathogenic variants in the ECHS1 gene. The first proband, a 15-month-old girl, presented with developmental delays and metabolic acidosis, with an MRI revealing abnormal signals in the basal ganglia. The second proband, a 6.5-year-old girl with movement-induced dystonia, exhibited lethargy following recurrent fever and vomiting, with similar MRI findings. Genetic testing identified novel compound heterozygous variants: c.759_762del (p.Gly255Valfs*21) and c.489G>A (p.Pro163=) in Proband 1 and c.518C>T (p.Ala173Val) and c.244G>A (p.Val82Met) in Proband 2. The c.759_762del (p.Gly255Valfs21) variant, identified for the first time, likely results in severe symptoms due to a loss of normal function. These findings expand the ECHS1 mutational spectrum and emphasize the importance of genetic testing for early diagnosis and personalized management of ECHS1D. Interventions such as dietary valine restriction and the avoidance of triggering factors may improve clinical outcomes, while further research is needed to explore targeted therapeutic strategies.
2024-08-17 | Valine restriction extends survival in a Drosophila model of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency
Summary Short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in the ECHS1 gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. Here we report on the establishment of a Drosophila model of ECHS1D. Flies carrying mutations in Echs1 (CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. The Echs1 null larvae recapitulated human ECHS1D phenotypes including elevated biomarkers (S-(2-carboxypropyl)cysteamine and 2,3-dihydroxy-2-methylbutyric acid), poor motor behaviour and early mortality, and could be rescued by expression of a human ECHS1 transgene. We observed that both restriction of valine in isolation, or all branched-chain amino acids (BCAAs - leucine, isoleucine, and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting that Echs1 loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities between Drosophila and human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder.
gene therapies
2022-09-14 | ECHS1 deficiency and its biochemical and clinical phenotype.
ECHS1 gene encodes a mitochondrial enzyme, short-chain enoyl-CoA hydratase (SCEH). SCEH is involved in fatty acid oxidation ([Sharpe and McKenzie (2018); Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency, 7: 46]) and valine catabolism ([Fong and Schulz (1977); Purification and properties of pig heart crotonase and the presence of short chain and long chain enoyl coenzyme A hydratases in pig and guinea pig tissues, 252: 542-547]; [Wanders et al. (2012); Enzymology of the branched-chain amino acid oxidation disorders: The valine pathway, 35: 5-12]), and the dysfunction of SCEH leads to a severe Leigh or Leigh-like Syndrome phenotype in patients ([Haack et al. (2015); Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement, 2: 492-509]; [Peters et al. (2014); ECHS1 mutations in Leigh disease: A new inborn error of metabolism affecting valine metabolism, 137: 2903-2908]; [Sakai et al. (2015); ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome, 36: 232-239]; [Tetreault et al. (2015); Whole-exome sequencing identifies novel ECHS1 mutations in Leigh, 134: 981-991]). This study aims to further describe the ECHS1 deficiency phenotype using medical history questionnaires and standardized tools assessing quality of life and adaptive skills. Our findings in this largest sample of ECHS1 patients in literature to date (n = 13) illustrate a severely disabling condition causing severe developmental delays (n = 11), regression (n = 10), dystonia/hypotonia and movement disorders (n = 13), commonly with symptom onset in infancy (n = 10), classical MRI findings involving the basal ganglia (n = 11), and variability in biochemical profile. Congruent with the medical history, our patients had significantly low composite and domain scores on Vineland Adaptive Behavior Scales, Third Edition. We believe there is an increasing need for better understanding of ECHS1 deficiency with an aim to support the development of transformative genetic-based therapies, driven by the unmet need for therapies for patients with this genetic disease.
2018-04-03 | Enoyl coenzyme A hydratase 1 protects against high-fat-diet-induced hepatic steatosis and insulin resistance
Metabolic disorders, including obesity, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and diabetes, are complex and progressive diseases. Enoyl coenzyme A hydratase 1 (Ech1) is an enzyme that participates in mitochondrial fatty acid β-oxidation; however, little is known regarding the significance of Ech1 in the pathogenesis of metabolic disorders. Here, we report that high-fat-diet (HFD)-induced and genetic obesity could increase Ech1 expression in mouse liver. The overexpression of Ech1 using adeno-associated virus (AAV2/8) ameliorated HFD-induced liver lipid accumulation and accompanying liver injury. Additionally, Ech1 overexpression resulted in improved dyslipidemia and insulin resistance in HFD-fed mice. Further, the studies revealed that Ech1 could directly inhibit lipogenesis gene expressions and attenuate the insulin pathway induced by an HFD. Together, our results demonstrate that Ech1 protects against HFD-induced hepatic steatosis and insulin resistance and that its inhibitory effects on lipogenesis and insulin signaling may partly explain its role in metabolic disorders.
2006-01-12 | Systemic Correction of a Fatty Acid Oxidation Defect by Intramuscular Injection of a Recombinant Adeno-Associated Virus Vector
Mitochondrial β-oxidation of fatty acids is required to meet physiologic energy requirements during illness and periods of fasting or physiologic stress, and is most active in liver and striated muscle. Acyl-CoA dehydrogenases of varying chain-length specificities represent the first step in the mitochondria for each round of β-oxidation, each of which removes two-carbon units as acetyl-CoA for entry into the tricarboxylic acid cycle. We have used recombinant adeno-associated virus (rAAV) vectors expressing short-chain acyl-CoA dehydrogenase (SCAD) to correct the accumulation of fatty acyl-CoA intermediates in deficient cell lines. The rAAV-SCAD vector was then packaged into either rAAV serotype 1 or 2 capsids and injected intramuscularly into SCAD-deficient mice. A systemic effect was observed as judged by restoration of circulating butyryl- carnitine levels to normal. Total lipid content at the injection site was also decreased as demonstrated by noninvasive magnetic resonance spectroscopy (MRS). SCAD enzyme activity in the injected muscle was found at necropsy to be above the normal control mouse level. This study is the first to demonstrate the systemic correction of a fatty acid oxidation disorder with rAAV and the utility of MRS as a noninvasive method to monitor SCAD correction after in vivo gene therapy.
small molecules
2026-07-02 | Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming.
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of Echs1 in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, Echs1 deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator Atf4, acquire H3K9cr. Atf4 then upregulates fatty acid synthase (Fasn), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting Fasn can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or Atf4 inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an Echs1-H3K9cr-Atf4-Fasn axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.
2025-06-14 | Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China.
To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations. This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS). Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3-60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, n = 18; SPI, n = 13; LP, n = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS < 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (p < 0.05). In terms of genetics, all patients were compound heterozygous variants in the ECHS1 gene, with 21 novel variants identified. The most common variant was the c.489G > A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes. This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G > A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.
2025-05-31 | Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
Deficiency in the short-chain enoyl-CoA hydratase 1 (ECHS1) gene causes Leigh syndrome (LS), a rare inherited metabolic disorder. Despite LS that arises as a result of inborn errors of energy metabolism, the specific contributions of ECHS1 deficiency to energy metabolism processes, developmental delay, and its mediated signaling mechanism remain unclear. Here, we identify a novel compound heterozygous variant [c.724G > A (p.Glu242Lys) and c.865G > A (Asp289Asn)] in the ECHS1 gene from a family of Han Chinese descent, with the affected individual displaying typical LS symptoms. The ECHS1 variants exhibit reduced 2-enoyl-CoA hydratase activity, resulting in a restricted ATP production rate, but the cellular ATP levels remains unchanged. ECHS1 deficiency also decreases cell viability and proliferation. Mechanistically, ECHS1 interacts with ADRB2, and its variants suppress the ADRB2/protein kinase A (PKA) signaling. Treatment with PKA signaling agonists or overexpression of PKA subunits in ECHS1-deficient cells can rescue the ATP production rate and restore cell viability. Additionally, the mitochondrial E3 ligase MUL1 mediates the ubiquitylation and degradation of ECHS1 protein variants. In conclusion, our study suggests that ECHS1 deficiency impairs mitochondrial respiratory efficiency, thereby lowering the ATP production rate, and reveals a promising therapeutic approach by targeting ADRB2/PKA signaling to combat ECHS1 deficiency-induced LS.
2025-04-07 | Expanding the Clinical and Genetic Spectrum of Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency: Insights From Two Unrelated Chinese Families.
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare autosomal recessive disorder affecting valine metabolism, with clinical severity ranging from neonatal death to survival into adulthood. Despite advances in understanding ECHS1D, the genetic basis remains underexplored, particularly in underrepresented populations. This study aimed to investigate the clinical and genetic characteristics of ECHS1D in two unrelated Chinese families and identify novel pathogenic variants. Clinical and genetic data were collected, and whole-genome sequencing was performed to identify pathogenic variants in the ECHS1 gene. The first proband, a 15-month-old girl, presented with developmental delays and metabolic acidosis, with an MRI revealing abnormal signals in the basal ganglia. The second proband, a 6.5-year-old girl with movement-induced dystonia, exhibited lethargy following recurrent fever and vomiting, with similar MRI findings. Genetic testing identified novel compound heterozygous variants: c.759_762del (p.Gly255Valfs*21) and c.489G>A (p.Pro163=) in Proband 1 and c.518C>T (p.Ala173Val) and c.244G>A (p.Val82Met) in Proband 2. The c.759_762del (p.Gly255Valfs21) variant, identified for the first time, likely results in severe symptoms due to a loss of normal function. These findings expand the ECHS1 mutational spectrum and emphasize the importance of genetic testing for early diagnosis and personalized management of ECHS1D. Interventions such as dietary valine restriction and the avoidance of triggering factors may improve clinical outcomes, while further research is needed to explore targeted therapeutic strategies.
2024-08-17 | Valine restriction extends survival in a Drosophila model of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency
Summary Short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in the ECHS1 gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. Here we report on the establishment of a Drosophila model of ECHS1D. Flies carrying mutations in Echs1 (CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. The Echs1 null larvae recapitulated human ECHS1D phenotypes including elevated biomarkers (S-(2-carboxypropyl)cysteamine and 2,3-dihydroxy-2-methylbutyric acid), poor motor behaviour and early mortality, and could be rescued by expression of a human ECHS1 transgene. We observed that both restriction of valine in isolation, or all branched-chain amino acids (BCAAs - leucine, isoleucine, and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting that Echs1 loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities between Drosophila and human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder.
gene therapies
2022-09-14 | ECHS1 deficiency and its biochemical and clinical phenotype.
ECHS1 gene encodes a mitochondrial enzyme, short-chain enoyl-CoA hydratase (SCEH). SCEH is involved in fatty acid oxidation ([Sharpe and McKenzie (2018); Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency, 7: 46]) and valine catabolism ([Fong and Schulz (1977); Purification and properties of pig heart crotonase and the presence of short chain and long chain enoyl coenzyme A hydratases in pig and guinea pig tissues, 252: 542-547]; [Wanders et al. (2012); Enzymology of the branched-chain amino acid oxidation disorders: The valine pathway, 35: 5-12]), and the dysfunction of SCEH leads to a severe Leigh or Leigh-like Syndrome phenotype in patients ([Haack et al. (2015); Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement, 2: 492-509]; [Peters et al. (2014); ECHS1 mutations in Leigh disease: A new inborn error of metabolism affecting valine metabolism, 137: 2903-2908]; [Sakai et al. (2015); ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome, 36: 232-239]; [Tetreault et al. (2015); Whole-exome sequencing identifies novel ECHS1 mutations in Leigh, 134: 981-991]). This study aims to further describe the ECHS1 deficiency phenotype using medical history questionnaires and standardized tools assessing quality of life and adaptive skills. Our findings in this largest sample of ECHS1 patients in literature to date (n = 13) illustrate a severely disabling condition causing severe developmental delays (n = 11), regression (n = 10), dystonia/hypotonia and movement disorders (n = 13), commonly with symptom onset in infancy (n = 10), classical MRI findings involving the basal ganglia (n = 11), and variability in biochemical profile. Congruent with the medical history, our patients had significantly low composite and domain scores on Vineland Adaptive Behavior Scales, Third Edition. We believe there is an increasing need for better understanding of ECHS1 deficiency with an aim to support the development of transformative genetic-based therapies, driven by the unmet need for therapies for patients with this genetic disease.
2018-04-03 | Enoyl coenzyme A hydratase 1 protects against high-fat-diet-induced hepatic steatosis and insulin resistance
Metabolic disorders, including obesity, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and diabetes, are complex and progressive diseases. Enoyl coenzyme A hydratase 1 (Ech1) is an enzyme that participates in mitochondrial fatty acid β-oxidation; however, little is known regarding the significance of Ech1 in the pathogenesis of metabolic disorders. Here, we report that high-fat-diet (HFD)-induced and genetic obesity could increase Ech1 expression in mouse liver. The overexpression of Ech1 using adeno-associated virus (AAV2/8) ameliorated HFD-induced liver lipid accumulation and accompanying liver injury. Additionally, Ech1 overexpression resulted in improved dyslipidemia and insulin resistance in HFD-fed mice. Further, the studies revealed that Ech1 could directly inhibit lipogenesis gene expressions and attenuate the insulin pathway induced by an HFD. Together, our results demonstrate that Ech1 protects against HFD-induced hepatic steatosis and insulin resistance and that its inhibitory effects on lipogenesis and insulin signaling may partly explain its role in metabolic disorders.
2006-01-12 | Systemic Correction of a Fatty Acid Oxidation Defect by Intramuscular Injection of a Recombinant Adeno-Associated Virus Vector
Mitochondrial β-oxidation of fatty acids is required to meet physiologic energy requirements during illness and periods of fasting or physiologic stress, and is most active in liver and striated muscle. Acyl-CoA dehydrogenases of varying chain-length specificities represent the first step in the mitochondria for each round of β-oxidation, each of which removes two-carbon units as acetyl-CoA for entry into the tricarboxylic acid cycle. We have used recombinant adeno-associated virus (rAAV) vectors expressing short-chain acyl-CoA dehydrogenase (SCAD) to correct the accumulation of fatty acyl-CoA intermediates in deficient cell lines. The rAAV-SCAD vector was then packaged into either rAAV serotype 1 or 2 capsids and injected intramuscularly into SCAD-deficient mice. A systemic effect was observed as judged by restoration of circulating butyryl- carnitine levels to normal. Total lipid content at the injection site was also decreased as demonstrated by noninvasive magnetic resonance spectroscopy (MRS). SCAD enzyme activity in the injected muscle was found at necropsy to be above the normal control mouse level. This study is the first to demonstrate the systemic correction of a fatty acid oxidation disorder with rAAV and the utility of MRS as a noninvasive method to monitor SCAD correction after in vivo gene therapy.
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