Medium‐chain Acyl‐COA dehydrogenase deficiency: Pathogenesis, diagnosis, and treatment

Mason, Emily; Hindmarch, Charles; Dunham‐Snary, Kimberly J.

doi:10.1002/edm2.385

Cited by 13 publications

(16 citation statements)

References 75 publications

(227 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cellular oxidative stress and defense-mechanism-related metabolites such as oxidized lipids and glutathione were significantly affected. Some of our findings have been reported previously [1,28]; however, for the first time, we reported that the DBS from MCADD newborns had elevated glutathione and had altered certain types of oxidized lipids, notably those not reported before, which is suggestive of increased oxidative stress events. These findings may be used as potential biomarkers for MCADD as a complementary diagnostic approach in addition to the most currently known acylcarnitine biomarkers.…”

Section: Untargeted Metabolomics As a Complementary Diagnostic Approa...supporting

confidence: 78%

See 1 more Smart Citation

Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots

Sebaa

Almogren

Alseraty

et al. 2023

IJMS

View full text Add to dashboard Cite

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid β-oxidation, especially in newborns. MCADD is clinically diagnosed using Newborn Bloodspot Screening (NBS) and genetic testing. Still, these methods have limitations, such as false negatives or positives in NBS and the variants of uncertain significance in genetic testing. Thus, complementary diagnostic approaches for MCADD are needed. Recently, untargeted metabolomics has been proposed as a diagnostic approach for inherited metabolic diseases (IMDs) due to its ability to detect a wide range of metabolic alterations. We performed an untargeted metabolic profiling of dried blood spots (DBS) from MCADD newborns (n = 14) and healthy controls (n = 14) to discover potential metabolic biomarkers/pathways associated with MCADD. Extracted metabolites from DBS samples were analyzed using UPLC-QToF-MS for untargeted metabolomics analyses. Multivariate and univariate analyses were used to analyze the metabolomics data, and pathway and biomarker analyses were also performed on the significantly identified endogenous metabolites. The MCADD newborns had 1034 significantly dysregulated metabolites compared to healthy newborns (moderated t-test, no correction, p-value ≤ 0.05, FC 1.5). A total of 23 endogenous metabolites were up-regulated, while 84 endogenous metabolites were down-regulated. Pathway analyses showed phenylalanine, tyrosine, and tryptophan biosynthesis as the most affected pathways. Potential metabolic biomarkers for MCADD were PGP (a21:0/PG/F1alpha) and glutathione, with an area under the curve (AUC) of 0.949 and 0.898, respectively. PGP (a21:0/PG/F1alpha) was the first oxidized lipid in the top 15 biomarker list affected by MCADD. Additionally, glutathione was chosen to indicate oxidative stress events that could happen during fatty acid oxidation defects. Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. However, further validations of these biomarkers are needed in future studies to ensure their accuracy and reliability as complementary markers with established MCADD markers for clinical diagnosis.

show abstract

Section: Untargeted Metabolomics As a Complementary Diagnostic Approa...supporting

confidence: 78%

“…Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is one of the inherited metabolic disorders (IMDs) that are associated with metabolic disturbances [1]. MCADD is the most common inherited fatty acid β-oxidation disorder, and it is caused by various genetic mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene.…”

Section: Introductionmentioning

confidence: 99%

Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots

Sebaa

Almogren

Alseraty

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…MCAD is a medium-chain fatty acid oxidase, and MCAD deficiency is one of the most common mitochondrial fatty acid β-oxidation disorders[ 81 ]. MCAD deficiency prevents the dehydrogenation step of β-oxidation in the mitochondria, leading to decreased acetyl-CoA production and the accumulation of acylcarnitine caused by carnitine transport from medium-chain fatty acids, resulting in disorders of intrahepatic lipid metabolism[ 82 ]. SREBP1c is a key adipogenic transcription factor that is activated by insulin in the postprandial state.…”

Section: Discussionmentioning

confidence: 99%

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

Jiang,

Zhou,

Zhong

et al. 2024

World J Gastroenterol

View full text Add to dashboard Cite

BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances. However, its contribution to the progression of liver damage remains unclear. AIM To determine the role and mechanism of UGT1A1 in liver damage progression. METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research. Additionally, the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study. RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage, while patients with acute-on-chronic liver failure (ACLF) exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis. This suggests that low UGT1A1 levels may be associated with the progression of liver damage. In mouse models of liver injury induced by carbon tetrachloride (CCl4) and concanavalin A (ConA), the hepatic levels of UGT1A1 protein were found to be increased. In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression, the hepatic protein levels of UGT1A1 were decreased, which is consistent with the observations in patients with ACLF. UGT1A1 knockout exacerbated CCl4- and ConA-induced liver injury, hepatocyte apoptosis and necroptosis in mice, intensified hepatocyte endoplasmic reticulum (ER) stress and oxidative stress, and disrupted lipid metabolism. CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury, and interference with this upregulation process may worsen liver injury. UGT1A1 reduces ER stress, oxidative stress, and lipid metabolism disorder, thereby mitigating hepatocyte apoptosis and necroptosis.

show abstract

“…ACADM is primarily responsible for the decomposition of medium-chain fatty acyl-CoA into short-chain fatty acyl-CoA and acetyl-CoA. When ACADM is deficient, it leads to hypoketotic hypoglycemia in neonates, which eventually leads to their death [ 31 ]. In HCC, the expression of ACADM is low.…”

Section: Discussionmentioning

confidence: 99%

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

QIU,

YANG,

SUN

et al. 2024

View full text Add to dashboard Cite

This research aims to identify the key fatty acid beta-oxidation (FAO) genes that are altered in kidney renal clear cell carcinoma (KIRC) and to analyze the role of these genes in KIRC. The Gene Expression Omnibus (GEO) and FAO datasets were used to identify these key genes. Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain (ACADM) between KIRC and non-cancer samples. The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features. The diagnostic performance of ACADM for KIRC was assessed using a diagnostic receiver operating characteristic (ROC) curve. The co-expressed genes of ACADM were identified in LinkedOmics database, and their function and pathway enrichment were analyzed. The correlation between ACADM expression level and immune infiltration was analyzed by Gene Set Variation Analysis (GSVA) method. Additionally, the proliferation, migration, and invasion abilities of KIRC cells were assessed after overexpressing ACADM. Following differential analysis and intersection, we identified six hub genes, including ACADM. We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic effect (AUC = 0.916). Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis. According to correlation analysis, a variety of clinical features were associated with the expression level of ACADM. By analyzing the infiltration level of immune cells, we found that ACADM may be related to the enrichment of immune cells. Finally, ACADM overexpression inhibited proliferation, migration, and invasion of KIRC cells. In conclusion, our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis. These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC, offering a reference for clinicians in diagnosis and treatment.

show abstract

Medium‐chain Acyl‐COA dehydrogenase deficiency: Pathogenesis, diagnosis, and treatment

Cited by 13 publications

References 75 publications

Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots

Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

Contact Info

Product

Resources

About