Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency

Mahapatra, Sidharth; Ananth, Amitha; Baugh, Nancy; Damian, Mihaela; Enns, Gregory M.

doi:10.1007/8904_2017_36

Cited by 16 publications

(20 citation statements)

References 17 publications

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“…For the solute carrier family 25 member 20 (SLC25A20 or CACT), a key carnitine-acylcarnitine translocase exchanging for free carnitine across the mitochondrial membrane in mitochondrial beta-oxidation, little information has been acknowledged on its pathophysiologic mechanisms in CVD except for several case reports about the CACT-deficiency in cardiomyopathy, arrythmias and cardiogenic shock ( 40 – 42 ). However, the current study found for the first time a markedly up-regulation of SLC25A20 transcriptional level in doxorubicin-induced HF, which was further validated with a 1.74-fold change in a HF cohort compared to the healthy control.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics identification of potential candidate blood indicators for doxorubicin‑induced heart failure

Wan

Xia

et al. 2018

Exp Ther Med

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The care of individual patients requiring anthracyclines remains challenging as uncertainty persists on predictors of cardiotoxicity. The aim of the present study was to identify potential candidate blood indicators of doxorubicin-induced heart failure. The gene expression profiles of GSE40447 and GSE9128 microarray data were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) using the R/Limma package or GEO2R. Functional and pathway enrichment analysis on DEGs were performed using DAVID database. The cardiovascular disease (CVD)-related DEGs were screen out based on the CardioGenBase database. The protein-protein interaction (PPI) network was constructed with STRING database and visualized by using Cytoscape. Then, the CVD-related DEGs were validated by intersection analysis with DEGs in GSE9128. The overlapping DEGs with a consistent expression pattern in GSE40447 and GSE9128 were identified as candidate indicators for doxorubicin-induced heart failure. A total of 516 DEGs potentially associated with doxorubicin-induced heart failure in GSE40447 were identified, which were mainly enriched in the gene ontology terms related to B cells, leukocytes, lymphocyte activation and B cell receptor signaling pathway. Of the DEGs, 42 were screened out as CVD-related DEGs by using CardioGenBase. Seven genes with high connectivity degree were presented in the PPI network. Finally, 5/6 CVD-related DEGs revealed by the intersection analysis were validated by GSE9128 and highlighted as candidate indicators of doxorubicin-induced heart failure: CD163, CD28, SLC25A20, ANPEP and TLR5. Several genes, including the 5 previously mentioned, were proposed as potential candidate blood indicators for doxorubicin-induced heart failure. Further experimental validations are greatly warranted for future clinical application.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics identification of potential candidate blood indicators for doxorubicin‑induced heart failure

Wan

Xia

et al. 2018

Exp Ther Med

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“…[ 22 ] In addition, triheptanoin (UX007), a novel investigational drug composed of synthetic medium-chain triglycerides (MCT), has recently been used as a compassionate use protocol for the emergency management of patients with several FAO disorders and severe cardiomyopathy. Mahapatra et al [ 23 ] described a case of an infant with CACTD admitted in severe metabolic crisis that devolving into cardiogenic shock who was successfully treated by triheptanoin.…”

Section: Discussionmentioning

confidence: 99%

Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation

Huang

Ahmed

et al. 2017

Medicine

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Rationale:Carnitine-acylcarnitine translocate deficiency (CACTD) is a rare and life-threatening, autosomal recessive disorder of fatty acid β-oxidation characterized by hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, liver dysfunction, and muscle weakness; culminating in early death. To date, CACTD cases screened from the Chinese mainland population, especially patient with compound heterozygote with c.199-10T>G and a novel c.1A>G mutation in the SLC25A20 gene has never been described.Patient concerns:Herein, we report 2 neonatal cases of CACTD identified from the mainland China. These 2 patients were presented with severe metabolic crisis and their clinical conditions deteriorate rapidly and both died of cardiorespiratory collapse in the first week of life. We present the clinical and biochemical features of 2 probands and a brief literature review of previously reported CACTD cases with the c.199-10T>G mutation.Diagnoses:The acylcarnitine profiles by tandem-mass-spectrometry and the mutation analysis of SLC25A20 gene confirmed the diagnosis of CACTD in both patients. Mutation analysis demonstrated that patient No. 1 was homozygous for c.199-10T>G mutation, while patient No. 2 was a compound heterozygote for 2 mutations, a maternally-inherited c.199-10T>G and a paternally-inherited, novel c.1A>G mutation.Interventions:Both patients were treated with an aggressive treatment regimen include high glucose and arginine infusion, respiratory, and circulatory support.Outcomes:The first proband died 3 days after delivery due to sudden cardiac arrest. The second patient's clinical condition, at one time, was improved by high glucose infusion, intravenous arginine, and circulatory support. However, the patient failed to wean from mechanical ventilation. Unfortunately, her parents refused further treatment due to fear of financial burdens. The patient died of congestive heart failure in the 6th day of life.Lessons:We report the first 2 cases of CACTD identified from the mainland China. Apart from a founder mutation c.199-10T>G, we identified a novel c.1A>G mutation. Patients with CACTD with a genotype of c.199-10T>G mutation usually presents with a severe clinical phenotype. Early recognition and appropriate treatment is crucial in this highly lethal disorder. This case series highlights the importance of screening for metabolic diseases including CACTD in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period.

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“…White matter abnormalities are common in this condition although the manifestation does not always correlate with disease course [7,18]. .Survival in early onset CACT deficiency is rare [4,19,20]. Multi-organ failure and death is the usual reported outcome.…”

Section: Discussionmentioning

confidence: 99%

The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

Bhattacharya

Matar

Tolun³

et al. 2020

Orphanet J Rare Dis

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Background: Ketone bodies form a vital energy source for end organs in a variety of physiological circumstances. At different times, the heart, brain and skeletal muscle in particular can use ketones as a primary substrate. Failure to generate ketones in such circumstances leads to compromised energy delivery, critical end-organ dysfunction and potentially death. There are a range of inborn errors of metabolism (IEM) affecting ketone body production that can present in this way, including disorders of carnitine transport into the mitochondrion, mitochondrial fatty acid oxidation deficiencies (MFAOD) and ketone body synthesis. In situations of acute energy deficit, management of IEM typically entails circumventing the enzyme deficiency with replenishment of energy requirements. Due to profound multi-organ failure it is often difficult to provide optimal enteral therapy in such situations and rescue with sodium DL-3-hydroxybutyrate (S DL-3-OHB) has been attempted in these conditions as documented in this paper. Results: We present 3 cases of metabolic decompensation, one with carnitine-acyl-carnitine translocase deficiency (CACTD) another with 3-hydroxyl, 3-methyl, glutaryl CoA lyase deficiency (HMGCLD) and a third with carnitine palmitoyl transferase II deficiency (CPT2D). All of these disorders are frequently associated with death in circumstance where catastrophic acute metabolic deterioration occurs. Intensive therapy with adjunctive S DL-3OHB led to rapid and sustained recovery in all. Alternative therapies are scarce in these situations. Conclusion: S DL-3-OHB has been utilised in multiple acyl co A dehydrogenase deficiency (MADD) in cases with acute neurological and cardiac compromise with long-term data awaiting publication. The use of S DL-3-OHB is novel in non-MADD fat oxidation disorders and contribute to the argument for more widespread use.

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Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency

Cited by 16 publications

References 17 publications

Bioinformatics identification of potential candidate blood indicators for doxorubicin‑induced heart failure

Bioinformatics identification of potential candidate blood indicators for doxorubicin‑induced heart failure

Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation

The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

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