Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency

Engelstad, Kristin; Salazar, Rachel; Koenigsberger, Dorcas; Stackowtiz, Erin; Brodlie, Susan; Brandabur, Melanie; Vivo, Darryl C. De

doi:10.1002/acn3.51359

Cited by 3 publications

(4 citation statements)

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“…[ 13 ], but their efficiency is debatable. Moreover, vitamin cocktails are useless [ 35 ]. A ketogenic diet, prolonged propofol infusions, and valproic acid should be avoided [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…A new proposed therapy is represented by Triheptanoin (7 carbon fatty acid), which has already been used with variable results in intractable epilepsy in children and adults [ 39 , 40 ]. Triheptanoin, an anaplerotic treatment, increases energy generation via the tricarboxylic acid cycle or the Krebs cycle [ 35 , 36 ]. Triheptanoin directly enters mitochondria as a C7 fatty acid, which is metabolized to one C3 Propionyl CoA and two C2 Acetyl CoA.…”

Section: Discussionmentioning

confidence: 99%

“…Triheptanoin directly enters mitochondria as a C7 fatty acid, which is metabolized to one C3 Propionyl CoA and two C2 Acetyl CoA. The latter enters the Krebs cycle directly, while one C3 Propionyl CoA is converted to methylmalonyl-CoA and then to succinyl-CoA, a Krebs cycle intermediate [ 35 , 39 ]. Triheptanoin is a medium-chain triglyceride with 3 odd fatty acids, tasteless, and well-tolerated in ascending doses up to 100 mL/day (up to 40% of daily caloric intake), with mild gastrointestinal side-effects [ 39 ], and may represent a treatment option in ECHS1 deficiency [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

Muntean

Tripon

Bogliș

et al. 2022

IJERPH

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ECHS1 gene mutations are known to cause mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, a neurodegenerative disorder characterized by psychomotor development delay, lactic acidosis, and basal ganglia lesions resembling Leigh syndrome. Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a very rare and new disorder, with a wide phenotypic spectrum and different outcomes ranging from neonatal death to survival into adulthood. Since the identification of ECHS1 deficiency in 2014, almost 63 patients with pathogenic mutations in the ECHS1 gene have been described to date. This paper focuses on the clinical and molecular findings as well as the evolution of a Caucasian girl diagnosed with ECHS1 deficiency who carries a new compound heterozygous mutation in the ECHS1 gene. Polymorphic symptoms, namely failure to thrive, significant global developmental delay/regression, movement disorders, ocular abnormalities, hearing loss, seizure, and cardiac myopathy, may be a challenge in mitochondrial disorder suspicion. Early diagnosis, an appropriate diet with valine restriction, and trigger avoidance are essential, as there is no effective therapy for the disease. This disorder influences life quality in these patients and their caregivers, and it has the potential to be fatal.

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“…[ 13 ], but their efficiency is debatable. Moreover, vitamin cocktails are useless [ 35 ]. A ketogenic diet, prolonged propofol infusions, and valproic acid should be avoided [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

Muntean

Tripon

Bogliș

et al. 2022

IJERPH

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“…These molecular diagnoses exemplify 3 of the numerous medically actionable LS-defects with defect-specific potentially disease-modifying treatments, the development of which is only made possible by knowledge of the disease pathomechanism. Further examples include, but are not limited to, the beneficial effects of ketogenic diet for PDH deficiency, 49 triheptanoin for the ECHS1 defect, 50 and the mTOR inhibitor rapamycin for specific causes of LS, such as the NDUFS4 defect. 51,52 To conclude, our data pave the way to defining the phenotype, onset, and survival data of LS in a defectspecific manner, providing indispensable knowledge on the genetic defect-level needed for assessing the efficacy of experimental treatments in clinical trials, and adding considerably to existing knowledge concerning features associated with specific gene defects or predictive of disease outcome.…”

Section: Discussionmentioning

confidence: 99%

Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital

Stenton

Zou

Cheng

et al. 2022

Annals of Neurology

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Objective: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. Methods: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. Results: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176T>C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993T>C and m.9176T>C), SURF1, and ALDH5A1 (≤50% 3 year's survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year's survival). Interpretation: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counseling, and to the design and monitoring of future clinical trials, the next frontier of LS research.

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Valine restriction extends survival in aDrosophilamodel of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency

Mele,

Martelli,

Barlow

et al. 2024

Preprint

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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.

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Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency

Cited by 3 publications

References 42 publications

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital

Valine restriction extends survival in aDrosophilamodel of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency

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