Clinical, Biochemical and Metabolic Characterization of Patients with Short-chain Enoyl-CoA Hydratase(ECHS1) Deficiency: Two Case Reports and the Review of the Literature

Overview

Journal BMC Pediatr

Publisher Biomed Central

Specialty Pediatrics

Date 2020 Feb 5

PMID 32013919

Citations 11

Authors

Hua Yang

Dan Yu

Affiliations

Soon will be listed here.

Abstract

Background: Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare congenital metabolic disorder caused by biallelic mutations in the ECHS gene. Clinical phenotype includes severe developmental delay, regression, dystonia, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). SCEH is most notably involved in valine catabolism. There is no effective treatment for the disease, patients may respond to dietary restriction of valine and supplementation of N-acetylcysteine .

Case Presentation: We describe two patients who presented in infancy or early childhood with SCEH deficiency. Both patients were shown to harbor heterozygous or homozygous variants in the ECHS1 gene, and developmental retardation or regression as the onset manifestation. Brain MRI showed abnormal signals of bilateral pallidus. Urine metabolic examination showed increased levels of 2,3-dihydroxy-2-methylbutyric acid and S-(2-carboxypropyl) cysteamine S-(2-carboxypropoxypropyl) cysteamine (SCPCM). A valine restricted diet and combined of N-acetylcysteine supplementation were utilized in the two patients.

Conclusions: In clinical practice, The elevated urinary 2,3-dihydroxy-2-methylbutyrate, S-(2-carboxypropyl) cysteine, S-(2-carboxypropyl) cysteine and N-acetyl-S-(2-carboxypropyl) cysteine levels might be clues for diagnosis of SCEH deficiency which can be confirmed throughGenetic sequencing of ECHS1 gene. Early cocktail therapy, valine restrictied diet and N-acetylcysteine supplementation could improve the prognosis of patients.

Citing Articles

[Leigh syndrome caused by the mitochondrial m.8993T>G mutation with hypocitrullinemia: a report of four cases and literature review].

Li Y, Wang D, Zhou M, Sun H, Hong S, Jiang L Zhongguo Dang Dai Er Ke Za Zhi. 2024; 26(9):940-945.

PMID: 39267509 PMC: 11404460. DOI: 10.7499/j.issn.1008-8830.2404036.

Valine and Inflammation Drive Epilepsy in a Mouse Model of ECHS1 Deficiency.

Eller M, Zuberi A, Fu X, Burgess S, Lutz C, Bailey R bioRxiv. 2024; .

PMID: 38915588 PMC: 11195255. DOI: 10.1101/2024.06.13.598697.

Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.

Maalej M, Sfaihi L, Fersi O, Khabou B, Ammar M, Felhi R Metab Brain Dis. 2024; 39(4):611-623.

PMID: 38363494 DOI: 10.1007/s11011-024-01343-6.

Biological Role and Mechanism of Lipid Metabolism Reprogramming Related Gene ECHS1 in Cancer.

Hu T, Chen X, Lu S, Zeng H, Guo L, Han Y Technol Cancer Res Treat. 2022; 21:15330338221140655.

PMID: 36567598 PMC: 9806408. DOI: 10.1177/15330338221140655.

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

Muntean C, Tripon F, Boglis A, Banescu C Int J Environ Res Public Health. 2022; 19(4).

PMID: 35206276 PMC: 8871535. DOI: 10.3390/ijerph19042088.

References

Sharpe A, McKenzie M . Mitochondrial Fatty Acid Oxidation Disorders Associated with Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency. Cells. 2018; 7(6). PMC: 6025059. DOI: 10.3390/cells7060046. View

Haack T, Jackson C, Murayama K, Kremer L, Schaller A, Kotzaeridou U . Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol. 2015; 2(5):492-509. PMC: 4435704. DOI: 10.1002/acn3.189. View

Al Mutairi F, Shamseldin H, Alfadhel M, Rodenburg R, Alkuraya F . A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency. Clin Genet. 2016; 91(4):629-633. DOI: 10.1111/cge.12891. View

Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K, Matsunaga A . Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis. 2017; 40(5):685-693. PMC: 5579154. DOI: 10.1007/s10545-017-0042-6. View

Sakai C, Yamaguchi S, Sasaki M, Miyamoto Y, Matsushima Y, Goto Y . ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. 2014; 36(2):232-9. DOI: 10.1002/humu.22730. View

Carlston C, Ferdinandusse S, Hobert J, Mao R, Longo N . Extrapolation of Variant Phase in Mitochondrial Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency. JIMD Rep. 2018; 43:103-109. PMC: 6323015. DOI: 10.1007/8904_2018_111. View

Tetreault M, Fahiminiya S, Antonicka H, Mitchell G, Geraghty M, Lines M . Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet. 2015; 134(9):981-91. DOI: 10.1007/s00439-015-1577-y. View

Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J . ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain. 2014; 137(Pt 11):2903-8. DOI: 10.1093/brain/awu216. View

Nair P, Hamzeh A, Mohamed M, Malik E, Al-Ali M, Bastaki F . Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis. Metab Brain Dis. 2016; 31(5):1189-92. DOI: 10.1007/s11011-016-9842-x. View

10.

Olgiati S, Skorvanek M, Quadri M, Minneboo M, Graafland J, Breedveld G . Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. Mov Disord. 2016; 31(7):1041-8. DOI: 10.1002/mds.26610. View

11.

Ferdinandusse S, Friederich M, Burlina A, Ruiter J, Coughlin 2nd C, Dishop M . Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis. 2015; 10:79. PMC: 4474341. DOI: 10.1186/s13023-015-0290-1. View

12.

Peters H, Ferdinandusse S, Ruiter J, Wanders R, Boneh A, Pitt J . Metabolite studies in HIBCH and ECHS1 defects: Implications for screening. Mol Genet Metab. 2015; 115(4):168-73. DOI: 10.1016/j.ymgme.2015.06.008. View

13.

Fitzsimons P, Alston C, Bonnen P, Hughes J, Crushell E, Geraghty M . Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Am J Med Genet A. 2018; 176(5):1115-1127. PMC: 5947294. DOI: 10.1002/ajmg.a.38658. View

14.

Ganetzky R, Bloom K, Ahrens-Nicklas R, Edmondson A, Deardorff M, Bennett M . ECHS1 Deficiency as a Cause of Severe Neonatal Lactic Acidosis. JIMD Rep. 2016; 30:33-37. PMC: 5110442. DOI: 10.1007/8904_2016_538. View

15.

Huffnagel I, Redeker E, Reneman L, Vaz F, Ferdinandusse S, Poll-The B . Mitochondrial Encephalopathy and Transient 3-Methylglutaconic Aciduria in ECHS1 Deficiency: Long-Term Follow-Up. JIMD Rep. 2017; 39:83-87. PMC: 5953898. DOI: 10.1007/8904_2017_48. View

16.

Mahajan A, Constantinou J, Sidiropoulos C . ECHS1 deficiency-associated paroxysmal exercise-induced dyskinesias: case presentation and initial benefit of intervention. J Neurol. 2017; 264(1):185-187. DOI: 10.1007/s00415-016-8381-z. View

17.

Balasubramaniam S, Riley L, Bratkovic D, Ketteridge D, Manton N, Cowley M . Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency. J Inherit Metab Dis. 2017; 40(5):745-747. DOI: 10.1007/s10545-017-0036-4. View

18.

Shayota B, Soler-Alfonso C, Bekheirnia M, Mizerik E, Boyer S, Xiao R . Case report and novel treatment of an autosomal recessive Leigh syndrome caused by short-chain enoyl-CoA hydratase deficiency. Am J Med Genet A. 2019; 179(5):803-807. PMC: 9873404. DOI: 10.1002/ajmg.a.61074. View

19.

Alkonyi I, Sandor A . Demonstration of an enzymatic transfer reaction between beta-methyl-crotonyl-coenzyme A and L-carnitine. Acta Biochim Biophys Acad Sci Hung. 1972; 7(2):149-50. View

20.

Bedoyan J, Yang S, Ferdinandusse S, Jack R, Miron A, Grahame G . Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017; 120(4):342-349. PMC: 5382105. DOI: 10.1016/j.ymgme.2017.02.002. View