Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.
Tobias B. Haack,Christopher B. Jackson,Kei Murayama,Laura S. Kremer,André Schaller,Urania Kotzaeridou,Maaike de Vries,Gudrun Schottmann,Saikat Santra,Boriana Büchner,Thomas Wieland,Elisabeth Graf,Peter Freisinger,Seila Eggimann,Akira Ohtake,Yasushi Okazaki,Masakazu Kohda,Yoshihito Kishita,Yoshimi Tokuzawa,Sascha Sauer,Yasin Memari,Anja Kolb-Kokocinski,Richard Durbin,Oswald Hasselmann,Kirsten Cremer,Beate Albrecht,Dagmar Wieczorek,Hartmut Engels,Dagmar Hahn,Alexander M. Zink,Charlotte L. Alston,Robert W. Taylor,Richard J. Rodenburg,Regina Trollmann,Wolfgang Sperl,Tim M. Strom,Georg F. Hoffmann,Johannes A. Mayr,Thomas Meitinger,Ramona Bolognini,Markus Schuelke,Jean-Marc Nuoffer,Stefan Kölker,Holger Prokisch,Thomas Klopstock,Thomas Klopstock +45 more
TLDR
The broad phenotypic spectrum and pathobiochemistry of individuals with autosomal‐recessive ECHS1 deficiency is described.Abstract:
OBJECTIVE
Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency.
METHODS
Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay.
RESULTS
Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation.
INTERPRETATION
In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.read more
Citations
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A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.
Masakazu Kohda,Yoshimi Tokuzawa,Yoshihito Kishita,Hiromi Nyuzuki,Yohsuke Moriyama,Yosuke Mizuno,Tomoko Hirata,Yukiko Yatsuka,Yzumi Yamashita-Sugahara,Yutaka Nakachi,Hidemasa Kato,Akihiko Okuda,Shunsuke Tamaru,Nurun Nahar Borna,Kengo Banshoya,Toshiro Aigaki,Yukiko Sato-Miyata,Kohei Ohnuma,Tsutomu Suzuki,Asuteka Nagao,Hazuki Maehata,Fumihiko Matsuda,Koichiro Higasa,Masao Nagasaki,Jun Yasuda,Masayuki Yamamoto,Takuya Fushimi,Masaru Shimura,Keiko Kaiho-Ichimoto,Hiroko Harashima,Taro Yamazaki,Masato Mori,Kei Murayama,Akira Ohtake,Yasushi Okazaki +34 more
TL;DR: These approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings and will improve patient care of this complex disorder.
Journal ArticleDOI
Mitochondrial β-oxidation of Saturated Fatty Acids in Humans
María M. Adeva-Andany,Natalia Carneiro-Freire,Mónica Seco-Filgueira,Carlos Fernández-Fernández,David Mouriño-Bayolo +4 more
TL;DR: Accumulation of non-oxidized fatty acids promotes their conjugation with glycine and l-carnitine and alternate ways of oxidation, such as ω-oxidation, which usually includes hypoketotic hypoglycemia triggered by fasting or infections.
Journal ArticleDOI
Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease
TL;DR: Current understanding of the interactions between FAO and OXPHOS proteins is reviewed and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis is reviewed.
Journal ArticleDOI
Enzymes involved in branched-chain amino acid metabolism in humans
María M. Adeva-Andany,Laura López-Maside,Cristóbal Donapetry-García,Carlos Fernández-Fernández,Cristina Sixto-Leal +4 more
TL;DR: It was established at the beginning of the twentieth century that the plasma level of the branched-chain amino acids is increased in conditions associated with insulin resistance such as obesity and diabetes mellitus, however, the potential clinical relevance is uncertain.
Journal ArticleDOI
Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy
Laura S. Kremer,Felix Distelmaier,Bader Alhaddad,Maja Hempel,Arcangela Iuso,Clemens Küpper,Clemens Küpper,Chris Mühlhausen,Reka Kovacs-Nagy,Robin Satanovskij,Elisabeth Graf,Riccardo Berutti,Gertrud Eckstein,Richard Durbin,Sascha Sauer,Sascha Sauer,Georg F. Hoffmann,Tim M. Strom,René Santer,Thomas Meitinger,Thomas Klopstock,Thomas Klopstock,Holger Prokisch,Tobias B. Haack +23 more
TL;DR: The results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement and Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial β-oxidation.
References
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Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA
Tobias B. Haack,Penelope Hogarth,Michael C. Kruer,Allison Gregory,Thomas Wieland,Thomas Schwarzmayr,Elisabeth Graf,Lynn Sanford,Esther Meyer,Esther Meyer,Eleanna Kara,Stephan M. Cuno,Sami I. Harik,Vasuki Dandu,Nardo Nardocci,Giovanna Zorzi,Todd Dunaway,Mark A. Tarnopolsky,Steven Skinner,Steven J. Frucht,Era Hanspal,Connie Schrander-Stumpel,Delphine Héron,Cyril Mignot,Barbara Garavaglia,Kailash P. Bhatia,John Hardy,Tim M. Strom,Nathalie Boddaert,Henry Houlden,Manju A Kurian,Manju A Kurian,Thomas Meitinger,Holger Prokisch,Susan J. Hayflick +34 more
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Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: Clinical Presentation and Follow-Up of 50 Patients
Margarethe E. J. den Boer,Ronald J.A. Wanders,Andrew A. M. Morris,Lodewijk IJlst,Hugo S. A. Heymans,Frits A. Wijburg +5 more
TL;DR: LCHAD deficiency often presents with a combination of chronic nonspecific symptoms, and survival can be improved by prompt diagnosis, but morbidity remains alarmingly high despite current therapeutic regimes.
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