Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.
Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.
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DOI：
10.1002/acn3.189
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发表时间：
2015-05
影响因子：
5.3
通讯作者：
Klopstock T
中科院分区：
文献类型：
--
作者：
Haack TB;Jackson CB;Murayama K;Kremer LS;Schaller A;Kotzaeridou U;de Vries MC;Schottmann G;Santra S;Büchner B;Wieland T;Graf E;Freisinger P;Eggimann S;Ohtake A;Okazaki Y;Kohda M;Kishita Y;Tokuzawa Y;Sauer S;Memari Y;Kolb-Kokocinski A;Durbin R;Hasselmann O;Cremer K;Albrecht B;Wieczorek D;Engels H;Hahn D;Zink AM;Alston CL;Taylor RW;Rodenburg RJ;Trollmann R;Sperl W;Strom TM;Hoffmann GF;Mayr JA;Meitinger T;Bolognini R;Schuelke M;Nuoffer JM;Kölker S;Prokisch H;Klopstock T
短链烯酰辅酶a水合酶（ECHS1）是一种多功能线粒体基质酶，参与脂肪酸和必需氨基酸（如缬氨酸）的氧化。在这里，我们描述了常染色体隐性ECHS1缺乏症个体的广泛表型谱和病理生化。通过外显子组测序，我们鉴定出10个携带ECHS1杂合或纯合复合突变的无亲缘关系个体。对患者源性成纤维细胞系的功能研究包括免疫印迹、酶活性测定和棕榈酸盐负荷测定。患者表现出异质性表型，疾病发病在生命的第一年，病程从新生儿死亡到存活到成年。最突出的临床特征是脑病（10/10）、耳聋（9/9）、癫痫（6/9）、视神经萎缩（6/10）和心肌病（4/10）。血清乳酸升高，脑磁共振成像显示白质改变或类似线粒体能量代谢紊乱的leigh样模式。对患者成纤维细胞系（6/10）的分析显示，ECHS1蛋白水平降低，2-烯酰辅酶a水合酶活性降低，进一步证明了各自突变的致病性。虽然血清酰基肉碱谱基本正常，但患者成纤维细胞的体外棕榈酸负荷显示丁基肉碱增加，揭示了线粒体β-氧化短链脂肪酸的功能缺陷。尿中2-甲基-2,3-二羟基丁酸盐（丙烯酰辅酶a在缬氨酸分解代谢途径中的潜在衍生物）的排泄显著增加，表明缬氨酸氧化受损。总之，我们定义了一种由ECHS1缺乏引起的新综合征的表型谱。我们推测，β-氧化缺陷和l-缬氨酸代谢障碍，以及有毒甲基丙烯酰辅酶a和丙烯酰辅酶a的积累，都是导致这种疾病的原因，可能需要代谢治疗方法。
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. 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. 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. 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.
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DOI：
10.1016/b978-0-444-59565-2.00035-6
发表时间：
2013-01-01
期刊：
PEDIATRIC NEUROLOGY, PT III
影响因子：
--
作者：
Tein, Ingrid
通讯作者：
Tein, Ingrid
影响因子：
2.6
作者：
Elstner, Matthias;Andreoli, Christophe;Prokisch, Holger
通讯作者：
Prokisch, Holger
影响因子：
9.8
作者：
Haack, Tobias B.;Hogarth, Penelope;Hayflick, Susan J.
通讯作者：
Hayflick, Susan J.
影响因子：
4.2
作者：
Wanders, Ronald J. A.;Duran, Marinus;Loupatty, Ference J.
通讯作者：
Loupatty, Ference J.
影响因子：
3.8
作者：
Gallant, Natalie M.;Leydiker, Karen;Wang, Raymond Y.
通讯作者：
Wang, Raymond Y.