Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6.
Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6.
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DOI：
10.1016/j.mito.2018.01.001
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发表时间：
2019-01
期刊：
影响因子：
4.4
通讯作者：
Weisfeld-Adams, James D.
中科院分区：
文献类型：
--
作者：
Larson, Austin A.;Balasubramaniam, Shanti;Christodoulou, John;Burrage, Lindsay C.;Marom, Ronit;Graham, Brett H.;Diaz, George A.;Glamuzina, Emma;Hauser, Natalie;Heese, Bryce;Horvath, Gabriella;Mattman, Andre;van Karnebeek, Clara;Rutledge, S. Lane;Williamson, Amy;Estrella, Lissette;Van Hove, Johan K. L.;Weisfeld-Adams, James D.
关键词：
血液中特定的酰基肉碱的升高反映了羧基酶的缺乏，并在新生儿筛查危及生命的有机酸血症和其他遗传性代谢性疾病方面有实用价值。在这篇报道中，我们描述了在MT-ATP6线粒体DNA(MtDNA)突变的个体中发现的一个新发现的多发性羧酸酶缺乏症的生化特征的关联，其中排除了有机酸血症和多发性羧基酶缺乏症。通过回顾图表，我们发现11例丙酰卡尼汀(C3)或羟基异戊基卡尼汀(C5OH)异常升高的个体存在MT-ATP6突变，最常见的突变是高异质性或同质性的m.8993T>；G。大多数患者是在新生儿筛查中确诊的；大多数患者都进行了正常的酶或分子基因测试，以排除生物素酶和全羧酸酶合成酶缺陷。MT-ATP6与一些Leigh病病例有关；我们队列中的临床结果从儿童早期死于神经退行性疾病到经过几年的随访后临床和发育正常。这些病例扩大了与MT-ATP6突变相关的生化表型，特别是m.8993T>；G，包括模拟羧基酶缺乏状态的酰肉碱异常。临床医生应该意识到这种关联及其对新生儿筛查的影响，并考虑在表现出类似的酰卡尼汀异常的患者中进行线粒体DNA测序，这些异常是生物素反应迟钝的，并且已经排除了其他酶缺陷。
Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T > G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T > G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.
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影响因子：
4.2
作者：
Rips, Jonathan;Almashanu, Shlomo;Spiegel, Ronen
通讯作者：
Spiegel, Ronen
影响因子：
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Häberle J;Boddaert N;Burlina A;Chakrapani A;Dixon M;Huemer M;Karall D;Martinelli D;Crespo PS;Santer R;Servais A;Valayannopoulos V;Lindner M;Rubio V;Dionisi-Vici C
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Thorburn, DR
影响因子：
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作者：
van Karnebeek, Clara D.;Sly, William S.;Stockler-Ipsiroglu, Sylvia
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Stockler-Ipsiroglu, Sylvia
影响因子：
4.2
作者：
WOLF, B;GRIER, RE;HEARD, GS
通讯作者：
HEARD, GS