Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.
J Intern Med. 2020 Jun;287(6):609-633. doi: 10.1111/joim.13054. Epub 2020 Apr 7.
Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.
在儿童期表现出的线粒体疾病的特点是临床、生化和遗传的复杂性。一些儿童受到经典综合征的影响，但大多数都有非典型的多系统疾病表现，涉及身体几乎任何器官。每个孩子都有独特的临床特征和疾病轨迹组合，这导致在诊断和管理这些异质性疾病方面存在巨大挑战。这篇综述讨论了在儿童期最常出现的经典线粒体综合征，然后从基于器官的角度介绍了一些不太常与线粒体疾病相关的系统，如皮肤和毛发异常以及免疫功能障碍。然后提出了一种诊断方法，包括临床评估以及生化、神经影像学和遗传学研究，并强调了表型模拟的问题。讨论了下一代测序的影响，以及对从未与线粒体疾病相关的新型遗传变异进行功能验证的重要性。最后简要讨论了目前可及和新兴的治疗方法。在过去的 30 年中，线粒体医学领域取得了巨大进展，现在已经有两个基因组中的 400 多个不同基因与原发性线粒体疾病相关。然而，仍有许多重要的问题尚未得到解答，包括为什么具有相同基因缺陷的个体具有组织特异性和临床表现的可变性，以及缺乏疾病修饰疗法和生物标志物来监测疾病进展和/或治疗反应。
