Gropman Andrea, Uittenbogaard Martine, Brantner Christine A, Wang Yue, Wong Lee-Jun, Chiaramello Anne
Children's National Medical Center, Division of Neurogenetics and Developmental Pediatrics, Washington, DC 20010, USA.
Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Mol Genet Metab Rep. 2020 May 28;24:100609. doi: 10.1016/j.ymgmr.2020.100609. eCollection 2020 Sep.
Alternative hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder with an extensive phenotypic variability, resulting in a challenging clinical diagnosis. About 75% of AHC cases are caused by pathogenic variants mapping in the , or gene, leaving many AHC patients clinically and genetically undiagnosed. In this study, we report the case of a 9-year old proband clinically diagnosed with an atypical form of AHC presenting a suspected mitochondrial etiology and an obscure genetic diagnosis. Long-range PCR followed by next generation sequencing of the proband's mitochondrial genome identified a novel mitochondrial variant, m.12302C > A, mapping in the gene with a low heteroplasmic level in blood and fibroblasts. Whole exome sequencing revealed three known and novel pathogenic variants with different parental inheritance, all involved in the mitochondrial energy metabolism and thus far not associated with AHC. Live-cell mitochondrial metabolic study showed dysregulated mitochondrial oxidative phosphorylation pathway and metabolic plasticity preventing an efficient switch to glycolysis to sustain ATP homeostasis, congruent with the suspected mitochondrial etiology. In conclusion, our comprehensive genetic and metabolic analyses suggest an oligogenic inheritance among the nuclear and mitochondrial variants for the mitochondrial etiology of proband's atypical form of AHC, thereby providing critical insight in terms of genetic clues and bioenergetic deficit. This approach also improves the diagnostic process of atypical form of AHC with an unclear genotype-phenotype correlation to personalize therapeutic interventions.
儿童交替性偏瘫（AHC）是一种罕见的神经发育障碍，具有广泛的表型变异性，导致临床诊断具有挑战性。约75%的AHC病例由位于 、 或 基因中的致病变异引起，许多AHC患者在临床和基因方面仍未得到诊断。在本研究中，我们报告了一例9岁先证者的病例，该先证者临床诊断为非典型形式的AHC，表现出疑似线粒体病因和不明的基因诊断。对先证者的线粒体基因组进行长程PCR，随后进行二代测序，发现了一个新的线粒体变异，m.12302C>A，位于 基因中，在血液和成纤维细胞中的异质性水平较低。全外显子组测序揭示了三个已知和新的致病变异，具有不同的亲本遗传模式，均参与线粒体能量代谢，且迄今为止与AHC无关。活细胞线粒体代谢研究显示线粒体氧化磷酸化途径失调以及代谢可塑性受损，无法有效转换为糖酵解以维持ATP稳态，这与疑似线粒体病因一致。总之，我们全面深入的基因和代谢分析表明，先证者非典型形式AHC的线粒体病因中，核基因和线粒体变异之间存在寡基因遗传，从而在遗传线索和生物能量缺陷方面提供了关键见解。这种方法还改善了基因型 - 表型相关性不明确的非典型形式AHC的诊断过程，以实现个性化治疗干预。
