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 ATP1A3, ATP1A2 or GLUT1 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 MT-TL2 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.

儿童替代性偏瘫（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。大约75％的AHC病例是由ATP1A3，ATP1A2或GLUT1基因中的致病性变异图谱引起的，许多AHC患者在临床和遗传上均未得到诊断。在这项研究中，我们报告了一个9岁的先证者的临床案例，该先证者被诊断出具有非典型形式的AHC，表现出怀疑的线粒体病因和模糊的遗传学诊断。先证者的线粒体基因组的下一代测序之后进行的远程PCR鉴定了一种新的线粒体变体m.12302C> A，在MT-TL2中作图在血液和成纤维细胞中具有低异质水平的基因。整个外显子组测序揭示了三个已知的和新颖的具有不同亲本遗传的致病变体，它们均参与线粒体能量代谢，因此迄今与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和代谢可塑性阻止了有效地切换到糖酵解以维持ATP稳态，这与怀疑的线粒体病因相吻合。总之，我们全面的遗传和代谢分析表明，先证者非典型形式AHC的线粒体病因在核和线粒体变体之间具有寡聚遗传，从而在遗传线索和生物能缺乏方面提供了重要的见识。