Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
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DOI：
10.3389/fcell.2021.767407
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发表时间：
2021
影响因子：
5.5
通讯作者：
Chiaramello A
中科院分区：
文献类型：
--
作者：
Uittenbogaard M;Sen K;Whitehead M;Brantner CA;Wang Y;Wong LJ;Gropman A;Chiaramello A
在这项研究中，我们旨在通过确定先证者的致病性变异，建立先证者进行性神经退行性疾病的线粒体病因学，提示非典型Leigh综合征。脑部MRI显示大脑深灰色核、脑干、小脑、脊髓沿着有一系列多灶性时间上不一致的病变，伴有菱脑萎缩和视神经萎缩。在左侧大脑深灰色核同时进行的单体素1H MRS显示小的乳酸峰，谷氨酸和柠檬酸盐升高，怀疑线粒体病因。全外显子组测序显示三个杂合核变异映射在三个不同的基因已知导致利综合征。我们的线粒体生物能量研究显示线粒体能量代谢受损。先证者的整体ATP缺陷进一步加剧了氧化磷酸化和糖酵解之间的无效代谢重编程。代谢适应性不足和整体能量不足与先证者的神经系统症状相关，符合非典型Leigh综合征。总之，我们的研究提供了急需的见解，以支持非典型Leigh综合征的分子诊断和治疗策略的发展。
In this study, we aimed to establish the mitochondrial etiology of the proband’s progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband’s pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel 1H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology. Whole exome sequencing revealed three heterozygous nuclear variants mapping in three distinct genes known to cause Leigh syndrome. Our mitochondrial bioenergetic investigations revealed an impaired mitochondrial energy metabolism. The proband’s overall ATP deficit is further intensified by an ineffective metabolic reprogramming between oxidative phosphorylation and glycolysis. The deficient metabolic adaptability and global energy deficit correlate with the proband’s neurological symptoms congruent with an atypical Leigh syndrome. In conclusion, our study provides much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.
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影响因子：
4.5
作者：
Kohda M;Tokuzawa Y;Kishita Y;Nyuzuki H;Moriyama Y;Mizuno Y;Hirata T;Yatsuka Y;Yamashita-Sugahara Y;Nakachi Y;Kato H;Okuda A;Tamaru S;Borna NN;Banshoya K;Aigaki T;Sato-Miyata Y;Ohnuma K;Suzuki T;Nagao A;Maehata H;Matsuda F;Higasa K;Nagasaki M;Yasuda J;Yamamoto M;Fushimi T;Shimura M;Kaiho-Ichimoto K;Harashima H;Yamazaki T;Mori M;Murayama K;Ohtake A;Okazaki Y
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Okazaki Y
影响因子：
3.7
作者：
Baxter, Kristin Kathleen;Uittenbogaard, Martine;Chiaramello, Anne
通讯作者：
Chiaramello, Anne
影响因子：
12.6
作者：
Pang SY;Teo KC;Hsu JS;Chang RS;Li M;Sham PC;Ho SL
通讯作者：
Ho SL
影响因子：
3.6
作者：
Mai, Nicole;Chrzanowska-Lightowlers, Zofia M. A.;Lightowlers, Robert N.
通讯作者：
Lightowlers, Robert N.
影响因子：
6.4
作者：
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通讯作者：
Horvath R