AUTHOR=Uittenbogaard Martine , Sen Kuntal , Whitehead Matthew , Brantner Christine A. , Wang Yue , Wong Lee-Jun , Gropman Andrea , Chiaramello Anne 

TITLE=Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.767407

DOI=10.3389/fcell.2021.767407

ISSN=2296-634X

ABSTRACT=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. The proband’s clinical findings are consistent with an atypical form of Leigh syndrome. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, and spinal cord along with rhombencephalic atrophy, 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, known to cause Leigh syndrome due to impaired mitochondrial protein translation. 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. Our genetic and mitochondrial metabolic investigations support the concept of oligogenic inheritance of three heterozygous variants known to impair mitochondrial protein synthesis, which interface with each other to provoke a mitochondrial bioenergetic crisis, resulting in neurological manifestations with a mitochondrial etiology consistent with an atypical form of Leigh syndrome. In conclusion, our genetic and metabolic investigations provide much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.