Abstract
Purpose :
This study describes a never previously reported systemic mitochondrial disease with ocular manifestations based on the discovery of a novel mitochondrial mutation, correlated with subcellular visualization of dysfunctional mitochondrial morphology, and corroborated with cell culture-based disease modeling.
Methods :
We evaluated a young woman with multi-organ dysfunction including pigmentary retinopathy and discovered a novel mitochondrial disease. Retinal pigmented epithelial (RPE) cell are being cultured in this study, to modulate the expression (virally and with plasmids) of the identified mutation and to assess impacts on cell viability. This study was performed in compliance with the Declaration of Helsinki.
Results :
A 16 yr old Chinese American girl presented with gradually decreased vision and visual field (Fig 1e-f) in both eyes for 5 months. Fundus examination showed a pigmentary retinopathy in both eyes (Fig 1a-b) with outer retinal thinning (Fig 1c-d). MRI of the brain (Fig 1g-h) showed multifocal abnormal signals, while CT of the head (Fig 1i-j) showed extensive parenchymal calcification. Deltoid muscle biopsy showed increased granular staining (Fig 1k-n) with electron microscopy (Fig 1o-p) disclosed abnormal mitochondrial morphology. A kidney biopsy (Fig 1q) with transmission electron microscopy (TEM) (Fig 1r) of this tissue showed abnormal mitochondrial morphology, with disorganized tangles of electron dense inclusions, marked mitochondrial distension, and loss of the normal ultrastructural appearance of the cisternae. Interestingly, systemic genetic sequencing failed to reveal genomic abnormalities. However, targeted mitochondrial DNA sequencing presented a novel 12148 T>C variant in tRNA-His located in the D arm stem of the tRNA-His gene, changing the original A-T pairing to A-C pairing. Given that it is currently unknown how this mutation impacts mitochondrial function and metabolism, we are now modeling this this variant tRNA-His mutation in RPE culture.
Conclusions :
This is the first report of a new disease. Herein, we discovered a novel mitochondrial mutation correlated with subcellular visualization of dysfunctional mitochondrial morphology, and are undergoing corroboration with cell culture-based disease modeling.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.