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. 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.
Highlights
Leigh syndrome (LS; OMIM No 256000), originally described in 1951 by the British neuropathologist Dr Dennis Leigh, is a subacute necrotizing encephalomyelopathy with a frequency gliosis in several brain regions (Leigh, 1951)
Maternal history was significant with five miscarriages in the setting of hypercoagulability due to a factor 2 mutation for which she is treated with Lovenox
At 6 months, the proband had his first ophthalmology evaluation due to concerns for corneal opacities. He was diagnosed with bilateral infantile cataracts and congenital ptosis of the right upper lid. He underwent a surgical procedure for extraction of his right cataract and a sling for his right upper lid
Summary
Leigh syndrome (LS; OMIM No 256000), originally described in 1951 by the British neuropathologist Dr Dennis Leigh, is a subacute necrotizing encephalomyelopathy with a frequency gliosis in several brain regions (Leigh, 1951). It affects about 1 in 40,000 live births and can caused by more than 75 distinct genes (Lake et al, 2016). LS clinical heterogeneity can result in Leigh-like syndrome or atypical Leigh syndrome in patients with atypical neuropathology and clinical presentation with symptoms affecting the peripheral nervous system, including polyneuropathy and myopathy, and non-neurological symptoms, such as cardiomyopathy, renal failure, short stature, anemia, diabetes, and gastrointestinal dysfunctions (Finsterer, 2008)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
