On the dynamic and even reversible nature of Leigh syndrome: Lessons from human imaging and mouse models

Abstract

Leigh syndrome (LS) is a neurodegenerative disease characterized by bilaterally symmetric brainstem or basal ganglia lesions. More than 80 genes, largely impacting mitochondrial energy metabolism, can underlie LS, and no approved medicines exist. Described 70 years ago, LS was initially diagnosed by the characteristic, necrotic lesions on autopsy. It has been broadly assumed that antemortem neuroimaging abnormalities in these regions correspond to end-stage histopathology. However, clinical observations and animal studies suggest that neuroimaging findings may represent an intermediate state, that is more dynamic than previously appreciated, and even reversible. We review this literature, discuss related conditions that are treatable, and present two new LS cases with radiographic improvement. We review studies in which hypoxia reverses advanced LS in a mouse model. The fluctuating and potentially reversible nature of radiographic LS lesions will be important in clinical trial design. Better understanding of this plasticity could lead to new therapies.

Figure 1

T2-weighted MRI showing resolution of lesions. (a) Patient 1 basal ganglia and thalamic lesions at age 9 months with resolution of thalamic lesions at age 4 years (top) and red nuclei lesions at 9 months with resolution at age 4 years (bottom). (b) Patient 2 demonstrates improvement of dentate nuclei hyperintensities at age 16 months with marked improvement at age 4 years. MRI, magnetic resonance imaging.

Figure 2

Radiologic and histopathologic reversal of lesions in the Ndufs4^−/− mouse after hypoxia treatment. Top: T2 MRI; red arrows indicate hyperintensities in vestibular nuclei. Bottom: immunohistochemistry of coronal section labeling microglia with IBA1 and the nuclear counterstain DAPI (4′,6-diamidino-2-phenylindole). MRI adapted from Ferrari et al., 2017.