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MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load


MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load

Yi Shiau Ng et al. EBioMedicine.


Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

Keywords: Heteroplasmy; Lactic acidosis and stroke-like episodes (MELAS); Leigh syndrome (LS); Mitochondrial DNA; Mitochondrial encephalomyopathy; Neuropathology.


Fig. 1
Fig. 1
Cranial and spine MRI. Axial T2-weighted view of Patient 1·2 showed hyperintensities involving the cortical and subcortical areas of left frontal lobe when she presented with the first stroke-like episode (A); the cranial MRI performed during the subsequent stroke-like episode showed hyperintensities involving the left parietal lobe and right cerebellar cortex, suggestive of cross cerebellar diaschisis (B) and extensive signal abnormalities in the brainstem (C, coronal view). Axial T2-weighted view of Patient 2 showed an isolated, left thalamic lesion (D). Axial T2 view (E) showed a discrete signal abnormality in the right cerebellum, and asymmetrical hyperintensities in the medulla in Patient 4. The sagittal T2 view (F) showed an anterior, long hyperintensity in the cervical cord spanning C2-6 levels in Patient 5, corroborated with the signal abnormalities shown in the axial view (G).
Fig. 2
Fig. 2
Heteroplasmy levels of the m.13094T>C mutation. (A) A negative correlation between age and blood mutant heteroplasmy level. (B) Distribution of mutant heteroplasmy levels for individual patient. The numbering of X-axis corresponds to the patient number of Table 1.
Fig. 3
Fig. 3
Neuropathological features of Patient 1.2 and 8. Patient 1.2: The posterior cerebellar cortex is affected by multiple necrotic lesions (demarcated by *) demonstrating atrophy of the molecular layer, Purkinje cell dropout and granule cell loss (A; LFB H&E) and total necrosis of the cortex and underlying white matter (B; LFB H&E). The basis pontis demonstrates a devastating lesion with total neuronal cell loss (C; red dashed line; LFB H&E). Scale bar = 100 μm. Patient 8: The lower midbrain shows devastated inferior colliculus with prominent capillary proliferation (arrows), microvacuolation and severe neuronal cell loss (D; H&E). The thalamus (E; LFB H&E) and subthalamic nucleus (F; H&E) are devastated featuring prominent capillary proliferation (arrows), microvacuolation, severe neuronal cell loss and morphologically normal neurons scattered throughout (arrowhead). The occipital lobes reveal microvacuolation and laminar necrosis of the cortical layers within Broadmann area 17 (G; LFB H&E) with the underlying white matter demonstrating myelin pallor relative to otherwise preserved myelin. The cortex features microvacuolation, severe neuronal cell loss and capillary proliferation. Surviving neurons within the inferior colliculus lack complex I subunit expression (H; NDUFB8 IHC, arrows) while mitochondrial mass is high (I; SDHA IHC, arrows).

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