Understanding the Epilepsy in POLG Related Disease

Abstract

Epilepsy is common in polymerase gamma (POLG) related disease and is associated with high morbidity and mortality. Epileptiform discharges typically affect the occipital regions initially and focal seizures, commonly evolving to bilateral convulsive seizures which are the most common seizure types in both adults and children. Our work has shown that mtDNA depletion-i.e., the quantitative loss of mtDNA-in neurones is the earliest and most important factor of the subsequent development of cellular dysfunction. Loss of mtDNA leads to loss of mitochondrial respiratory chain (MRC) components that, in turn, progressively disables energy metabolism. This critically balanced neuronal energy metabolism leads to both a chronic and continuous attrition (i.e., neurodegeneration) and it leaves the neurone unable to cope with increased demand that can trigger a potentially catastrophic cycle that results in acute focal necrosis. We believe that it is the onset of epilepsy that triggers the cascade of damage. These events can be identified in the stepwise evolution that characterizes the clinical, Electroencephalography (EEG), neuro-imaging, and neuropathology findings. Early recognition with prompt and aggressive seizure management is vital and may play a role in modifying the epileptogenic process and improving survival.

Keywords: POLG; epilepsy; mechanism; mitochondria; mtDNA; occipital lobe epilepsy; status epilepticus; stroke-like episodes.

Conflict of interest statement

The authors declare no financial or other conflicts of interest.

Figures

Figure 1

Schematic showing how POLG mutation can cause neuronal death and the role of epilepsy. Recessive mutations in the catalytic subunit of polymerase gamma (POLG) cause neuronal depletion of mtDNA. The level falls to ~40% and we believe that this is the threshold for neurones under which survival cannot be maintained. Depletion impairs the production of MRC components, and this particularly appears to affect complex I, which in turn leads to progressive loss of respiratory chain activity. We also find that over time (i.e., the longer a patient lives with this disease) patient neurones accumulate increasing amounts of mtDNA deletion and point mutation. Whether the greater the mtDNA mutational load has pathological consequences is unclear but possible. Based on our clinical and pathological studies, POLG related disease follows an acute on chronic course and our explanation for this is the presence of the critical neuronal energy level. Gradual loss of neurones, i.e., neurodegeneration is associated with the clinical correlates of ataxia, encephalopathy and cerebral atrophy etc. As soon as the patient develops epilepsy the picture changes dramatically .Focal necrotic lesions develop [4,17] and these are easily identified on magnetic resonance imaging (MRI), (the so-called stroke-like episodes). Such focal damage can also act as a trigger for further seizures.

Figure 2

Typical EEG, imaging, and neuropathology in POLG encephalopathy. Representative findings are shown from a 41-year-old patient, homozygous for the p.W748S mutation (EEG and histology) and an 8-year-old patient compound heterozygous in trans for the p.A467T and p.G303R (MRI). (A) Interictal EEG recording showing periodic sharp activity around 1Hz frequency in in occipital leads O1 and O2; (B) Axial T2-weighted MRI shows bilateral high T2-signal consistent with cortical edema, in the occipitotemporal regions (white arrows); (C) Hematoxylin and eosin stained section of the medial occipital cortex showing severe vacuolation of the neuropil and neuronal loss. Arrows mark examples of eosinophilic neuronal necrosis (magnification: 200×, scalebar: 50 µm).