POLG1-Related Epilepsy: Review of Diagnostic and Therapeutic Findings

Abstract

Background: The clinical spectrum associated with POLG1 gene mutations ranges from non-syndromic epilepsy or mild isolated neurological signs to neurodegenerative disorders. Our aim was to review diagnostic findings, therapeutic approaches and outcomes of reported cases of epilepsy related to POLG1 mutation. Methods: The articles for review were identified through a systematic research on PubMed and EMBASE databases from January 2003 to April 2020, searching for the terms “Epilepsy AND POLG OR polymerase gamma,” OR “POLG1”. Results: Forty-eight articles were selected for review, which included 195 patients. Two main peaks of age at epilepsy onset were found: at ages 1 and 13 years. The most frequent seizure type was myoclonic. The occurrence of Status Epilepticus was reported in 46.4% of cases. Epileptiform and slow abnormalities were most frequently seen over occipital regions. Brain Magnetic Resonance Imaging (MRI) revealed increased T2 signal intensities in thalamic regions. Genetic analysis revealed a prevalence of A467T, W748S and G848S (74.2% of patients) mutations. Survival at 5 years was estimated at very low levels (30.2% of patients). Conclusion: In this review, we included cases with both pediatric and adult epilepsy onset. The analysis of data regarding prognosis showed that survival is related to age at onset of epilepsy.

Seizure Semiology, EEG, and Imaging Findings in Epilepsy Secondary to Mitochondrial Disease

“…In a series of 19 patients with POLG1, occipital rhythmic slowing was present in 7 patients and occipital interictal discharges was present in 18 patients, demonstrating an occipital predilection in POLG ( 15 ). This finding, as seen in our study over the disease course, is concordant with electrophysiologic data reported by other authors ( 10 , 16 , 28 , 29 ). Occipital status epilepticus and occipital seizures have also been previously reported in MELAS; this manifestation may precede other clinical signs of the disease and serve as a potential diagnostic clue ( 29 , 32 , 33 ).…”

“…Our findings are supported by previous patient series and literature reviews on epilepsy features in mitochondrial disorders (Table 3) (8,10,16,(28)(29)(30)(31). Focal seizures were the predominant seizure type in our series, which is in agreement with the previous review by Anagnostou et al in POLG and a recent case series in MELAS by Li et al (10,28).…”

“…Published information on specific seizure semiology and electroencephalogram (EEG) findings in mitochondrial disorders is limited compared to what is known about other genetic and metabolic epilepsies, likely owing to the significant variability between and within specific mitochondrial disorders (10). While seizures are not unique to a mitochondrial etiology (11)(12)(13), it has been previously noted that EEG abnormalities in these disorders tend to have a posterior cerebral predilection (14)(15)(16). Within the central nervous system, mitochondrial dysfunction frequently results in structural injury, which can manifest as characteristic neuroimaging abnormalities (17,18).…”

A new pathogenic POLG variant

“…Magnetic resonance imaging (MRI) of the brain often demonstrates T2 and FLAIR hyperintensities in the cortical and subcortical regions, particularly in the occipital lobes. Similar lesions are also seen in the thalamus and cerebellum [ 33 ]. Electroencephalography (EEG) findings are variable but occipital discharges and slowing are frequently seen, as are rhythmic high-amplitude delta with superimposed spikes (RHADS) [ 33 ].…”

“…Myoclonus is the most common presented seizure type and patients often develop status epilepticus or epilepsy partialis continua. The seizures become refractory to treatment and worsen prognosis [ 33 ]. Valproic acid is contraindicated as it can precipitate or accelerate liver failure by inhibition of fatty acid beta-oxidation which impairs mitochondrial function [ 11 , 12 , 15 , 26 ].…”