Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate‐induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy

Abstract

Summary Objective Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA‐induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy. Methods Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected. Results A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion. Significance POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.

IQSEC2‐related encephalopathy in males due to missense variants in the pleckstrin homology domain

“…There is an emerging clinical picture of ID, epileptic encephalopathy with speech and language deficits and autism due to a broad range of variants in the IQSEC2 gene, including the missense variants in the PH domain that we report here. When we include the five novel cases presented in this study, there are 29 distinct nonsynonymous missense variants in the IQSEC2 gene reported in 34 unrelated cases and families 2,3,12,14‐20 . Most of these variants occur in known functional domains.…”

“…When we include the five novel cases presented in this study, there are 29 distinct nonsynonymous missense variants in the IQSEC2 gene reported in 34 unrelated cases and families. 2,3,12,[14][15][16][17][18][19][20] Most of these variants occur in known functional domains. Within the catalytic Sec7 domain, nine missense variants with three recurrent variants across eight separate cases or families, impact a total of 44 affected individuals (39 males and five females).…”

Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy

“…The study also showed that valproate administration increased thiobarbituric acid reagent content and nitric oxide (NO) production in the liver tissue, attributing to increased oxidative/nitrosative stress [ 27 ]. Interestingly, a 2018 cohort study noticed that POLG1 was not solely associated with an increased risk of valproate-induced liver toxicity but required a combination of other pathogenic mutations as well [ 82 ], thereby suggesting that only epileptic patients with the aforementioned pathologies/mutations may be prone to develop liver toxicity post valproate treatment.…”

Novel Clinical Biomarkers for Drug-Induced Liver Injury

“…POLG which codes mitochondrial DNA polymerase γ (polγ) is associated with an increased risk of VPA-induced hepatotoxicity, and even fatal damage to liver cells (Saneto et al, 2010;Stewart et al, 2010;Sitarz et al, 2014) with a >20-fold risk elevation (Stewart et al, 2010). When a large retrospective analysis was performed, no association was demonstrated in the VPA DILI patients (Hynynen et al, 2018), suggesting a genetic variation in the population and prospective RCT studies are still invaluable.…”