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.