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.

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.

Etiology, syndrome diagnosis, and cognition in childhood-onset epilepsy: A population-based study.

OBJECTIVE: To evaluate the prevalence of various etiologies of epilepsies and epilepsy syndromes and to estimate cognitive function in cases of childhood-onset epilepsy. METHODS: A population-based retrospective registry study. We identified all medically treated children with epilepsy born in 1989-2007 in Finland's Kuopio University Hospital catchment area, combining data from the birth registry and the national registry of special-reimbursement medicines. We reevaluated the epilepsy diagnoses and syndromes and gathered data on etiologies and cognitive impairment. RESULTS: We identified 289 children with epilepsy. The annual incidence rate of epilepsies and epilepsy syndromes was 38 in 100,000, and the misdiagnosis rate was 3%. A specific etiology was identified in 65% of the cases, with a structural etiology accounting for 29% and a genetic or presumed genetic etiology for 32%. Most patients with unknown-etiology epilepsy had focal epilepsy and were of normal intelligence. Intellectual disability was detected in 35% of cases, and only 17% in this group had an unknown etiology for the epilepsy. Electroclinical syndromes (mainly West syndrome) were recognized in 35% of the patients. SIGNIFICANCE: Epilepsy is a complex disease that encompasses many etiologies and rare syndromes. The etiology and specific epilepsy syndrome are important determinants of the outcome and key factors in treatment selection. Etiological diagnosis can be achieved for the majority of children and syndromic diagnosis for only a third.

Infertility treatment and umbilical cord length-novel markers of childhood epilepsy?

BACKGROUND: Epilepsy is one of the most common neurologic disorders of childhood, affecting about 0.4-0.8% of all children up to the age of 20. METHODOLOGY: A population-based retrospective cohort study. Aim was to determine incidence and identify perinatal and reproductive risk factors of epilepsy in children born between 1989 and 2008 among women (n = 43,389) delivered in Kuopio University Hospital. Risk factors of childhood epilepsy were determined by using logistic regression analysis. PRINCIPAL FINDINGS: The incidence of childhood epilepsy was 0.7% (n = 302 of 43,389). Maternal epilepsy, major congenital anomalies and use of assisted reproductive technology (ART) were associated with 4.25-, 3.61-, and 1.67- fold increased incidence of childhood epilepsy. A 10 cm increase in umbilical cord length was associated with a 15% decrease in the incidence of epilepsy (adjusted OR 0.85, 95% CI 0.78-0.94). However, the above reproductive factors accounted for less than 2% of total incidence, whereas maternal epilepsy proved to be the highest risk factor. CONCLUSIONS: Perinatal and reproductive factors were shown to be minor risk factors of childhood epilepsy, implying that little can be done in obstetric care to prevent childhood epilepsy. Infertility treatment and umbilical cord length, independent of gestational age and congenital malformations, may be novel markers of childhood epilepsy.