POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders

Abstract

Purpose To review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures. Methods Four patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing. Results Four patients of multiple different ethnicities, age 3–18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intrac partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers–Huttenlocher syndrome. Conclusion Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers–Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression.

Therapeutic Efficacy of Magnesium Valproate in Succinic Semialdehyde Dehydrogenase Deficiency

“…For example, Mg has been used to mitigate refractory status epilepticus in patients with POLG-1 mutations (Pandey et al 2010;Visser et al 2011). With the recent clinical emphasis on avoiding valproate in children with POLG-1 mutations because of potential precipitation of epilepsia partialis continuans (Saneto et al 2010), it is possible that magnesium had an important therapeutic role in our patient despite the general clinical tendency to avoid valproate in SSADH deficiency due to potential inhibition of residual enzymatic activity (Shinka et al 2003). Overall, it appears that valproate was beneficial toward seizure amelioration and improved behavioral features for our patient's condition, and there may have been a therapeutic role for magnesium, which will require further characterization.…”

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…The use of high-dose anticonvulsants and/or treatment with more than 1 medication often becomes necessary to control refractory seizures. It is very important to avoid valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) in treating seizures in MDS, particularly POLG-related disorders, because of the risk of precipitating and/or accelerating liver disease [121,122].…”

Mitochondrial Disease in Childhood: Nuclear Encoded

“…AHS is inherited in an autosomal recessive pattern, with the finding of 2 pathogenic mutations usually acquired in a compound heterozygote state [60,61]. Infants usually develop normally until disease onset, which is typically before 4 years of age.…”

“…Hepatic dysfunction varies from early to late in the course of the disease, and could progress to fulminant end-stage liver disease in a few months-especially when exposed to certain anticonvulsants. Valproic acid must be used with extreme caution when the etiology of seizures is unknown, as it can precipitate liver dysfunction in AHS [61,62]. Other neurologic symptoms include migraine with visual auras, cortical blindness, hypotonia, ataxia, extrapyramidal movements, peripheral neuropathy, and progressive spastic paraparesis [63].…”

“…Valproic acid has been avoided in young children with idiopathic epilepsy owing to the risk of valproic acid -induced hepatoxicity and concern for AHS, with gene testing of POLG recommended prior to its use [61,117].…”