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

Saneto, Russell P.; Lee, Inn-Chi; Koenig, Mary Kay; Bao, Xinhua; Weng, Shao-Wen; Naviaux, Robert K.; Wong, Lee-Jun C.

doi:10.1016/j.seizure.2010.01.002

« Previous Next »Seizure: European Journal of Epilepsy
Volume 19, Issue 3 , Pages 140-146, April 2010

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

Russell P. Saneto
- Division of Pediatric Neurology, Seattle Children's Hospital/University of Washington, Seattle, WA 98105, USA
- These authors contributed equally.
Inn-Chi Lee
- Department of Pediatrics, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA
- These authors contributed equally.
Mary Kay Koenig
- Division of Child & Adolescent Neurology, University of Texas Medical School at Houston, TX 77030, USA
Xinhua Bao
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
Shao-Wen Weng
- Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA
Robert K. Naviaux
- Departments of Medicine and Pediatrics, University of California San Diego, La Jolla, CA, USA
Lee-Jun C. Wong
- Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA
- Corresponding author. Tel.: +1 713 798 1940; fax: +1 713 798 8937.

Received 28 October 2009; received in revised form 31 December 2009; accepted 7 January 2010. published online 08 February 2010.

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 intractable 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.

Abbreviations: POLG, polymerase gamma, VPA, valproic acid, MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, MERRF, myoclonus, epilepsy with ragged red fibers, MRI, magnetic resonance imaging, MRS, proton (1H) magnetic resonance spectroscopy, FLAIR, fluid attenuated inversion recovery, MPV17, mitochondrial inner membrane protein, TWINKLE, gene encoding mitochondrial helicase, PCR, polymerase chain reaction