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


CONCLUSIONS
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.
Division of Pediatric Neurology, Seattle Children's Hospital/University of Washington, Seattle, WA 98105, USA.
Russell P
RP
Saneto
Inn-Chi
IC
Lee
Mary Kay
MK
Koenig
Xinhua
X
Bao
Shao-Wen
SW
Weng
Robert K
RK
Naviaux
Lee-Jun C
LJ
Wong
D000293:Adolescent; D000927:Anticonvulsants / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D017093:Liver Failure / Q000139:chemically induced*; D008279:Magnetic Resonance Imaging; D008297:Male; D014635:Valproic Acid / Q000009:adverse effects*
D000927:Anticonvulsants; D014635:Valproic Acid; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human