Prospective study of POLG mutations presenting in children with intractable epilepsy: Prevalence and clinical features. (28th February 2013)

• Record Type: Journal Article
• Authors: Uusimaa, Johanna; Gowda, Vasantha; McShane, Anthony; Smith, Conrad; Evans, Julie; Shrier, Annie; Narasimhan, Manisha; O'Rourke, Anthony; Rajabally, Yusuf; Hedderly, Tammy; Cowan, Frances; Fratter, Carl; Poulton, Joanna
• Is Part Of: Epilepsia. Volume 54:issue 6(2013:Jun.)
• Page Start: 1002
• Page End: 1011
• Publication Date: 2013-02-28
• Subjects: Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.12115
• Languages: English
• ISSNs: 0013-9580

Abstract

<abstract abstract-type="main" xml:lang="en" id="epi12115-abs-0001"> <title>Summary</title> <sec id="epi12115-sec-0001" sec-type="section"> <title>Purpose</title> <p>To assess the frequency and clinical features of childhood‐onset intractable epilepsy caused by the most common mutations in the <italic>POLG</italic> gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma.</p> </sec> <sec id="epi12115-sec-0002" sec-type="section"> <title>Methods</title> <p>Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population‐based study. Blood samples were analyzed for the three most common <italic>POLG</italic> mutations. If any of the three tested mutations were found, all the exons and the exon–intron boundaries of the <italic>POLG</italic> gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found <italic>POLG</italic> mutations. All available clinical data were collected by questionnaire and by reviewing the medical records.</p> </sec> <sec id="epi12115-sec-0003" sec-type="section"> <title>Key Findings</title> <p>We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common <italic>POLG</italic> mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged.</p> </sec> <sec id="epi12115-sec-0004" sec-type="section"> <title>Significance</title> <p>Mutations in <italic>POLG</italic> are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for <italic>POLG</italic> mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA‐induced liver failure in patients with <italic>POLG</italic> mutations. We recommend <italic>POLG</italic> gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T<sub>2</sub>‐weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.</p> </sec> </abstract>