title: Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus.
abstract: OBJECTIVE
  Polymerase gamma (POLG) is the sole enzyme in the replication of mitochondrial DNA (mtDNA). Numerous mutations in the POLG1 gene have been detected recently in patients with various phenotypes including a classic infantile-onset Alpers-Huttenlocher syndrome (AHS). Here we studied the molecular etiology of juvenile-onset AHS manifesting with status epilepticus and liver disease in three teenagers.
  
  
  METHODS
  We examined 14- and 17-year-old female siblings (patients 1 and 2) and an unrelated 15-year-old girl (patient 3) with juvenile-onset AHS, sequenced POLG1, and the entire mtDNA, examined mtDNA deletions by amplification of the full-length mtDNA with the long PCR method and used real-time PCR to quantify mtDNA in the tissue samples.
  
  
  RESULTS
  The initial manifestations were migraine-like headache and epilepsy, and the terminal manifestations status epilepticus and hepatic failure. A homozygous W748S mutation in POLG1 was detected in the three patients. No deletions or pathogenic point mutations were found in mtDNA, but all three patients had mtDNA depletion.
  
  
  CONCLUSIONS
  POLG mutations should be considered in cases of teenagers and young adults with a sudden onset of intractable seizures or status epilepticus, and acute liver failure. The W748S POLG1 mutation seems to lead to tissue-specific, partial mtDNA depletion in patients with juvenile-onset Alpers syndrome. Valproic acid should be avoided in the treatment of epileptic seizures in these patients.
authors.affiliation: Department of Pediatrics, University of Oulu, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.forename: Reetta
authors.initials: R
authors.lastname: Hinttala
authors.forename: Heikki
authors.initials: H
authors.lastname: Rantala
authors.forename: Markku
authors.initials: M
authors.lastname: Päivärinta
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.forename: Matias
authors.initials: M
authors.lastname: Röyttä
authors.forename: Heidi
authors.initials: H
authors.lastname: Soini
authors.forename: Jukka S
authors.initials: JS
authors.lastname: Moilanen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
authors.forename: Ilmo E
authors.initials: IE
authors.lastname: Hassinen
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D003937:Diagnosis, Differential; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D004569:Electroencephalography; D004830:Epilepsy, Tonic-Clonic / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D008881:Migraine Disorders / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D017422:Sequence Analysis, DNA; D013226:Status Epilepticus / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human