title: Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene.
abstract: BACKGROUND
  POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion.
  
  
  METHODS
  A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations.
  
  
  RESULTS
  The p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion).
  
  
  CONCLUSIONS
  Our results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.
authors: Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute Warsaw, Poland. e.pronicka@czd.pl
authors: Ewa
authors: E
authors: Pronicka
authors: Anna
authors: A
authors: Weglewska-Jurkiewicz
authors: Maciej
authors: M
authors: Pronicki
authors: Jolanta
authors: J
authors: Sykut-Cegielska
authors: Pawel
authors: P
authors: Kowalski
authors: Magdalena
authors: M
authors: Pajdowska
authors: Irena
authors: I
authors: Jankowska
authors: Katarzyna
authors: K
authors: Kotulska
authors: Piotr
authors: P
authors: Kalicinski
authors: Joanna
authors: J
authors: Jakobkiewicz-Banecka
authors: Grzegorz
authors: G
authors: Wegrzyn
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D002648:Child; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D004351:Drug Resistance; D004827:Epilepsy / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D011180:Postmortem Changes; D013053:Spectrophotometry; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D014635:Valproic Acid; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human