title: Acute liver failure after valproate exposure in patients with POLG1 mutations and the prognosis after liver transplantation.
abstract: Patients with mutations in the POLG1 gene encoding mitochondrial DNA polymerase gamma have an increased risk of valproate-induced liver failure. POLG1 mutations are common, and these patients often suffer from intractable seizures. The role of liver transplantation in the treatment of patients with mitochondrial diseases has been controversial. We studied valproate-induced liver failure associated with POLG1 mutations and the prognosis for these patients after liver transplantation. POLG1 was analyzed in blood DNA, mitochondrial DNA (mtDNA) was quantified in liver samples, and clinical data were collected. Five patients with valproate-induced liver failure associated with POLG1 mutations were retrospectively identified. Three patients were previously suspected to have Wilson's disease. Four patients with homozygous p.W748S and p.E1143G mutations had mtDNA depletion in the liver. One of these patients died before anticipated transplantation; the other 3 patients with liver transplantation have survived 4 to 19 years. Two patients have presented with occasional epileptic seizures, and 1 patient has been seizure-free for 11 years. One patient with a heterozygous p.Q1236H mutation (but without mtDNA depletion in the liver) died suddenly 2 years after liver transplantation. In conclusion, the POLG1 mutation status and the age at presentation of valproate-induced liver failure can affect the prognosis after liver transplantation. A heterozygous POLG1 p.Q1236H mutation was related to valproate-induced liver failure without mtDNA depletion, whereas patients homozygous for POLG1 p.W748S and p.E1143G mutations had mtDNA depletion. An analysis of the POLG1 gene should be performed for all patients with suspected mitochondrial disease before the introduction of valproate therapy, and treatment with valproic acid should be avoided in these patients.
authors: Institute of Clinical Medicine, Department of Pediatrics, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors: Johanna
authors: J
authors: Hynynen
authors: Tuomas
authors: T
authors: Komulainen
authors: Eija
authors: E
authors: Tukiainen
authors: Arno
authors: A
authors: Nordin
authors: Johanna
authors: J
authors: Arola
authors: Reetta
authors: R
authors: Kälviäinen
authors: Leena
authors: L
authors: Jutila
authors: Matias
authors: M
authors: Röyttä
authors: Reetta
authors: R
authors: Hinttala
authors: Kari
authors: K
authors: Majamaa
authors: Heikki
authors: H
authors: Mäkisalo
authors: Johanna
authors: J
authors: Uusimaa
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000235:genetics / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D019737:Transplants / Q000473:pathology; D014635:Valproic Acid / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D004272:DNA, Mitochondrial; D014635:Valproic Acid; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human