title: POLG1 manifestations in childhood.
abstract: OBJECTIVE
  Mitochondrial DNA polymerase γ (POLG1) mutations in children often manifest as Alpers syndrome, whereas in adults, a common manifestation is mitochondrial recessive ataxia syndrome (MIRAS) with severe epilepsy. Because some patients with MIRAS have presented with ataxia or epilepsy already in childhood, we searched for POLG1 mutations in neurologic manifestations in childhood.
  
  
  METHODS
  We investigated POLG1 in 136 children, all clinically suspected to have mitochondrial disease, with one or more of the following: ataxia, axonal neuropathy, severe epilepsy without known epilepsy syndrome, epileptic encephalopathy, encephalohepatopathy, or neuropathologically verified Alpers syndrome.
  
  
  RESULTS
  Seven patients had POLG1 mutations, and all of them had severe encephalopathy with intractable epilepsy. Four patients had died after exposure to sodium valproate. Brain MRI showed parieto-occipital or thalamic hyperintense lesions, white matter abnormality, and atrophy. Muscle histology and mitochondrial biochemistry results were normal in all.
  
  
  CONCLUSIONS
  POLG1 analysis should belong to the first-line DNA diagnostic tests for children with an encephalitis-like presentation evolving into epileptic encephalopathy with liver involvement (Alpers syndrome), even if brain MRI and morphology, respiratory chain activities, and the amount of mitochondrial DNA in the skeletal muscle are normal. POLG1 analysis should precede valproate therapy in pediatric patients with a typical phenotype. However, POLG1 is not a common cause of isolated epilepsy or ataxia in childhood.
authors.affiliation: University of Helsinki, Helsinki, Finland. pirjo.isohanni@helsinki.fi
authors.forename: P
authors.initials: P
authors.lastname: Isohanni
authors.forename: A H
authors.initials: AH
authors.lastname: Hakonen
authors.forename: L
authors.initials: L
authors.lastname: Euro
authors.forename: I
authors.initials: I
authors.lastname: Paetau
authors.forename: T
authors.initials: T
authors.lastname: Linnankivi
authors.forename: E
authors.initials: E
authors.lastname: Liukkonen
authors.forename: T
authors.initials: T
authors.lastname: Wallden
authors.forename: L
authors.initials: L
authors.lastname: Luostarinen
authors.forename: L
authors.initials: L
authors.lastname: Valanne
authors.forename: A
authors.initials: A
authors.lastname: Paetau
authors.forename: J
authors.initials: J
authors.lastname: Uusimaa
authors.forename: T
authors.initials: T
authors.lastname: Lönnqvist
authors.forename: A
authors.initials: A
authors.lastname: Suomalainen
authors.forename: H
authors.initials: H
authors.lastname: Pihko
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D055815:Young Adult
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human