title: Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.
abstract: Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders, Departments of Pediatrics, Laboratory of Pediatrics and Neurology and Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.devries@cukz.umcn.nl
authors.forename: Maaike C
authors.initials: MC
authors.lastname: de Vries
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Edwin P M
authors.initials: EP
authors.lastname: van Kaauwen
authors.forename: Henk
authors.initials: H
authors.lastname: ter Laak
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Mullaart
authors.forename: Irina N
authors.initials: IN
authors.lastname: Snoeck
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.forename: Peter
authors.initials: P
authors.lastname: Harding
authors.forename: Lambert P W
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
mesh_terms: D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics* / Q000503:physiopathology; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human