title: Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction.
abstract: BACKGROUND
  Inherited mtDNA depletion syndromes (MDS) are a group of severe mitochondrial disorders resulting from defects in nucleus-encoded factors and often associated with severe or fatal liver failure.
  
  
  METHODS
  In this article, we describe the case of an 18-month-old patient with recurrent hypoketotic hypoglycaemia and fatal hepatic dysfunction with liver mtDNA depletion.
  
  
  METHODS
  The assessment of mtDNA copy number was performed on leucocytes, liver and muscle biopsy by Quantitative Real Time PCR and total RNA from liver biopsy was used as a template to amplify the cDNA of the POLG1 gene.
  
  
  RESULTS
  Sequence analysis identified two previously undescribed mutations (1868T>G and 2263A>G) located in the gene coding the catalytic subunit of mitochondrial DNA polymerase gamma (POLG), predicting an L623W and K755E amino acid change, respectively. Both mutations were located in the highly conserved linker region of the protein and were absent in more than 200 healthy unrelated control subjects. The identification of these two mutations allowed us to perform genetic counselling and prenatal diagnosis.
  
  
  CONCLUSIONS
  Our data further expand the spectrum of POLG1 gene mutations and the unique phenotype reported (late onset isolated liver disease without lactic acidosis) increase the variability of clinical presentations associated with mutations in this gene.
authors.affiliation: Children's Neurology and Psychiatry Unit, Institute of Child Health IRCCS, Burlo Garofolo, Via dell'Istria, Trieste, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Bortot
authors.forename: E
authors.initials: E
authors.lastname: Barbi
authors.forename: S
authors.initials: S
authors.lastname: Biffi
authors.forename: G
authors.initials: G
authors.lastname: Lunazzi
authors.forename: R
authors.initials: R
authors.lastname: Bussani
authors.forename: A
authors.initials: A
authors.lastname: Burlina
authors.forename: S
authors.initials: S
authors.lastname: Norbedo
authors.forename: A
authors.initials: A
authors.lastname: Ventura
authors.forename: M
authors.initials: M
authors.lastname: Carrozzi
authors.forename: G M
authors.initials: GM
authors.lastname: Severini
mesh_terms: D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D017809:Fatal Outcome; D006801:Humans; D007003:Hypoglycemia / Q000201:enzymology / Q000235:genetics*; D007223:Infant; D007662:Ketosis / Q000150:complications; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human