title: Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure.
abstract: OBJECTIVE
  To determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations.
  
  
  METHODS
  We studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase γ, MPV17, and DGUOK were sequenced using standard analyses.
  
  
  RESULTS
  We identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations).
  
  
  CONCLUSIONS
  Mutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.
authors: Division of Pediatric Gastroenterology, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Electronic address: aa_alhussaini@yahoo.com.
authors: Abdulrahman
authors: A
authors: Al-Hussaini
authors: Division of Medical Genetics, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Eissa
authors: E
authors: Faqeih
authors: Division of Medical Genetics, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Ayman W
authors: AW
authors: El-Hattab
authors: Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors: Majid
authors: M
authors: Alfadhel
authors: Division of Pediatric Gastroenterology, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Ali
authors: A
authors: Asery
authors: Division of Pediatric Gastroenterology, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Badr
authors: B
authors: Alsaleem
authors: Department of Radiology, King Saud bin Abdulaziz University for Health Sciences, King Fahad Medical City, Riyadh, Saudi Arabia.
authors: Eman
authors: E
authors: Bakhsh
authors: Department of Pathology, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors: Ashraf
authors: A
authors: Ali
authors: Division of Medical Genetics, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Ali
authors: A
authors: Alasmari
authors: Division of Pediatric Gastroenterology, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Khurram
authors: K
authors: Lone
authors: Division of Pediatric Gastroenterology, The Children's Hospital, King Fahad Medical City, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors: Ahmed
authors: A
authors: Nahari
authors: Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors: Wafaa
authors: W
authors: Eyaid
authors: Department of Pathology, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors: Mohammed
authors: M
authors: Al Balwi
authors: Newcastle Mitochondrial Highly Specialized Services Diagnostic Laboratory, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: Kate
authors: K
authors: Craig
authors: Newcastle Mitochondrial Highly Specialized Services Diagnostic Laboratory, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: Anna
authors: A
authors: Butterworth
authors: Newcastle Mitochondrial Highly Specialized Services Diagnostic Laboratory, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: Langping
authors: L
authors: He
authors: Newcastle Mitochondrial Highly Specialized Services Diagnostic Laboratory, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: Robert W
authors: RW
authors: Taylor
mesh_terms: D000140:Acidosis, Lactic / Q000150:complications; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile; D002779:Cholestasis / Q000150:complications* / Q000401:mortality; D004272:DNA, Mitochondrial / Q000032:analysis; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007962:Leukocytes / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D017093:Liver Failure / Q000150:complications* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics / Q000401:mortality; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000737:chemistry; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000032:analysis; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D004272:DNA, Mitochondrial; C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000509:alpha-Fetoproteins; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase