title: ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.
abstract: BACKGROUND
  There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families.
  
  
  METHODS
  Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients.
  
  
  RESULTS
  We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres.
  
  
  CONCLUSIONS
  Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Zuhair N
authors.initials: ZN
authors.lastname: Al-Hassnan
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mazhor
authors.initials: M
authors.lastname: Al-Dosary
authors.affiliation: Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Majid
authors.initials: M
authors.lastname: Alfadhel
authors.affiliation: Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa A
authors.initials: EA
authors.lastname: Faqeih
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Maysoon
authors.initials: M
authors.lastname: Alsagob
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Rosan
authors.initials: R
authors.lastname: Kenana
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Rawan
authors.initials: R
authors.lastname: Almass
authors.affiliation: Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Olfat S
authors.initials: OS
authors.lastname: Al-Harazi
authors.affiliation: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hindi
authors.initials: H
authors.lastname: Al-Hindi
authors.affiliation: Pediatrics Department, King Abdullah Medical City, Maternity & Children's Hospital, Al-Madīnah al-Munawarah, Riyadh, Saudi Arabia.
authors.forename: Omhani I
authors.initials: OI
authors.lastname: Malibari
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Faten B
authors.initials: FB
authors.lastname: Almutari
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Sahar
authors.initials: S
authors.lastname: Tulbah
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Faten
authors.initials: F
authors.lastname: Alhadeq
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Tarfa
authors.initials: T
authors.lastname: Al-Sheddi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Rana
authors.initials: R
authors.lastname: Alamro
authors.affiliation: Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: AlAsmari
authors.affiliation: Department of Radiology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors.forename: Makki
authors.initials: M
authors.lastname: Almuntashri
authors.affiliation: Department of Radiology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors.forename: Hesham
authors.initials: H
authors.lastname: Alshaalan
authors.affiliation: College of Medicine, Alfaisal University, Riyadh, Saudi Arabia Department of Cell Biology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Futwan A
authors.initials: FA
authors.lastname: Al-Mohanna
authors.affiliation: Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Namik
authors.initials: N
authors.lastname: Kaya
mesh_terms: D000328:Adult; D038261:Alexander Disease / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017422:Sequence Analysis, DNA; D066127:White Matter / Q000002:abnormalities / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D007506:Iron-Sulfur Proteins
keywords: Genetics