Article Text

PDF
Original article
ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder
  1. Zuhair N Al-Hassnan1,2,
  2. Mazhor Al-Dosary3,
  3. Majid Alfadhel4,
  4. Eissa A Faqeih5,
  5. Maysoon Alsagob3,
  6. Rosan Kenana3,
  7. Rawan Almass3,
  8. Olfat S Al-Harazi6,
  9. Hindi Al-Hindi7,
  10. Omhani I Malibari8,
  11. Faten B Almutari3,
  12. Sahar Tulbah3,
  13. Faten Alhadeq3,
  14. Tarfa Al-Sheddi3,
  15. Rana Alamro3,
  16. Ali AlAsmari5,
  17. Makki Almuntashri9,
  18. Hesham Alshaalan9,
  19. Futwan A Al-Mohanna2,10,
  20. Dilek Colak6,
  21. Namik Kaya3,6
  1. 1Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  2. 2College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  3. 3Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  4. 4Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia
  5. 5Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
  6. 6Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  7. 7Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  8. 8Pediatrics Department, King Abdullah Medical City, Maternity & Children's Hospital, Al-Madīnah al-Munawarah, Riyadh, Saudi Arabia
  9. 9Department of Radiology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  10. 10Department of Cell Biology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  1. Correspondence to Dr Namik Kaya, Department of Genetics, Neurogenetics Unit, King Faisal Specialist Hospital and Research Center, MBC: 03, Riyadh 11211, Saudi Arabia; nkaya{at}kfshrc.edu.sa, namikkaya{at}gmail.com

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.

  • Genetics

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.