Zuhair N Al-Hassnan1, Mazhor Al-Dosary2, Majid Alfadhel3, Eissa A Faqeih4, Maysoon Alsagob2, Rosan Kenana2, Rawan Almass2, Olfat S Al-Harazi5, Hindi Al-Hindi6, Omhani I Malibari7, Faten B Almutari2, Sahar Tulbah2, Faten Alhadeq2, Tarfa Al-Sheddi2, Rana Alamro2, Ali AlAsmari4, Makki Almuntashri8, Hesham Alshaalan8, Futwan A Al-Mohanna9, Dilek Colak5, Namik Kaya10. 1. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 2. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 3. Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia. 4. Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. 5. Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 6. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 7. Pediatrics Department, King Abdullah Medical City, Maternity & Children's Hospital, Al-Madīnah al-Munawarah, Riyadh, Saudi Arabia. 8. Department of Radiology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. 9. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia Department of Cell Biology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 10. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.