| Autor: |
Misceo D; Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway., Strømme P; Division of Pediatrics and Adolescent Medicine, Oslo University Hospital and Faculty of Medicine, University of Oslo, 0450 Oslo, Norway., Bitarafan F; Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway., Chawla MS; Department of Neuroradiology, Oslo University Hospital, 0450 Oslo, Norway., Sheng Y; Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway., Bach de Courtade SM; Department of Biochemistry, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway., Eide L; Department of Biochemistry, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway., Frengen E; Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway. |
| Abstrakt: |
Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called "primary mitochondrial disorders" (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient's fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome. |
