NDUFAF3 variants that disrupt mitochondrial complex I assembly may associate with cavitating leukoencephalopathy |
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| Authors: | A. Ishiyama K. Muramatsu S. Uchino C. Sakai Y. Matsushima N. Makioka T. Ogata E. Suzuki H. Komaki M. Sasaki M. Mimaki Y.‐I. Goto I. Nishino |
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| Affiliation: | 1. Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), National Center Hospital, Tokyo, Japan;2. Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan;3. Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan;4. Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan;5. Department of Pediatrics, Jichi Medical University, Tochigi, Japan;6. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Tokyo, Japan;7. Department of Pediatrics, Faculty of Medicine, Teikyo University, Tokyo, Japan |
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| Abstract: | Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a 1‐year‐old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17% to 21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C > A:p.Pro169Thr). Two‐dimensional, blue‐native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate‐PAGE revealed reductions in Q‐module (NDUFS2, NDUFS3, and NDUFA9) and P‐module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3. |
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| Keywords: | assembly factor 2D‐BN‐PAGE/SDS‐PAGE mitochondrial complex I
NDUFAF3 respiratory enzyme activity |
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