NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern

S.H.G. Kevelam, R.J. Rodenburg, N.I. Wolf, P. Ferreira, R.J. Lunsing, L.G. Nijtmans, A. Mitchell, H.A. Arroyo, D. Rating, A. Vanderver, C.G.M. van Berkel, G.E.M. Abbink, P. Heutink, M.S. van der Knaap, Truus E. M. Abbink

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75 Citations (Scopus)


Objective: To identify the mutated gene in a group of patients with an unclassified heritable white matter disorder sharing the same, distinct MRI pattern. Methods: We used MRI pattern recognition analysis to select a group of patients with a similar, characteristic MRI pattern. We performed whole-exome sequencing to identify the mutated gene. We examined patients' fibroblasts for biochemical consequences of the mutant protein. Results: We identified 6 patients from 5 unrelated families with a similar MRI pattern showing predominant abnormalities of the cerebellar cortex, deep cerebral white matter, and corpus callosum. The 4 tested patients had a respiratory chain complex I deficiency. Exome sequencing revealed mutations in NUBPL, encoding an iron-sulfur cluster assembly factor for complex I, in all patients. Upon identification of the mutated gene, we analyzed the MRI of a previously published case with NUBPL mutations and found exactly the same pattern. A strongly decreased amount of NUBPL protein and fully assembled complex I was found in patients' fibroblasts. Analysis of the effect of mutated NUBPL on the assembly of the peripheral arm of complex I indicated that NUBPL is involved in assembly of iron-sulfur clusters early in the complex I assembly pathway. Conclusion: Our data show that NUBPL mutations are associated with a unique, consistent, and recognizable MRI pattern, which facilitates fast diagnosis and obviates the need for other tests, including assessment of mitochondrial complex activities in muscle or fibroblasts. © 2013 American Academy of Neurology.
Original languageEnglish
Pages (from-to)1577-1583
Issue number17
Publication statusPublished - 2013

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