Journal
NEUROLOGY
Volume 80, Issue 17, Pages 1577-1583Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e31828f1914
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Funding
- ZonMw TOP grant
- Dana Foundation
- NIH, National Institute for Neurologic Disorders and Stroke [1K08NS060695]
- Tipharma
- NWO
- SenterNovem
- Nederlands Regie Orgaan Genomics, Center for Medical Systems Biology
- Prinses Beatrix Fonds
- ZonMw
- Optimix Foundation
- Nuts-Ohra Foundation
- Phelps Foundation
- Dutch Brain Foundation
- ZonMw TOP grant [91211005]
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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. deficiency. Exome sequencing revealed mutations in NUBPL, encoding an iron-sulfur cluster assembly factor for complex., 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.
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