Abstract
The C10orf2 gene encodes Twinkle, a protein involved in mitochondrial DNA (mtDNA) replication. Twinkle mutations cause mtDNA deletion or depletion and are associated with a large spectrum of clinical symptoms including dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and early-onset encephalopathy. The diagnosis remains difficult because of the wide range of symptoms and lack of association with specific metabolic changes. We report herein a child with early-onset encephalopathy, unusual abnormal movements, deafness, and axonal neuropathy. All laboratory investigations were normal with the exceptions of high alpha-fetoprotein levels and an abnormal glycosylation profile. These abnormal parameters resulted in misdiagnosis as a previously unidentified congenital disorder of glycosylation (CDG) type I syndrome. Whole exome sequencing revealed two point mutations in C10orf2 that were confirmed by Sanger sequencing; neither had been previously reported. This report enlarges the clinical phenotype of Twinkle mutations and suggests that an abnormal glycosylation profile suggestive of CDG type I associated with high blood alpha-fetoprotein levels without obvious cause should prompt Twinkle sequencing.
Competing interests: None declared
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Acknowledgments
This work was partially supported by grant ERARE11-135 of the ERA-Net for Research Programs on Rare Diseases Joint Transnational Call 2011 (EURO-CDG). The whole exome study was funded by Fondation Maladies Rares under the program “High throughput sequencing and Rare Diseases” (Call for proposals-2013, May).
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Communicated by: Jaak Jaeken
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Take-Home Message
Twinkle mutations can be associated with elevated alpha-fetoprotein and an abnormal CDG profile.
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Juliette Bouchereau, Sandrine Vuillaumier Barrot, Thierry Dupré, Stuart E. H. Moore, Ruxandra Cardas, Yline Capri, Pauline Gaignard, Abdelhamid Slama, Hélène Ogier de Baulny, Nathalie Seta, Manuel Schiff, and Laurent Servais declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the family of the patient for being included in the study.
Details of the Contributions of Individual Authors
Juliette Bouchereau analyzed the results and wrote the paper.
Sandrine Vuillaumier Barrot performed the experiments.
Thierry Dupré performed the experiments.
Stuart E. H. Moore performed the experiments.
Ruxandra Cardas performed the experiments.
Yline Capri performed the experiments.
Pauline Gaignard performed the experiments.
Abdelhamid Slama performed the experiments.
Hélène Ogier de Baulny performed the experiments.
Nathalie Seta performed the experiments.
Manuel Schiff wrote the paper.
Laurent Servais wrote the paper.
Manuel Schiff and Laurent Servais contributed equally to the manuscript.
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Bouchereau, J. et al. (2016). Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 29. JIMD Reports, vol 29. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_526
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DOI: https://doi.org/10.1007/8904_2016_526
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