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Brain Advance Access published online on October 5, 2007
Brain, doi:10.1093/brain/awm242
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

Anna H. Hakonen1,*, Pirjo Isohanni1,2,*, Anders Paetau3, Riitta Herva4, Anu Suomalainen1,5 and Tuula Lönnqvist2

1Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 2Department of Child Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, 3Department of Pathology, University of Helsinki, and HUSLAB, Helsinki, 4Oulu University Hospital, Oulu and 5Department of Neurology, Helsinki University Central Hospital, Finland

Correspondence to: Anu Suomalainen, Biomedicum-Helsinki, Research Program of Molecular Neurology, r. c523B, P.O. Box 63, University of Helsinki, 00290 Helsinki, Finland E-mail: anu.wartiovaara{at}helsinki.fi

Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA). We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement. The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases. The liver showed mtDNA depletion, whereas the muscle mtDNA was only slightly affected. Alpers–Huttenlocher syndrome has previously been associated with mutations of polymerase gamma, a replicative polymerase of mtDNA. We show here that recessive mutations of the close functional partner of the polymerase, the Twinkle helicase, can also manifest as early encephalopathy with liver involvement, a phenotype reminiscent of Alpers syndrome, and are a new genetic cause underlying tissue-specific mtDNA depletion.

Key Words: twinkle; IOSCA; Alpers; encephalopathy; mtDNA

Abbreviations: IOSCA, infantile onset spinocerebellar ataxia; PEO, progressive external ophthalmoplegia; MIRAS, mitochondrial recessive ataxia syndrome

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Received May 25, 2007. Revised August 9, 2007. Accepted September 10, 2007.

*These authors contributed equally to this work.


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