Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion (original) (raw)

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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

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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

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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

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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

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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

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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

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Revision received:

09 August 2007

Accepted:

10 September 2007

Published:

05 October 2007

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Anna H. Hakonen, Pirjo Isohanni, Anders Paetau, Riitta Herva, Anu Suomalainen, Tuula Lönnqvist, Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion, Brain, Volume 130, Issue 11, November 2007, Pages 3032–3040, https://doi.org/10.1093/brain/awm242
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Abstract

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.

© 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

Topic:

• phenotype
• mutation
• mitochondria
• ataxia
• athetosis
• dna, mitochondrial
• heterozygote
• ophthalmoplegia
• relationship - sibling
• signs and symptoms
• liver
• muscle hypotonia
• encephalopathy
• alpers syndrome
• infantile-onset spinocerebellar ataxia
• refractory epilepsy
• symptom onset

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