Journal Article

Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

Anna H. Hakonen, Pirjo Isohanni, Anders Paetau, Riitta Herva, Anu Suomalainen and Tuula Lönnqvist

in Brain

Published on behalf of The Guarantors of Brain

Volume 130, issue 11, pages 3032-3040
Published in print November 2007 | ISSN: 0006-8950
Published online October 2007 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awm242
Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

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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.

Keywords: twinkle; IOSCA; Alpers; encephalopathy; mtDNA

Journal Article.  5326 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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