A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia Marcus Deschauer a,b , Reinhard Kiefer c , Emma L. Blakely a , Langping He a , Stephan Zierz b , Douglass M. Turnbull a, * , Robert W. Taylor a a Department of Neurology, The Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK b Department of Neurology, Martin-Luther-Universitaet Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle/Saale, Germany c Department of Neurology, Westfaelische Wilhelms-Universitaet, Albert-Schweitzer-Str. 33, 48129 Muenster, Germany Received 10 January 2003; received in revised form 20 March 2003; accepted 25 March 2003 Abstract Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions. q 2003 Elsevier B.V. All rights reserved. Keywords: Mitochondrial disease; Autosomal dominant progressive external ophthalmoplegia; Multiple mitochondrial DNA deletions; Novel mutation; Twinkle gene 1. Introduction Autosomal dominant progressive external ophthalmo- plegia (adPEO) is characterised by ptosis and weakness of the extraocular muscles and is caused by the accumulation of multiple mitochondrial DNA (mtDNA) deletions. Many patients present with limb weakness, whilst some have multisystemic involvement including hearing loss, neuro- pathy, ataxia, or psychiatric abnormalities [1,2]. Typically, muscle biopsy reveals ragged-red and cytochrome c oxidase (COX) deficient fibres. Recent molecular genetic studies have documented mutations in three different nuclear genes, POLG1, ANT1, and Twinkle. The mtDNA polymerase gamma (POLG1) gene encodes for DNA polymerase responsible for mtDNA replication [3], the adenine nucleotide translocator 1 gene (ANT1) encodes for the heart/muscle isoform that controls adenosine triphosphate (ATP) and adenosine diphosphate (ADP) shuttling at the mitochondrial inner membrane [4], whilst the Twinkle gene encodes for a putative mitochon- drial helicase protein that co-localizes with mtDNA [5]. Here we describe a German family with adPEO in whom we have identified a novel mutation in the Twinkle gene. The index case also highlights some of the diagnostic difficulties in this disorder since the muscle biopsy exhibited fairly subtle changes in terms of histochemical and mtDNA abnormalities. 2. Case report and methods 2.1. Clinical investigations The index patient (IV-1 in Fig. 1) first presented at the age of 36 years, with a 14-year history of bilateral progressive ptosis and a 3-year history of diplopia. Neurological examination revealed an incomplete external ophthalmo- plegia affecting all external ocular muscles and bilateral ptosis. There was no limb weakness or other abnormal neurological or psychiatric features. General clinical Neuromuscular Disorders 13 (2003) 568–572 www.elsevier.com/locate/nmd 0960-8966/03/$ - see front matter q 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0960-8966(03)00071-3 * Corresponding author. Tel.: þ44-191-222-8334; fax: þ 44-191-222- 8553. E-mail address: d.m.turnbull@ncl.ac.uk (D.M. Turnbull).