Case report A novel heteroplasmic tRNA Ser(UCN) mtDNA point mutation associated with progressive external ophthalmoplegia and hearing loss Elena Cardaioli a,1 , Paola Da Pozzo a , Gian Nicola Gallus a , Alessandro Malandrini a , Simona Gambelli a , Carmen Gaudiano a , Edoardo Malfatti a , Carlo Viscomi b , Enza Zicari a , Gianna Berti a , Giovanni Serni a , Maria Teresa Dotti a , Antonio Federico a, * a Department of Neurological and Behavioural Sciences, University of Siena, Viale Bracci 2, Siena 53100, Italy b Unit of Molecular Neurogenetics, National Neurological Institute C. Besta, Milan 20126, Italy Received 19 December 2006; received in revised form 20 April 2007; accepted 2 May 2007 Abstract We sequenced all mitochondrial tRNA genes from a patient with sporadic external ophthalmoplegia (PEO) and 5% COX- fibersin muscle biopsy, who had no detectable large mtDNA deletions. Direct sequencing showed a heteroplasmic mutation at nucleotide 7506 in the dihydrouridine stem of the tRNA Ser(UCN) gene. RFLP analysis confirmed that 30% of muscle and 20% of urina epithelium mtDNA harbored the mutation, which was absent in other tissues of the proband as well as in mtDNA of his mo patients with various encephalomyopathies. Several point mutations on mitochondrial tRNA genes have been reported in P without large-scale rearrangements of mtDNA but no point mutations have hitherto been found in the gene coding for tRN Ser(UCN) . Ó 2007 Elsevier B.V. All rights reserved. Keywords: Progressive external ophthalmoplegia; Mitochondrial DNA; tRNA Ser(UCN) 1. Introduction Progressive external ophthalmoplegia (PEO), a common clinical mitochondrialphenotype,is associatedwith large-scalerearrangementsof mitochondrial DNA (mtDNA) in more than 60% of cases[1], with point mutations of tRNA genes being the second most common genetic cause (Mitomap: http://www.mitomap.org). Here, we report a sporadic case of PEO without deletions. Sequence analysis of all tRNA genes revealed a novel het- eroplasmic muscle mtDNA mutation in the tRNA Ser(UCN) gene at nucleotide position (np) 7506. This mutation, the first ever reported in a tRNA Ser gene associated with a PEO phenotype, met the criteria for pathogenic mtDNA mutations. 2. Case report The patient, a 26-year-old man, had healthy unrelated parents and a family medical history negative for genetic disorders. Motor milestones were normal. Slowly progressive bilateral ptosis began at 16 years ofage.At 26 years, neurological examination showed bilateral ptos more accentuated on the left side.Brain MR showed a dysplasia in the right insular cortex. The lesion remained unchanged at subsequent MR examinations. Audiometry showed slightbilateralneurosensory deafness. Routine chemistryshowed a moderateincreasein serum CK (444 UI/L; NV < 170).Venous lactic acid was lightly increased (1.6 mmol/l; normalvalue:0.3–1.3 mmol/l), but 0960-8966/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2007.05.001 * Corresponding author. Tel.: +39 0577 585763 60; fax: +39 0577 40327. E-mail address: federico@unisi.it (A. Federico). 1 Research grant from Associazione Anni Verdi, Rome, Italy. www.elsevier.com/locate/nmd Neuromuscular Disorders 17 (2007) 681–683