MERRF syndrome without ragged-red fibers: The need for molecular diagnosis Michelangelo Mancuso a, * , Lucia Petrozzi a , Massimiliano Filosto b , Claudia Nesti a , Anna Rocchi a , Anna Choub a , Sabina Pistolesi c , Roberto Massetani d , Gabriella Fontanini c , Gabriele Siciliano a a Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy b Neurological Institute, University of Brescia, Italy c Department of Surgery, University of Pisa, Italy d Neurological Clinic, Carrara, Italy Received 15 January 2007 Available online 26 January 2007 Abstract We report a patient with myoclonic epilepsy who underwent muscle biopsy for suspected mitochondrial disease (myoclonic epilepsy with ragged-red fibers, MERRF). In spite of normal histochemical studies and of the absence of a severe COX deficiency, the molecular analysis showed the common MERRF mutation (A8344G) in the tRNA Lys gene on mitochondrial DNA. The case serves to illustrate the importance of pursuing the proposed mitochondrial genetic abnormality, even in patients with normal biopsy findings. Ó 2007 Elsevier Inc. All rights reserved. Keywords: MERRF; mtDNA; Ragged-red fibers; Genetic testing Myoclonic epilepsy with ragged-red fibers (RRFs) (MERRF) is a multisystem disorder characterized by myoclonus, generalized epilepsy, ataxia, hearing loss, exer- cise intolerance, lactic acidosis, and RRFs with modified Gomori trichrome stain on the muscle biopsy [1,2]. The fibers also react intensely with the succinate dehydrogenase (SDH) stain. Further, both RRFs and some non-RRFs fail to stain with the histochemical reaction for cytochrome c oxidase (COX). MERRF biopsies also show strongly SDH-reactive blood vessels (SSVs), which are uniformly COX-negative [1]. Analyses of respiratory chain enzymes in muscle extracts show decreased activities of respiratory chain complexes containing mitochondrial DNA (mtDNA) encoded subunits, especially COX deficiency [3]. Virtually all MERRF patients have mutations in the mtDNA tRNA Lys gene, and the A8344G mutation is responsible for 80–90% of cases [1]. Recently, a mutation in tRNA Phe gene has been associated with MERRF [4]. In patient with severe myoclonic epilepsy but without other major signs suggestive of MERRF, or in patient with a phenotype suggestive of MERRF but with normal mus- cle morphology and histochemistry, the mitochondrial eti- ology is not usually taken into consideration, and a screening for other causes of myoclonic epilepsy (i.e., pro- gressive myoclonic epilepsy, PME [5]) is therefore per- formed. This may lead not only to making an incorrect diagnosis, but also to errors in choosing the best therapy. Here, we describe a young man with clinical features of MERRF, in whom we detected the A8344G mutation despite the normal muscle morphology and histochemistry. Case report A 22-year-old man, the only son from non-consanguin- eous healthy parents, developed normally until the age of 0006-291X/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2007.01.099 * Corresponding author. Fax: +39 050 554808. E-mail address: mmancuso@inwind.it (M. Mancuso). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 354 (2007) 1058–1060