1. A mutation of the mitochondria Katarina Mendoza and Kaytee Smith Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

2.  MERRF is a rare mitochondrial disorder with juvenile onset that includes symptoms of:  Stroke-like episodes (Pathognomonic sign) and generalized myoclonic epilepsy, ataxia, and ragged-red fibers (RRF) in muscle biopsies (Lorenzoni et al., 2011)  Dementia, cardiomyopathy, lipomatosis, neuropathy, and optic atrophy are more rare symptoms that may occur (Lorenzoni et al., 2011)  Histopathological finding of ragged red fibers in skeletal muscle tissue (Brackmann et al., 2012)  Causes: The two most frequent MERRF mutations are A to G transition at nucleotide 8344 and T to C transition at nucleotide 8356 in the mitochondrial tRNALys gene.  The A8344G tRNALys mutation causes poor aminoacylation of the mutant tRNA (Du et al., 2009)  Maternal lineage family members are found to have significant phenotypic heterogeneities of MERRF pedigrees (Lorenzoni et al., 2011)  (only the egg passes on the mitochondria) Introduction

3.  The T8356C tRNALys mutation shows severe reduction in protein synthesis, synthesis of aberrant translation products and defective aminoacylation of the tRNA  This A to G transition affects structure stabilization, methylation, aminoacylation and codon recognition (Du et al., 2009) Mitochondrial Mutation

4.  The disease was first named 1982, and was called “Fukuhara disease” by Rowland.  The first reported patient had been diagnosed with Ramsay Hunt syndrome associated with Friedreich's ataxia  BUT the patients seemed to have a different disease altogether, later named MERRF. History and Discovery

5.  Patients can only be diagnosed with MERRF by undergoing muscle biopsies or molecular studies (Lorenzoni et al., 2011)  Muscle biopsies often confirm the diagnosis of MERRF by revealing the presence of RRF (Ragged Red Fibers) with MGT and SDH staining and deficiencies in COX activity  A large proportion of muscle fibers (RRF and non-RRF) with deficient COX activity and reduced presence of SSV, can help distinguish MERRF from other mitochondrial myopathies (Lorenzoni et al., 2011).  An elevated serum lactate level is an important MERRF indicator because it may indicate mitochondrial dysfunction (DiMauro et al., 2002; Ozawa et al., 1995)  Creatine kinase levels in muscles may also indicate the presence of the disease because of possible correlation between myoclonic epilepsy and the kinases (Brackmann et al., 2012)  Recommended first molecular test when MERRF is suspected: PCR/RFLP for the A8344G (Lorenzoni et al., 2011)  it is a simple test for this genetic defect  Second recommended diagnostic test: the molecular analysis of the tRNALys gene by direct sequencing (Lorenzoni et al., 2011)  tRNALys mutations are frequently involved in the MERRF phenotype Diagnostic Tests

6.  Symptomatic treatment of MERRF includes management of myoclonus with antiepileptic drugs (Lorenzoni et al., 2011).  Valproate is the first-line antiepileptic drug for generalized seizures and epileptic form abnormalities (spike, polyspike, and spike–wave complex)  Myoclonus is often refractory to conventional treatment, but Clonazepam has been shown to be beneficial in many patients (Lorenzoni et al, 2011)  New biochip that could help in diagnosing the disease Treatments

7.  Patients with MERRF show neuronal loss and gliosis of the brain, including the basal ganglia, cerebellum and spinal cord (Lorenzoni et al., 2011)  The accumulation of mitochondria in muscle fibers has been found in up to 92% of MERRF patients (Lorenzoni et al., 2011).  A large proportion of muscle fibers (RRF and non-RRF) with deficient COX activity and reduced presence of SSV, can help distinguish MERRF from other mitochondrial myopathies (Lorenzoni et al. 2011)  There is an association between cerebellar ataxia and weakness and the A8344G mutation. Clinical Consequences if MERRF is untreated

8.  Development of a novel biochip format for efficient discriminating of single base substitution in a panel of 31 known mtDNA mutations of MELAS and MERRF  This biochip would be beneficial in: 1. improving quality of life 2. prognosis of the often neglected or overlooked entities of the disease  Biochip format, when modified, would also be applicable to expand the screening spectrum of any potential mutations identified in the mitochondrial diseases  allows for better diagnosis RECENT RESEARCH: Detection of known base substitution mutations in human mitochondrial DNA of MERRF and MELAS by biochip technology (Du et al., 2009)

9.  Brackmann, F., Abicht, A., Ahting, U., Schröder, R., Trollmann, R. (2012). Classical MERRF phenotype associated with mitochondrial tRNALeu (m.3243A>G) mutation. Eur J Pediatr, 171, 859–862. doi: 10.1007/s00431-011-1662-8  Du, W., Li, W., Chen, G., Cao, H., Tang, H., Tang, X., Jin, Q., Sun, Z., Zhao, H., Zhou, W., He, S., Lv, Y., Zhao, J., Zhang, X. (2009). Detection of known base substitution mutations in human mitochondrial DNA of MERRF and MELAS by biochip technology.. Biosensors and Bioelectronics 24, 2371–2376. doi:10.1016/j.bios.2008.12.008  Fukuhara, N. (2008). Fukuhara Disease. Brain Nerve 60, 53-58.  Lorenzoni, P. J., Scola, R. H., Kay, C. S. K., Arndt, R. C., Silvado, C. E., Werneck, L. C. (2011). MERRF: Clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion 11, 528–532. doi:10.1016/j.mito.2011.01.003 References