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Myoclonic Epilepsy With Ragged Red Fibers (MERRF)
Myoclonic Epilepsy With Ragged Red Fibers (MERRF)
MERRF at a Glance
Maternal Inheritance
Paternal mitochondrial DNA is destroyed during fertilization
Ataxia: incoordination of muscle movement Myoclonus: involuntary muscle movement In 80% of cases, MERRF is caused by a single base pair mutation (A changes to G) in mitochondrial DNA (mtDNA), at location 8344.
Reduces the activity tRNAlys by 50-60%, thereby slowing down the synthesis of physiologically important mitochondrial proteins and the process of oxidative phosphorylation
General Muscle Wasting & Weakness Myoclonus (major phenotypic feature of illness) Ataxia (major phenotypic feature of illness) Sensorineural hearing loss Slowed nerve condition velocities Mildly elevated blood and cerebrospinal fluid lactate levels Muscle biopsy detected abnormal mitochondria Deficient staining for cytochrome oxidase Red with Gomori Trichrom stain (ragged-red fibers detected)
Initial Evaluation
Secondary Evaluation
Ragged red fibers identified in some muscle groups High probability that family members are carriers of the mtDNA mutation
Figure A: Deficiency of Cytochrome C Oxidase (Complex IV in Mitochondria), shown in blue. Figure B: Close up of Figure A; asterisk indicated deficiency of Cytochrome C
Sensorineural hearing loss happens due to loss of function in Cranial Nerve VIII
Weakness (myopathy)
Progressive Stiffness (Spasticity)
Uncle
Maternal
Aunt
Grandfather
Maternal
Extremities Myoclonus
Labs:
Labs:
Risk Level: The raised CSF lactate level present clinical characteristics such as:
MRI Imaging:
Risk Level: Damage to cerebrum affects consciousness, thought and voluntary processes. This may be one reason the patient is presenting symptoms of:
Ataxia and Myoclonus Sensorineural hearing loss Slowed nerve condition velocities Can eventually cause dementia
Atrophy refers to damage or loss of cells in the tissue. Cerebral atrophy can be caused by epilepsy and/or abnormal electrochemical gradients discharges caused by mtDNA mutation.
Non-Laboratory Tests:
Electroencephalogram (EEG) showed slowing and frequent intermittent generalized epileptiform discharges
Hypsarrhythmia (spike-slow wave complex) is known to cause: Infantile spasms Myoclonus Generalized epilepsy
Mitochondrial activity declines gradually Expression of defects manifest in late teens or early 20s
Weakness (myopathy)
Diagnosis
The clinical diagnosis of MERRF (myoclonic epilepsy with ragged red fibers) is based on the following four "canonical" features:
Muscle twitches (myoclonus)
Generalized epilepsy Ataxia (incoordination of muscle and/or eye movements) Ragged Red Fibers in muscle biopsy
Exercise intolerance
Optic atrophy
Genetic Basis
Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes contained in the mitochondria cause MERRF.
Figure 2: MT-TK Gene
From: MT-TK."
Natural History
Classic phonotypical features:
Myoclonic epilepsy, Mitochondrial myopathy, Ragged-Red Fibers
Absence of ragged-red fibers in muscle biopsy specimen DOES NOT exclude MERRF. Severity of oxidative phosphorylation deficit correlates with AGE and PERCENTAGE of mutant mtDNA: Young Adult Young Adult 5% normal mtDNA Severe Phenotype Older Adult
Treatment Strategies
No therapies are currently available.
Most patients are given the following enzymes to optimize oxidative phosphorylation
Coenzyme Q, an enzyme in the Electron Transport Chain L-carnitine supplements helps turn fat into energy Figure: Coenzyme Q
Disease Incidence
MERRF is a rare disease. Incidence in Countries of Western Europe (1:100,000)
1.6 1.4 1.2 1
Finland (Adult Population), 1.5
0.8 0.6
0.4 0.2 0
Finland (Adult Population)
England (Adult Population), 0.25 Western Sweden (Pedatric Population), 0.25
From: "The Rare Mitochondrial Disease Service for Adults and Children."
Gene
From: "MT-TK."
Figure 5: Sensorineural hearing loss happens due to loss of function in Cranial Nerve VIII
0.8 0.6
0.4 0.2 0
Finland (Adult Population)
England (Adult Population), 0.25 Western Sweden (Pedatric Population), 0.25
Cited Literature
1. Genetic Diseases Clinical Case Studies Thompson & Thompson Genetics in Medicine 7th edition Nussbaum, McInnes, Willard & Homosh Saunders (Elsevier) ISBN: 978-1-4160-3080-5 "MT-TK." - Mitochondrially Encoded TRNA Lysine. National Institue of Health. Web. 03 Apr. 2012. http://ghr.nlm.nih.gov/gene/MT-TK. "The Rare Mitochondrial Disease Service for Adults and Children." The Rare Mitochondrial Disease Service for Adults and Children. National Health Service, United Kingdom. Web. 03 Apr. 2012. http://www.mitochondrialncg.nhs.uk/pa_genetics.html. Larsson, NG, M H Tulinius, and E Holme. "Segregation and manifestations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.." National Center for Biotechnology Information. The American Journal of Human Genetics, n.d. Web. 3 Apr. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682923/>. Salvatore, DiMauro, MD, and Hirano, MD Michio. "MERRF - GeneReviews - NCBI Bookshelf." National Center for Biotechnology Information. N.p., n.d. Web. 3 Apr. 2012. http://www.ncbi.nlm.nih.gov/books/NBK1520/
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Zhou, Li, Anne Chomyn, Giuseppe Attardi, and Carol Miller. "The Journal of Neuroscience" Myoclonic Epilepsy and Ragged Red Fibers (MERRF) Syndrome: Selective Vulnerability of CNS Neurons Does Not Correlate with the Level of Mitochondrial TRNAlys Mutation in Individual Neuronal Isolates. Journal of Neuroscience, 15 Oct. 1997. Web. 03 Apr. 2012. <http://www.jneurosci.org/content/17/20/7746.full>.