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Myoclonic Epilepsy with Ragged Red Fibers

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

Chief Complaint (CC)
R.S. is a 15 year old male, admitted for Mycolonic Epilepsy Electroencephalogram (EEG) was characterized by burst of slow wave and spike complexities (Hypsarrhythmia)

History of Present Illness or Problem (HPI)
On Examination

• 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

Autopsy of dead uncle

• 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

Gomori Trichrom stain for Ragged-Red Fibers in muscle tissue

Sensorineural hearing loss happens due to loss of function in Cranial Nerve VIII

Past Medical History of Patient (PHM)
Before the seizures, the patient was developing normally. Not other past history provided. But, typically MERRF symptoms are characterized by:

 Involuntary Muscle Twitches (Myoclonus)
 Short stature  Incoordination of muscle movement (ataxia)

 Weakness (myopathy)
 Progressive Stiffness (Spasticity)

Family History (FH)
Maternal

Uncle

Maternal

Aunt

Grandfather

Maternal

Died of myopathic disorder at 53
Autopsy revealed ragged-red fibers identified

Progressive Dementia and ataxia at age 37

Suffered from deafness, diabetes, and renal dsyfunction in old age.

Personal and Social History
Not provided in case history. Assuming that patient lives with parents. Patient is a 15-year-old male high school student, so the following social history can be assumed:  Alcohol Intake: None

 Cigarette smoking: None
 Other Drug Use: None  Marital Status: Single  Sexual History: 1 past partner, heterosexual, not currently active  Work History (type, duration, exposures): High School Student

Review of Systems (ROS)
In case history:
General • Weakness • Fatigue Neurologic • Weakness • Tingling • Involuntary twitching Ears • Hearing loss and/or deafness Hematologic • Elevated lactic acid levels

Not in case history:
Skin •Color changes •Rashes •Lumps Eyes •Blurred / Poor night vision •Cataract defects •Eye abnormalities Neurologic •Seizures •Frequent headaches •Dementia General •Short stature

Physical Exam Results
Not in case history:
Head •Low density of cerebellar white matter and cerebral atrophy Eyes •Blurred / poor night vision •Droopy eye lids •Limited mobility of eyes •Cardiac defects Ears •Hearing loss (Cranial nerve VIII) Mental Status •Slow progressive unsteadiness •Mild cognition decline

Extremities •Myoclonus

Neurologic •Hypsarrhythmia •Myoclonus

Motor Strength •Jerky movements (ataxia)

Heart •Chest pain •Tightness •Heart rhythm disturbance

Process Diagram for Lactate Breakdown

Labs:

Elevated Blood Lactate Levels (2.75 mmol/L)
Hyperlactatemia is characterized by an elevated plasma lactate (2-5 mmol/L).
Summary: Hyperlactatemia is an indication that the patient’s metabolic pathways are unable to sufficiently breakdown lactate to pyruvate. Risk Level: If hyperlactatemia continues unabated, lactic acid can build up in the body and makes the blood more acidic. The liver tries to convert lactic acid into pyruvate, but if blood lactate levels rise, the liver cannot keep up and the blood becomes acidic. Lactic acidosis can kill tissues and cells.

Labs:

Process Diagram for Lactate Breakdown

Elevated Cerebrospinal Fluid (CSF) Lactate Levels
(2.25 mmol/L)
Elevated Cerebrospinal Fluid (CSF) lactate is characterized by an elevated plasma lactate (1.5-5 mmol/L).

Risk Level: The raised CSF lactate level present clinical characteristics such as:

 Optic Atrophy (early onset observed as poor night vision)
 Bilateral hearing loss  Convulsion and ataxia

 Symmetrical cerebral calcification strongly suggested some kinds of mitochondrial disease.
From: http://www.ncbi.nlm.nih.gov/pubmed/16722983

MRI Imaging:

(not in case history)

Subcortical white matter lesions and cerebellar atrophy
Cerebral atrophy is a common feature of diseases that affect the brain.

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

Figure 2: EEG shows spike-slow wave complex

Molecular Testing Lab:

Skeletal muscle biopsy reveled mutations in mitochondrial DNA (mtDNA).
A heteroplasmic mutation (8344G>A, tRNAlys gene: Mutation is known to be associated with myoclonic epilepsy with ragged-red fibers (MERRF), in 80% of the mtDNA from muscle.  Single point mutation at location 8344, replacing A with G.  Affects the activity or generation of tRNAlys by 5060%, thereby slowing down the synthesis of physiologically important mitochondrial proteins and the process of oxidative phosphorylation Figure 3: tRNAlys Anticodon, 8344G>A mutation

Blood Samples of Mother, Maternal Aunt and Grandfather:
Confirmed heteroplasmic mtDNA mutation
 Mitochondrial DNA is heteroplasmic and is contained within the mitochondria  MERRF is maternally inherited
 Sperm mitochondria destroyed during fertilization  First children of heteroplasmic mothers are widely affected

 mtDNA is more susceptible to mutations (10-fold) than nuclear DNA.
 High concentration of oxygen-free radicals from oxidative phosphorylation  No introns: Random mutation directly affect coding sequence  Lack of histone proteins and Ineffective DNA repair

 Mitochondrial activity declines gradually  Expression of defects manifest in late teens or early 20s

Autopsy of Deceased Maternal Uncle:
 Ragged-Red Fibers observed in some muscle groups  Died of myopathic disorder (muscular disease in which muscle fibers do not function properly) at 53  Manifesting carrier of mtDNA mutation  Maternal side of family confirmed as source of mutation
Gomori Trichrom stain for Ragged-Red Fibers in muscle tissue

Signs and Symptoms
Difficulty coordination movements (ataxia)

Muscle twitches (myoclonus)

Poor night vision

Weakness (myopathy)

Progressive Stiffness (spasticity)

Abnormal muscle cells (ragged-red fibers)

Recurrent seizures (epilepsy)

Loss of sensation in extremities

Deterioration of intellectual function

Hearing or optic loss (atrophy)

Short stature and heart abnormalities (cardiomyopathy)

Fatty tumors under the surface of the skin (lipomas)

From: "MERRF - GeneReviews™ - NCBI Bookshelf.”

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

Additional frequent manifestations include the following:
Sensorineural hearing loss Myopathy Peripheral neuropathy Dementia Short stature

Exercise intolerance

Optic atrophy

From: . "MERRF - GeneReviews™ - NCBI Bookshelf.”

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

mtDNA is more susceptible to mutations (10-fold) than nuclear DNA.
 High concentration of oxygen-free radicals from oxidative phosphorylation  No introns: Random mutation directly affect coding sequence  Lack of histone proteins and Ineffective DNA repair

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

• 15% normal mtDNA • Normal Phenotype

• 16% normal mtDNA • Severe Phenotype

From: Genetic Diseases – Clinical Case Studies

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

From: Genetic Diseases – Clinical Case Studies

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

England (Adult Population)

Western Sweden (Pedatric Population)

From: "MERRF - GeneReviews™ - NCBI Bookshelf."

Mechanism of Disease Inheritance
How is the disease inherited?
 Maternal inheritance: During fertilization, sperm cell’s mitochondria and mitochondrial DNA are destroyed.  Mother’s eggs incur high level of mtDNA mutation  Pattern of inheritance always is maternal and hetroplasmic (occurring in mitochondrial DNA)  F1 Generation (the patient) has a very high probability of acquiring mtDNA mutation from affected mother
 However, the mother may not present disease symptoms because her gametes (eggs) acquire the mutations

Figures for Disease Inheritance

Figure 1A: Mutations in Maternal mtDNA Figure 1B: Maternal Inheritance

R.S. Mother R.S.

R.S. – The Patient

From: "The Rare Mitochondrial Disease Service for Adults and Children."

Mechanism of the Disease:
Pathology of mtDNA mutation from microscopic to macroscopic
Tissue Cell Protein

Gene

Mechanism of Disease: Gene Level
Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes contained in the mitochondria cause MERRF.
Figure 2: MT-TK Gene

mtDNA is more susceptible to mutations (10-fold) than nuclear DNA.
 High concentration of oxygen-free radicals from oxidative phosphorylation  No introns: Random mutation directly affect coding sequence  Lack of histone proteins and Ineffective DNA repair

From: "MT-TK."

Mechanism of Disease: Protein Level
 MERRF is a heteroplasmic mutation (8344G>A, tRNAlys gene), meaning the mutation occurs at position 8344, where A is misplaced with G (missense mutation).  Affects the activity or generation of tRNAlys by 50-60%, thereby slowing down the synthesis of physiologically important mitochondrial proteins and the process of oxidative phosphorylation
Figure 3: tRNAlys Anticodon, 8344G>A mutation

From: Genetic Diseases – Clinical Case Studies

Mechanism of Disease: Subcellular Level
 Complexes I (NAHD Dehydrogenase) and IV (Cytochrome Oxidase Complex) in the ETC require a high volume of tRNAlys components and therefore are the most affected  Low activity of Complex I and IV means that Hydrogen Protons cannot be transferred out of the membrane to create an electrochemical gradient  Due to this malfunction, the ETC is not able to receive an electrochemical force strong enough to allow for high efficiency ATP (energy) generation
From: Genetic Diseases – Clinical Case Studies

Figure 4A: Complex I and IV in ETC

Figure 4B: Deficiency of Cytochrome C Oxidase (Complex IV in Mitochondria), shown in blue.

Mechanism of Disease: Tissue/Organ Level
High concentration of that Hydrogen Protons in the intracellular space means that:  Blood Acidity Increases  Can cause cell death This explains why R.S. is experiencing the following:  Sensorineural hearing loss (damage to Carnial Nerve due to elevate CSF lactate)  Slowed nerve condition velocities  Ataxia and Myoclonus  He will eventually suffer from dementia, deafness and will have cataract complications
From: Genetic Diseases – Clinical Case Studies

Figure 5: Sensorineural hearing loss happens due to loss of function in Cranial Nerve VIII

Figure 2: Disease Incidence
MERRF is a rare disease. It is genetically inherited and can affect the pediatric population but usually expresses in young adults in their early 20s. 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

England (Adult Population)

Western Sweden (Pedatric Population)

From: "MERRF - GeneReviews™ - NCBI Bookshelf."

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>.