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Myoclonic Epilepsy with Ragged Red Fibers
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Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Oct 23, 2014

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In 80% of cases, MERRF is caused by a single base pair mutation (A changes to G) in mitochondrial DNA (mtDNA), at location 8344.
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Page 1: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Myoclonic Epilepsy with Ragged Red

Fibers

Page 2: 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

Page 3: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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)

Page 4: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

History of Present Illness or Problem (HPI)

On Exa

mination

• General Muscle Wasting & Weakness• Myoclonus (major phenotypic feature of illness)• Ataxia (major phenotypic feature of illness)

Initial

Evaluatio

n

• Sensorineural hearing loss• Slowed nerve condition velocities• Mildly elevated blood and cerebrospinal fluid lactate levels

Secondar

y Evaluatio

n

• Muscle biopsy detected abnormal mitochondria • Deficient staining for cytochrome oxidase • Red with Gomori Trichrom stain (ragged-red fibers detected)

Autopsy of

dead uncl

e

• Ragged red fibers identified in some muscle groups• High probability that family members are carriers of the

mtDNA mutation

Page 5: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Gomori Trichrom stainfor Ragged-Red Fibers in muscle tissue

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

Page 6: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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)

Page 7: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Family History (FH)

Died of myopathic

disorder at 53Autopsy

revealed ragged-red fibers identified

Progressive Dementia and

ataxia at age 37

Suffered from deafness,

diabetes, and renal

dsyfunction in old age.

Maternal

UncleMaternal

AuntMaternal

Grandfather

Page 8: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Personal and Social HistoryNot 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

Page 9: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Review of Systems (ROS)

General

• Weakness

• Fatigue

Neurologic

• Weakness

• Tingling• Involunta

ry twitching

Ears

• Hearing loss and/or deafness

Hematologic

• Elevated lactic acid levels

Skin

• Color changes• Rashes• Lumps

Eyes

• Blurred / Poor night vision

• Cataract defects

• Eye abnormalities

Neurologic

• Seizures• Frequent headaches

• Dementia

General

• Short stature

In case history:

Not in case history:

Page 10: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Physical Exam Results

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

Not in case history:

Extremities

• Myoclonus

Neurologic

• Hypsarrhythmia

• Myoclonus

Motor Strength

• Jerky movements (ataxia)

Heart

• Chest pain• Tightness• Heart

rhythm disturbance

Page 11: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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.

Process Diagram for Lactate Breakdown

Page 12: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Labs: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

Process Diagram for Lactate Breakdown

Page 13: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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.

Page 14: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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

Page 15: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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 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

Page 16: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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

Page 17: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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 stainfor Ragged-Red Fibers in muscle

tissue

Page 18: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Signs and Symptoms

Muscle twitches

(myoclonus)

Difficulty coordination movements

(ataxia)

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 (cardiomyopat

hy)

Fatty tumors under the

surface of the skin (lipomas)

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

Page 19: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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.”

Page 20: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Genetic Basis

From: “MT-TK."

Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes contained in the mitochondria cause MERRF.

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

Figure 2: MT-TK Gene

Page 21: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Natural HistoryClassic 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

• 15% normal mtDNA

• Normal Phenotype

Young Adult

• 5% normal mtDNA

• Severe Phenotype

Older Adult

• 16% normal mtDNA

• Severe Phenotype

From: Genetic Diseases – Clinical Case Studies

Page 22: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Treatment StrategiesNo 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

From: Genetic Diseases – Clinical Case Studies

Figure: Coenzyme Q

Page 23: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Disease IncidenceMERRF is a rare disease.

00.40.81.21.6

Finland (Adult Population);

1.5

England (Adult Population);

0.25

Western Sweden (Pe-

datric Popula-tion); 0.25

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

Incidence in Countries of Western Europe (1:100,000)

Page 24: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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

Page 25: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Figures for Disease Inheritance

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

R.S. Mother

R.S.

R.S. – The Patient

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

Page 26: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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

Tissue

Cell

Protein

Gene

Page 27: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Mechanism of Disease: Gene Level

From: "MT-TK."

Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes contained in the mitochondria cause MERRF.

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

Figure 2: MT-TK Gene

Page 28: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Mechanism of Disease: Protein LevelMERRF 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

From: Genetic Diseases – Clinical Case Studies

Figure 3: tRNAlys

Anticodon, 8344G>A mutation

Page 29: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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

Figure 4A: Complex I and IV in ETC

From: Genetic Diseases – Clinical Case Studies

Figure 4B: Deficiency of Cytochrome C Oxidase

(Complex IV in Mitochondria), shown in blue.

Page 30: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Mechanism of Disease: Tissue/Organ LevelHigh 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

Page 31: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

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

00.40.81.21.6

Finland (Adult Population);

1.5

England (Adult Population);

0.25

Western Sweden (Pe-

datric Popula-tion); 0.25

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

Incidence in Countries of Western Europe (1:100,000)

Page 32: Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Cited Literature1. Genetic Diseases – Clinical Case Studies

Thompson & Thompson Genetics in Medicine 7th edition Nussbaum, McInnes, Willard & Homosh Saunders (Elsevier) ISBN: 978-1-4160-3080-5

2. "MT-TK." - Mitochondrially Encoded TRNA Lysine. National Institue of Health. Web. 03 Apr. 2012. http://ghr.nlm.nih.gov/gene/MT-TK.

3. "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.

4. 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/>.

5. 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/

6. 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>.