Myoclonic Epilepsy with Ragged Red Fibers
Oct 23, 2014
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 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
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
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)
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
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
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:
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
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
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
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 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
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 stainfor Ragged-Red Fibers in muscle
tissue
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.”
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
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
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
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
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)
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 mtDNAFigure 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
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
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
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.
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
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)
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>.