This document provides an overview of mitochondrial function and diseases, emphasizing the role of mitochondria in ATP production and apoptosis. It discusses mitochondrial DNA mutations, their inheritance patterns, and epidemiology, highlighting various mitochondrial cytopathies and their clinical manifestations. The document specifically focuses on MELAS syndrome, its characteristics, diagnosis, and associated clinical features.

1. MELAS
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Frank W Meissner MD RDMS RCDS FACP FACC FCCP CPHIMS
CCDS
PGY-2 Psychiatry Resident

3. • Intracellular organelle.
•100 to 1000s mitochondria/cell.
• Maternal Inheritance.
•Mitochondria unique DNA.
• Found in all cell types, except RBC.
• Major functions of mitochondria:
-Makes energy in the form of ATP.
-Programmed cell death (apoptosis).
Mitochondria
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4. • Found in all cell types, except the
RBC.
• Major functions of mitochondria:
-Makes energy in the form of ATP.
-Programmed cell death (apoptosis).
(cont.)
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5. • The mitochondria use electrons
and protons from metabolism
and molecular oxygen to reduce
water and generate proton-
motive force to produce ATP
from ADP: oxidative
phosphorylation.
(cont.)
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6. Role of ATP (energy)
1.Mechanical Work
Muscle contraction
2.Chemical Work
Na+/K+ Ion Pump
3.Synthetic Work [Anabolism]
Macromolecules
- Nucleic Acids
- Proteins
- Lipids
- Complex carbohydrates
Why is energy so important?
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7. Cellular Energy Overview

8. Glycolysis - 2 ATP

9. TCA Cycle- 2ATP

10. Mitochondrial ETC

11. Oxidative Phosphorylation - 23 ATP
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12. When this process is dysfunctional,
then disease can occur.
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13. Mitochondrial cytopathies
are
diseases of energy production.
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Mitochondrial DNA Genome
Each Mitochondria contains
approx 5 mtDNA moldecules
mtDNA circular molecule which
encodes polypeptides, tRNA, rRNA
Polypeptides from mtDNA &
the nuclear genome are needed
for ATP production via oxidative
phosphorylation
Mutations in mtDNA impairs
mitochondrial respiratory chain
leading to impaired ATP production
Definite pathogenic mechanism not
worked out

15. Frequency/Prevalence
Prevalence of more than 10.2 per 100,000 for the m.3243A → G
mutation in the adult Finnish population.
In US estimated prevalence 1:20,000
In Northern England, the prevalence of this mutation in the adult
population has been determined to be approximately 1 per 13,000.
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Epidemiology

16. Epidemiology
Three large studies looking at the prevalence of mitochondrial disorders
have shown:
The majority of adults with mitochondrial disease have an underlying
mtDNA mutation.
The majority of children with mitochondrial disease have an
underlying nuclear DNA mutation.
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17. Causes of mitochondrial disease
- DNA (DNA contained in the nucleus of the cell)
inheritance
- mtDNA (DNA contained in the mitochondria) inheritance
- Combination of mtDNA and nDNA defects
- Random occurrences
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18. Mitochondrial Inheritance
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19. Over 1000 proteins localized to mitochondria
13 are mitochondrial-encoded
Remainder are nuclear-encoded
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20. •16.6 kb (vs. 3 billion in the nuclear genome)
•37 genes
-22 tRNAs
-2 rRNAs
-13 proteins
All subunits of ETC
•mtDNA entirely devoted energy metabolism
Mitochondrial DNA (mtDNA)
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21. •Over 180 point mutations and almost as
many deletions associated with human
disease
•‘Maternally inherited’
•mtDNA come only from the ovum
Inheritance of mtDNA Mutations
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22. Sporadic
•Autosomal
•Nuclear-encoded regulatory proteins
interact with mtDNA (intragenomic
communication) and can result in
secondary mtDNA mutations
Inheritance of mtDNA Mutations (cont.)
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23. Mitochondrial Inheritance
Multiple organ disease

24. Mitochondrial vs. Nuclear Genome
Mitochondrial genome has
1.Smaller number of genes
2.Higher copy number
3.Less effective repair mechanisms
4.Higher mutation rate
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25. mtDNA vs. Nuclear DNA Mutations
•Nuclear: severe disease of infantile onset
•Mito: milder disease of later onset
• nuclear mutations predominate in small children
• mtDNA mutations predominate in those with adult-
onset symptoms
•Could be mutations in either genome at any age
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26. Maternal Inheritance
•mtDNA from mother to child(ren)
Child has identical sequence as matrilineal relatives mother—
sibs (through mom), maternal aunts/uncles, maternal
grandmother
•High recurrence risk in future sibs of an affected child (with a
point mutation), approaching 100%
•Marked inter- and intra- familial variation of symptoms, age of
onset and severity
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27. Maternal genetic transmission
An affected woman transmits the trait to all her children.
Affected men (represented by squares do not pass the trait to any
of their offspring
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28. Clinical Manifestation of
Mitochondrial Dysfunction
Multiple organ disease
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30. Mitochondrial Cytopathies: Clinical
Features
CNS
1.Myoclonus
2.Generalized Seizures
3.Stroke
4.Migraine Headache
5.Ataxia
6.Mental Retardation
7.Psychiatric Disease (?)
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31. MELAS Neurological Work Up

32. Clinical Manifestation of
Mitochondrial Dysfunction
Skeletal Muscle
1.Myopathy (hypotonia)
2.CPEO(Chronic Progressive External
Ophthalmoplegia)
3.Recurrent Myogloburia
4.Weakness/Fatigue
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33. Clinical Manifestation of
Mitochondrial Dysfunction
Bone Marrow
1.Siderblastic Anemia
2.Pancytopenia
Renal Function
Fanconi Syndrome
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34. Clinical Manifestation of
Mitochondrial Dysfunction
Systemic Symptoms
1.Lactic Acidosis
2.Short Stature
3.Fatigue
4.Failure to Gain Weight
5.Asthma
6.Intermittent Air Hunger
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35. Clinical Manifestation of
Mitochondrial Dysfunction
Endocrine
1.Diabetes Mellitus
2.Hypoparathyroidism
3.Exocrine Pancreatic Failure
4.Thyroid Disease
Heart
1.Cardiomyopathy
2.Conduction Defects
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36. Clinical Manifestation of
Mitochondrial Dysfunction
Vision
1.Optic Neuropathy
2.Retinitis Pigmentosa
Hearing
1.High-frequency Hearing Loss
2.Aminoglycoside-induced Deafness
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37. Clinical Manifestation of
Mitochondrial Dysfunction
Gastrointestinal
1.Pseudo-obstruction
2.Constipation
3.Vomiting
Liver
1.Hypoglycemia
2.Gluconeogenic Defects
3.Liver Failure and Cirrhosis
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38. mtDNA-related Syndromes
1.Mitochondrial encephalopathy, lactic
acidosis and stroke-like
episodes (MELAS)
2.Aminoglycoside-induced
deafness
3.Cyclic vomiting syndrome
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39. mtDNA-related Syndromes (cont.)
4.Kearns-Sayre syndrome (KSS)
5.Pearson syndrome
6.Leigh disease
7.Neuropathy, ataxia and retinitis pigmentosa
(NARP)
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40. mtDNA-related Syndromes (cont.)
8.Mitochondrial
neurogastrointestinal encephalopathy (MNGIE)
8.Myoclonic epilepsy and ragged-red fiber disease
(MERRF)
9.Leber’s hereditary optic
neuropathy (LHON)
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41. Mitochondrial Encephalomyopathy with Lactic Acidosis
and Stroke-like Episodes
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Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
(MELAS)
Stroke-like episodes, onset infancy to adulthood
Maternally inherited diabetes, deafness, cognitive impairment, short
stature, migraine
Most common cause is heteroplasmy for A3243G mutation (point
mutation in tRNA gene for leucine)
Other causes include T3271C and other point mutations, large
rearrangements and presumed nuclear defects

42. Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome
(MELAS) in PICU
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43. 7/31/16
Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome
(MELAS) in PICU

44. More Characteristics
MELAS affects no specific race or gender more so than
others
Presentation of the disease occurs with the first stroke-like
episode (usually 14-15 yrs of age)
This is a progressive disorder with a high mortality rate
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45. How does MELAS work?
Abnormal mitochondria do not metabolize pyruvate
Excess pyruvate is reduced to lactic acid which accumulates in blood
and other fluids
Large clumps of abnormal mitochondria form in the walls of small
arteries and capillaries in the brain and muscles
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46. Characteristics
It is the most common maternally inherited mitochondrial
disease
Clinical Features: Strokes, myopathy, muscle twitching,
dementia, and deafness
To a lesser extent: vomiting, migraine-like headaches,
diabetes, droopy eyelids, muscle weakness, and short
stature
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47. MELAS: Mitochondrial staining of intramuscular vessels
Succinic dehydrogenase (SDH) stain
Increased SDH staining of a
medium sized perimysial vessel
in a MELAS patient.
Normal: Mild SDH staining of a
medium sized perimysial vessel.
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48. Brain pathology in MELAS
MRI during episode of hemiparesis
Cortical lesion (Right side, posterior): Spares white matter
Lesion location
Not confined to territory of single vessel
Involves only part of territory of several vessels
Swelling
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49. MRI during episode of hemiparesis
FLAIR image T2 weighted image
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50. CT during episode of homonymous hemianopia
Medial occipital lesion (Arrow) Enlarged ventricles
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51. MELAS: Muscle fiber pathology
Scattered abnormal, vacuolated
fibers with clear rim: H & E
Scattered "ragged red" muscle fibers:
Gomori trichrome
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52. Late in disease course
MRI: Severe
involvement
of occipital cortex
Severly abnormal temporal
gray matter.
Temporal horn of ventricles
is enlarged.
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53. Prenatal Diagnosis for mtDNA
Can be done, as chorionic villus and amniocyte mutant loads in certain
situations
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54. Important Points
Mitochondrial Cytopathies
Suspect when:
> 2 unrelated organ systems are involved.
inheritance seems maternal.
the neurological exam seems paradoxical.
the usual presentation of a syndrome is not “usual” and history is
suspect for a bioenergetic disorder.
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55. References
Scaglia, Fernando, MD. MELAS Syndrome.
http://www.emedicine.com/ped/topic1406.htm. October 26, 2004
http://herkules.oulu.fi/isbn9514255674/html/graphic33.gif
Dahl H-HM, Thorburn DR (2001) Mitochodrial Diseases, Am J Medical
Genetics 106:1-115
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