Mitochondial disorders

Presented by:
Aqsa Ayoub
1
Kinnaird College For
Women Lahore

 Mitochondria are the main ‘‘powerhouse’’ for all cells in the body
except red blood cells.
 The individual mitochondrion is a bilayer structure and contains four
compartments:
(1) an outer mitochondrial membrane
(2) a heavily folded inner mitochondrial membrane
(3) an intermembrane space that exists between these two
membranes
(4) the matrix, which is contained within the inner membrane.
2

 Mitochondria participate in the process of oxidative
phosphorylation (OXPHOS), the transformation of energy
(from the breakdown of nutrients) in the presence of
oxygen to adenosine triphosphate (ATP).
 Disorders of OXPHOS may affect the brain (central,
peripheral, and autonomic nervous systems), muscles,
kidneys, heart, liver, eyes, ears, pancreas, skin, and other
organ systems.
3

 Mitochondrial DNA acquires mutations at 6 to 7 times the
rate of nuclear DNA because:
 It lack protective histones.
 It is in close proximity to the electron transport chain,
exposing it to high concentrations of free radicals, which
can damage the nucleotides.
 It lack DNA repair mechanisms, which results in mutant
tRNA, rRNA, and protein transcripts.

 Mitochondrial disease can arise through :
1. defect in mtDNA
2. defect in nuclear-encoded mitochondrial
protein
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 Circular, double stranded, and composed of heavy and
light chains or strands
16,569 bp 37
genes
22 tRNA
genes
2rRNA genes
13
polypeptide
gene
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MATERNAL MODE OF
INHERITANCE
9

10
HETEROPLASMY
Cells contain hundreds of
mitochondria , and each
mitochondria contains
hundreds of mtDNA. So
cells contain thousands of
copies of mtDNA.
For the most parts ,their
sequence will be non
identical (hetroplasmy )
BOTTLENECK
AND
SEGREGATION
Of the 1,50,000 mtDNA
molecules in human
oocytes ,only a small
proportion of mtDNA is
transmitted during
oogenesis and
subsequently to embryo.
In high intrafamilial
clinical variation
changing phenotype over
time
THRESHOLD
Disease occurs when
enough cells in a tissue
are affected
Cell can compensate for
reduced wild-type
mtDNA until a certain
threshold is met

Mutation arises in mtDNA
Mixed population of wild- type and mutant mtDNA within a single cell
( heteroplasmy )
Heteroplasmic cells divide and the mtDNA is distributed randomly to
daughter cells resulting in skewed populations of wild type or mutant
mtDNA
Random mitotic segregation of mtDNA causes varying proportions of
mutant mtDNA In daughter cells
Degree of heteroplasmy determines clinical phenotype
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 Mutation creates two
distinct classes of
mtDNA variants :
- single base pair
variants
- mtDNA
rearrangements
(deletions and
insertions)
13

 There are many more proteins encoded in the Nuclear
DNA (the number is estimated to be anywhere from a low
of 100 to a high of 1200), and they occur primarily in
electron transport chains.
 Currently there are 40 identified Nuclear Genes which
cause Nuclear DNA Mitochondrial Disease (there may be
as many as 1200).
 If problems occur in the Nuclear DNA, the transference to
the next generation would not be just through the mother
(egg) but would follow standard Mendelian Laws of
Inheritance.
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 Autosomal Recessive
would have a 25% risk
of inheritance
 Autosomal Dominant
disease would have a
50% risk of inheritance.
 Under these laws there
is also the possibility for
the disease to be X
linked,
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I. Muscle Biopsy
 A biopsy of skeletal muscle
permits histopathology, electron
microscopy, respiratory chain
enzymology, and mtDNA testing.
 The classic hallmark of
mitochondrial diseases is
subsarcolemmal and
intermyofibrillar accumulation of
mitochondria visualized on
Gomori trichrome stain.
The mitochondria appear as
bright red masses against the blue
background of the myofibers,
which led to the term
"ragged red fibers" (RRF)
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 Electron microscopy may show abnormal mitochondria with increased
size and abnormal cristae.
 Muscle respiratory chain enzymology
o Performed on frozen skeletal muscle tissue.
o The activities of the enzyme complexes involved in making adenosine
triphosphate (ATP) are measured and expressed relative to citrate
synthase, a marker enzyme.
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 Genetic analysis is needed for genetic counseling.
 If the patient fits a specific phenotype (ie LHON, MERRF, MELAS) a blood /
muscle test for a point mutation may be positive.
 Mitochondrial DNA length mutations (common deletion) are best detected by
Southern blot analysis in total mtDNA extracts from blood lymphocytes.
 In some patients the studies are negative, despite high clinical suspicion.
 However, even patients who have a known pathogenic mtDNA mutation may be
asymptomatic depending on the percentage load of mutant mtDNA.
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 Most common mitochondrial encephalomyopathy
 Maternally inherited point mutation
 A3243G point mutation in tRNA-80%
 Onset in majority patients is before the age of 20 yrs
 Seizures: partial or generalized, may be first sign
 Stroke like episodes, do not conform to a vascular distribution
 Associated condition, hearing loss, diabetes mellitus, growth
hormone deficiency
 Fatal outcome
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Normal: Mild SDH staining of a
medium sized perimysial vessel.
Increased SDH staining of a
medium sized perimysial vessel
in a MELAS patient.
MUSCLE BIOPSY – SDH STAIN
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 Adolescent
 Autosomal recessive
 Mutation in thymidine phosphorylase in Ch 22
 Thymidine phosphorylase activity is reduced and
plasma thymidine levels are elevated
 Peripheral neuropathy, CPEO, gastrointestinal
dysmotility
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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22710
32/
 http://hihg.med.miami.edu/code/http/modules/educa
tion/Design/Print.asp?CourseNum=2&LessonNum=4
 http://www.spandidos-publications.com/mmr/8/1/17
 http://en.wikipedia.org/wiki/Mitochondrial_neurogast
rointestinal_encephalopathy_syndrome
 http://en.wikipedia.org/wiki/Mitochondrial_neurogast
rointestinal_encephalopathy_syndrome
 http://hihg.med.miami.edu/code/http/modules/educa
tion/Design/Print.asp?CourseNum=2&LessonNum=4
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Mitochondial disorders

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