genetic diseases of mitochondrial origin

1. Genetic Diseases
of Mitochondrial
origin
NISHA K SUNNY
MSc BIOTECHNOLOGY

2. GENETIC DISEASES
CYTOCHROME C OXIDASE
DEFEICENCY
LEIGH SYNDROME
KEARN SYARE SYNDROME
LOHN
NON SYNDROMIC DEAFNESS
MYOPATHY
RETINOPATHY

3. CYTOCHROME C OXIDASE
(complex IV deficiency)
 Mutations in at least 14 mitochondrial genes
 The mitochondrial genes associated with cytochrome
c oxidase deficiency provide instructions for making
subunit proteins that are part of a large enzyme
complex called cytochrome c oxidase

4. • Cytochrome c oxidase is responsible for the last step
in oxidative phosphorylation before the generation
of ATP.
• The mitochondrial DNA mutations that cause this
condition alter the subunit proteins that make up
cytochrome c oxidase
• cytochrome c oxidase cannot function

5. • A lack of functional cytochrome c oxidase disrupts
the last step of oxidative phosphorylation, causing a
decrease in ATP production
• impaired oxidative phosphorylation can lead to cell
death in tissues that require large amounts of energy,
such as the brain, muscles, and heart.

6. • Signs and symptoms: begin before age 2 but can
appear later in mildly affected individuals.
• People who are mildly affected tend to have
(myopathy) and (hypotonia)
• Severely affected people have myopathy along with
(encephalomyopathy)
• An enlarged liver, lactic acidosis

7. • fatal in childhood, although some individuals with
mild signs and symptoms survive into adolescence or
adulthood.
• have a type of heart disease that enlarges and
weakens the heart muscle hypertrophic
cardiomyopathy
• specific group of features known as Leigh syndrome

8. Leigh syndrome
• Mutations in one of several different mitochondrial
genes can cause Leigh syndrome
• progressive brain disorder that usually appears in
infancy or early childhood
• Some of the genes associated with Leigh syndrome
provide instructions for making proteins that are part of
the large enzyme complexes necessary for oxidative
phosphorylation

9. • Some of the genes associated with Leigh syndrome
provide instructions for making proteins that are part
of the large enzyme complexes necessary for
oxidative phosphorylation
• the most commonly mutated mitochondrial gene in
Leigh syndrome, MT-ATP6, provides instructions for a
protein that makes up one part of complex V

10. • an important enzyme in oxidative phosphorylation
that generates ATP in the mitochondria.
• other genes provide instructions for making tRNA
molecules, which are essential for protein production
within mitochondria
• mitochondrial gene mutations that cause Leigh
syndrome impair oxidative phosphorylation
• impaired oxidative phosphorylation can lead to cell
death in sensitive tissues, which may cause the signs
and symptoms of Leigh syndrome

11. • Signs and symptoms: loss of mental function,
movement problems, hypertrophic cardiomyopathy,
eating difficulties, and brain abnormalities.
• Cytochrome c oxidase deficiency is one of the many
causes of Leigh syndrome.

13. • changes in mitochondrial DNA
• Some of the genetic changes alter single DNA
building blocks (nucleotides)
• whereas others rearrange larger segments of
mitochondrial DNA.
• These changes likely impair the ability of
mitochondria to produce energy

14. • impaired mitochondria may affect certain cells of the
autonomic nervous system
• nervous system that controls involuntary body
functions such as heart rate, blood pressure, and
digestion
• CVS typically develops during childhood, usually
between ages 3 and 7; although it often remits
during adolescence, it can persist into adult life.

15. • Signs and symptoms:
• recurring attacks of intense nausea, vomiting and
sometimes abdominal pain, headaches or migraines.
• There is no known cure for CVS, but there are
medications that can be used for treatment,
intervention, and prevention

16. Kearns-Sayre syndrome

17. • oculocraniosomatic disorder or Oculocraniosomatic
neuromuscular disorder
• mitochondrial myopathy with a typical onset before
20 years of age
• Most people with Kearns-Sayre syndrome have a
single, large deletion of mitochondrial DNA

18. • The deletions range from 1,000 to 10,000
nucleotides, and the most common deletion is 4,997
nucleotides
• primarily affects the eyes, causing weakness of the
eye muscles (ophthalmoplegia) and breakdown of
the light-sensing tissue at the back of the eye
(retinopathy).
• KSS involves a triad of Chronic progressive external
ophthalmoplegia (CPEO), as well as bilateral
pigmentary retinopathy, and cardiac conduction
abnormalities.

19. • The mitochondrial DNA deletions result in the loss of
genes that produce proteins required for oxidative
phosphorylation
• causing a decrease in cellular energy production.
• eyes are commonly affected by mitochondrial
defects because they are especially dependent on
mitochondria for energy.
• cerebellar ataxia, proximal muscle weakness,
deafness, diabetes mellitus, growth hormone
deficiency, hyperparathyroidism, or other
endocrinopathie

21. Leber hereditary neuropathy

23. • Mitochondrially inherited diseases
• degeneration of retinal ganglion cells
• Lohn is usually due to:
• Mutations in four mitochondrial genes, MT-ND1, MT-
ND4, MT-ND4L, and MT-ND6
• These genes provide instructions for making proteins
that are part of a large enzyme complex
• This enzyme, known as complex I, is necessary for
oxidative phosphorylation

24. • The mutations responsible for Lohn change single
amino acids in these proteins, which may affect the
generation of ATP within mitochondria.
• mutations are often limited to the nerve that relays
visual information from the eye to the brain (the
optic nerve).
• Vision in Lohn patients is weird.

26. Pearson marrow-pancreas syndrome

27. • deletion of mitochondrial DNA
• The size and location of mitochondrial DNA deletions
vary, usually ranging from 1,000 to 10,000
nucleotides
• It’s the same deletions present in the Kearns-Sayre
syndrome later in life.
• This severe condition affects the development of
blood cells and the function of the pancreas and
other organs

28. • Mitochondrial DNA deletions lead to the specific
signs and symptoms of Pearson marrow-pancreas
syndrome
• Some individuals with Pearson marrow-pancreas
syndrome who survive past early childhood develop
signs and symptoms of Kearns-Sayre syndrome later
in life.
• Affected individuals have (anemia, pallor, weakness,
fatigue, neutropenia, thrombocytopenia)

29. • reduced ability to absorb nutrients from the diet
(malabsorption)
• most affected infants have an inability to grow and
gain weight at the expected rate (failure to thrive).
• Another common occurrence in people with this
condition is buildup in the body of a chemical called
lactic acid lactic acidosis

30. Nonsyndromic deafness

31. • Mutations in two mitochondrial genes, MT-RNR1 and
MT-TS1
• These genes provide instructions for making different
types of RNA.
• The MT-RNR1 gene provides instructions for a
specific type of ribosomal RNA called 12S RNA
• A particular form of tRNA, designated as tRNASer(UCN),
is formed from the MT-TS1 gene

32. • Both of these RNA molecules help assemble amino
acids into full-length, functioning proteins within
mitochondria
• Mutations in the MT-RNR1 gene increase the risk of
hearing loss, particularly in people who take
prescription antibiotic medications called amino
glycosides
• Amino glycosides kill bacteria by binding to their
ribosomal RNA and disrupting the bacteria's ability to
make proteins

33. • Common genetic changes in the MT-RNR1 gene can
make the 12S RNA in human cells look similar to
bacterial ribosomal RNA.
• amino glycosides can target the altered 12S RNA just
as they target bacterial ribosomal RNA.
• Reduce the production of proteins needed for
oxidative phosphorylation, which may impair the
ability of mitochondria to make ATP.

34. • the effects of mutations in the MT-RNR1 and MT-TS1
genes are usually limited to cells in the inner ear that
are essential for hearing.