HBM3205 – Clinical Genetics

and Cellular Basis of Disease

Workshop 3 (Mitochondrial disorders) – Dr. Amanda Genders
Acknowledgement: Dr. Juliana Antonipillai
Mitochondria Questions
(Space Race or Discussion)
1. Mitochondria have many functions, but what is arguably their most important function?
2. Electron transport takes place on the inner or outer mitochondrial membrane?
3. Why is it important that the inner mitochondrial membrane is impermeable?
4. What molecule is produced as a final product of oxidative phosphorylation?
5. The folds in the inner mitochondrial membrane are known as what?
6. Where in the mitochondria does the TCA cycle take place?
7. What is mitochondrial DNA?
 Mitochondria

Mitochondria are membrane-bound cell organelles that generate most

of the chemical energy needed to power the cell's biochemical
reactions.
Chemical energy produced by the mitochondria is stored in a small
molecule called adenosine triphosphate (ATP).
Mitochondria contain their own small chromosomes.
Mitochondria inherited only from the mother.
Mitochondrial DNA
Unlike nuclear DNA, mtDNA is inherited strictly from mother to child.
Thus mtDNA is not unique for each individual since all the maternal relatives
have identical mtDNA sequence.
mtDNA is not the same between all populations and this is due to lack of
repair mechanisms and proofreading capabilities.
The mutation rates of mitochondrial DNA are 10 times higher than in nuclear
DNA.
High variability in mtDNA is useful in human identity testing and in
investigating the evolutionary relationships among individuals and species,
by interrogating its short variable sections.
http://embomolmed.e
mbopress.org/content/
7/12/1503
Human mtDNA was first sequenced in Sanger's
laboratory in Cambridge in 1981.
The sequences across HV1 and HV2 that are most
commonly used in forensic applications.
The genes that encode subunits 6 and 8 of the ATP
synthase (ATP6 and ATP8) are partly overlapping.
Other polypeptide-encoding genes specify seven Mitochondrial
NADH dehydrogenase subunits (ND4L and ND1-
ND6), three cytochrome c oxidase subunits (C01-
0O3), and cytochrome b (CYB).
DNA
tRNAgenes are represented with the name of the
amino acid that they bind.
For further information, see the MITOMAP
database at http://www.mitomap.org/.
 21,000 to 25,000

~1.5%

http://www.nature.com/nrg/journal/v6/n5/fig_tab/nrg1606_T1.html
 Inherited Mitochondrial Disease
More than 275 mutants have been identified.
When the mitochondria are not working properly, the body does not
have enough energy to carry out its normal functions.
This can lead to the variety of health problems associated with
mitochondrial genetic disorders
Genes involved in mitochondrial disease normally make proteins that
work inside mitochondria to make ATP.
Onset: Present at any age with almost any affected body
system. Brain, muscles, heart, liver, nerves, eyes, ears and
kidneys are the organs and tissues most commonly
affected.
Causes: Changes in either mitochondrial DNA or nuclear
DNA. Both acquired or inherited. Mutations in Inherited
mitochondrial DNA are transmitted by maternal
inheritance, while those caused by mutations in nuclear
DNA may follow an autosomal dominant, autosomal
mitochondrial
recessive, or X-linked pattern of inheritance. disease
Treatment:Varies based on the specific type of condition
and the signs and symptoms present in each person
 • Poor growth
• Loss of muscle coordination, Muscle weakness
• Seizures, Autism
• Problems with vision and/or hearing
General • Developmental delay, Learning disabilities
Symptoms •
•
Heart, liver, and/orkidney disease
Increased risk of infection
• Thyroid and/or adrenal abnormalities
• Autonomic dysfunction and Dementia
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)90244-1/fulltext
http://www.childneurologyfoundation.org/disorders/mitochondrial-diseases/
Inherited • Mitochondrial myopathy
• Leber's hereditary optic neuropathy (LHON)

Mitochondrial • Diabetes mellitus and deafness(DAD)

• Leigh syndrome, subacute sclerosing
Disease encephalopathy
• Neuropathy, ataxia, retinitis pigmentosa, and
ptosis(NARP)
• Myoneurogenic gastrointestinal encephalopathy
(MNGIE)
• Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
• mtDNA depletion
Mitochondrial
Myopathies
Mitochondrial myopathies are a group of neuromuscular
diseases caused by damage to the mitochondria
Nerve cells in the brain and muscles require more energy
and they damaged when mitochondrial dysfunction
occurs
Symptoms: muscle weakness or exercise intolerance,
heart failure, dementia, movement disorders, stroke-like
episodes, deafness, blindness, droopy eyelids, limited
mobility of the eyes, vomiting, and seizures.
Onset: Most mitochondrial myopathies occur before the
age of 20
Treatment: physical therapy, Vitamin therapies such as
riboflavin, coenzyme Q, and carnitine(a specialized amino
acid)
LHON
LHON is an inherited form of vision loss. Only affect a single organ!
Although this condition usually begins in a person's teens or twenties, rare cases
may appear in early childhood or later in adulthood.
More males are affected than females. But not sex link disorder ? Unknown reason.
Blurring and clouding of vision are usually the first symptoms of LHON
Eye disorder characterized by progressive loss of central vision due to degeneration
of the optic nerves and retina
Vision loss is permanent
Affects 1 in 50,000 people in Finland
 Mutations in the MT-ND1, MT-ND4, MT-ND4L, or
MT-ND6 gene can cause LHON.
Mutations in any of the genes disrupt this process
of Mitochondrial enzyme NADH dehydrogenase
that help to make ATP.
It remains unclear how these genetic changes
cause the death of cells in the optic nerve and
LHON lead to the specific features of LHON.
A significant percentage of people (more than 50
percent of males with a mutation and more than
85 percent of females with a mutation) with a
mutation that causes LHON do not develop any
features of the disorder.
LHON
A significant percentage of people with a mutation that causes LHON do not
develop any features of the disorder.
LHON could be a multifactorial disorder?
Environmental factors such as smoking and alcohol use may be involved, although
studies have produced conflicting results.
Researchers are also investigating whether changes in additional genes contribute
to the development of signs and symptoms.
All females with an mtDNA mutation, even those who do not have any signs or
symptoms, will pass the genetic change to their children.
Diagnosis: Molecular genetic testing of DNA extracted from a blood sample