What is Mitochondrial
Disease?
Mitochondrial Disease is the name for a group of conditions due
to any failure in the mitochondria of the body’s cells, which affects 1 in every
6,500 babies born. Generally the disease affects children under the age of 10
years old, but adult onset types of mitochondrial disease are becoming more
common. In people with mitochondrial disease, not enough energy in the form of ATP
(chemical energy in the body)is produced by the mitochondria, the body’s cells
do not have enough energy to carry out life processes, leading to cell damage
and death.
Mitochondria are organelles within the cells of the body
(except red blood cells) and are the site of cellular respiration. Respiration is
the metabolic process by which glucose, obtained from our food, and oxygen,
obtained from the air, are combined to give energy in the form of ATP (with
waste products of carbon dioxide and water). Mitochondria contain their own DNA
and can replicate independently of the cell. ATP is used to provide energy for metabolism
(reactions in the body), and so mitochondria provide 90% of the energy that the
body needs to survive. Also, mitochondria are responsible for breaking down,
building and recycling molecules; are involved in cell signalling; control cell
division, cell growth and programmed cell death(apoptosis). Additionally,
mitochondria are involved in specific processes related to the type of tissue cell
in which they reside, such as: cholesterol metabolism in the adrenal glands and
sex organs (to make steroid hormones such as testosterone and oestrogen); heme
synthesis in the bone marrow (to make the protein haemoglobin used to carry
oxygen in red blood cells) and detoxifying ammonia in the liver. Therefore,
mitochondrial disease may affect the other processes carried out by the
mitochondria not simply energy production, and may be tissue-specific (although,
generally, 3 or more organs are involved in mitochondrial disease).
Around 3000 genes are involved in building a mitochondrion (37
of which are encoded by genes in mitochondrial DNA, with the other being from
the nuclear DNA found in the cell’s nucleus). Mitochondrial DNA is inherited only
from the mother as egg cells, but not sperm cells, contribute to the
mitochondria of a developing embryo. Mitochondrial disease is a result of mutations
(inherited or spontaneous changes) in the genes that code for the proteins used
in mitochondria production and function. Mitochondria can be damaged by drugs
and infections. Mitochondrial disease may only have visible symptoms once the
number of affected mitochondria reaches a threshold level.
What are the types of
Mitochondrial Disease and their symptoms?
There are innumerable types of mitochondrial disease because
of the vast number of genes that are involved in mitochondrial production, and
even identical mutations will not cause the same clinical symptoms (we call
these diseases genocopies). It should be noted that conversely different
mutations could have the same symptoms (phenocopies). This means that
mitochondrial disease is often misdiagnosed.
Mild mitochondrial disease may result in exercise
intolerance as suffers cannot respire as effectively to provide the energy
needed. People with mitochondrial disease are at a high risk during and
following an illness or infection and so must be treated with a course of
antibiotics, keep up to date with vaccinations (often advised to be vaccinated
against seasonal flu) and may require IV fluids when ill. This is because
overcome an illness and stimulating an immune response, which requires a lot of
energy, and due to weakened systems, infection can lead to further neurological
or organ damage. Muscular dystrophy is often a symptom of mitochondrial
diseases. The conditions are degenerative and can often develop into dementia
or organ failure.
Some examples of mitochondrial disease include:
MELAS
(Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome) is
caused by mitochondrial DNA mutations (often the A3243G mutation)preventing the
formation of NADH, therefore preventing aerobic respiration. It can affect
either sex, but is inherited solely from the mother. Symptoms of MELAS (including
muscle pain or weakness, vomiting, seizures and loss of appetite)often appear
in childhood, with stroke-like symptoms (periods of weakness on one side of the
body, loss of consciousness, migraine-like headaches, seizures and problems
with vision) occurring before the age of 40. Encephalomyopathy refers to th
fact that MELAS affects both the brain and muscle tissue. Due to anaerobic
respiration (where less oxygen is used) lactic acid can build up in the blood,
leading to lactic acidosis, causing vomiting, pain, fatigue, difficulty
breathing, loss of bowel control and muscle weakness. People with MELAS may
also have involuntary muscle spasms or impaired muscle coordination (ataxia).
MERRF (Myoclonic
epilepsy and ragged-red fibers) is also caused by mutations in mitochondrial
DNA preventing the formation of proteins used in the RNA that carries the amino
acid lysine, so prevents the building of proteins in the mitochondria which are
used in respiration. Myoclonic epilepsy involves brief involuntary muscle
twitching that is frequent enough to be disabling. Ragged-red fibers refer to
when clumps of diseased mitochondria build up in muscle tissue and appear red
when stained with Gömöri trichrome stain (see image). Other symptoms of MERRF include
lactic acidosis, hearing loss, short stature and exercise intolerance.
KSS (Kearns-Sayre
syndrome) is caused by large deletions of mitochondrial DNA and so usually
mutations are caused by environmental factors and are not inherited, although
the average onset is below the age of 20. Typically KSS effects the eyesand
involves: drooping of the eyelids (ptosis); paralysis of eye muscles (CPEO/chronic
progressive external opthalmoparesis); degeneration of the retina (and so
inability to see in the dark) and abnormal accumulation of eye pigments (pigmentary
retinopathy). Other symptoms include diabetes mellitus, deafness, ataxia and
problems with electrical conduction in the heart (heart block) causing palpitations
and fainting.
LHON (Leber’s
hereditary optic neuropathy) is a caused by a mutation at one of three points
in mitochondrial DNA (11778, 3460 or 14484) and so is passed from mother to all
of her offspring. The condition is most common in men aged around 20. The condition
causes cell damage and death to optic nerve cells. Symptoms include blurriness
in one eye, leading to loss of vision in that eye, followed by the same in the
other eye, usually within the same year.
MNGIE
(Myoneurogenic gastrointestinal encephalopathy) is caused by a mutation in the TYMP
gene and often occurs in adults under 50. The mutation prevents the formation
of an enzyme used in metabolising (breaking down) parts of nucleic acids (e.g.
DNA nucleotides). IN MNGIE pseudo-obstruction of the gut causes peristalsis (contractions
of the gastrointestinal tract) to be less efficient, so less food is absorbed.
Diarrhoea, constipation, vomiting, GI tract paralysis, weight loss, damage to
the peripheral nerves and dysfunctional growth of the white matter of the brain
are common symptoms of MNGIE.
Maternally inherited mutations in mitochondrial DNA (ATP6
gene) affect the production of ATP synthetase which is the enzyme used in
making ATP, so reduce the energy available to cells, and cause the conditions NARP (Neuropathy, ataxia, retinitis
pigmentosa)and Leigh syndrome. In
NARP, 70-90% of mitochondria are affected and have the abnormal gene and symptoms
include: sensory neuropathy/numbness and pain in the limbs; muscle weakness;
problems with balance and co-ordination (ataxia); vision loss due to
deterioration of light sensing cells of the retina (retinitis pigmentosa) and
learning disabilities or developmental delays. Leigh syndrome occurs when
90-95% of mitochondrial DNA has the mutation of ATP6, but can also be caused by
mutations of the nuclear DNA of the cell containing the mitochondria (SURF1 and
COX assembly factors). Leigh’s disease usually affects infants (below 2 years
old). In Leigh syndrome, loss of mitochondrial function causes lack of energy
which occurs in cells of the brain stem (responsible for regulating the central
nervous system and the action of the heart and lungs) and basal ganglia
(responsible for motor control and learned behaviours). Loss of motor control,
seizures, vomiting, heart problems, muscle weakness and lactic acidosis are
common symptoms.
How do we currently
treat Mitochondrial Disease?
The prognosis for severe manifestations of mitochondrial
disease is poor, and most people who develop conditions as children do not survive
to adulthood. We do not have a cure for mitochondrial disease, but therapies
and treatments for the symptoms can help to extend life, prevent further damage
to the body or improve quality of life. Unfortunately in more severe cases,
treatment is rarely effective. Physical therapy for motor problems,
anti-epilepsy drugs for seizures, insulin injections for diabetes and ophthalmic
surgery for vision problems are examples of useful treatments to improve alleviate
symptoms. To avoid fatigue and weight loss it may be useful for suffers to have
a diet with regular nutrition (for example eating just before going to bed or in
the middle of the night) and IV feeding if they become ill. Similarly sufferers
should avoid getting too hot or cold, as poor thermoregulation is often
associated with the condition. Iron can generate free radicals which can cause
mitochondrial damage and DNA mutations so should not be supplemented. Alcohol
can speed up the progression of some conditions of the mitochondria and carbon
monoxide in cigarette smoke limits oxygen carrying capacity of the blood so
leads to anaerobic respiration and potentially lactic acidosis. Supplements
such as cofactor Q10 can be effective in improving mitochondria function.
What is three parent IVF and why has the government approved it?
Three parent IVF is an artificial reproductive technique
known as ooplasmic transfer where the
nuclear DNA of the mother (a carrier of mitochondrial disease due to mutations
in mitochondrial DNA) is inserted into the empty nucleus of a donor egg (with
healthy mitochondria) and fertilised with the father’s sperm outside of the
body, or the fused nuclei (and so genetic material) of the two parents is
inserted into the nuclei of the donor egg immediately after fertilisation. This
technique will prevent the inheritance of mutations in mitochondrial DNA which is
solely passed on by the mother. Therefore the child will have “three parents”
as around 1% of the child’s DNA (that in the mitochondria) will be that of the
egg donor.
This promising treatment provides hope to prospective mothers
who carry mitochondrial disease, but for those currently living with
mitochondrial disease, we are yet to find effective treatment.
New Scientist 23rd March 2013
