Glossary
3243A>G
This is one of the commonest point mutations in mitochondrial DNA and is associated with several different clinical presentations. The adenine (A) base is substituted with a guanine (G) base at position 3243.
8344A>G
A common mitochondrial DNA point mutation associated with a specific syndrome of myoclonic epilepsy and ragged red fibres (evident on muscle biopsy). An adenine (A) base is substituted with a guanine (G) base at position 8344
8993T>G/C
This substitution of guanine (G) or cytosine (C) for thymidine (T) at position 8993 in the ATPase 6 gene is a cause of NARP and Maternally Inherited Leigh Syndrome (MILS).
9176T>G/C
This is a substitution of guanine (G) or cytosine (C) for thymidine (T) at position 9176 in the ATPase 6 gene. This mutation has been associated with Leigh disease and bilateral striatal necrosis in children.
Adenosine Triphosphate (ATP)
A ubiquitous source of energy for cells, this compound is produced by a number of biochemical pathways in body tissues, but most importantly by ‘burning’ carbohydrates in the mitochondrial respiratory chain.
Alanine
This is an amino acid that is sometimes found at higher levels than usual in the blood and urine of patients with mitochondrial diseases.
Alpers’ (Alpers -Huttenlocher’s) disease
A disease frequently associated with depletion of mitochondrial DNA in liver and brain. Named after Dr Alpers’ the physician who first described the explosive onset of seizures followed neurodegeneration and liver failure. Mutations in DGOUK and POLG1 genes have been identified but do not explain all cases.
Amniocentesis
This describes a needle aspiration of amniotic fluid usually taken after 13 -16 weeks of pregnancy. DNA can be extracted from fetal cells floating in the amniotic fluid aspirate and analysed for known mutations.
ANT1
Adenine nucleotide transporter gene. Adenine is one of the building blocks of DNA and if supply is inadequate then ‘faulty’ DNA is produced. The adenine nucleotide transporter ensures the correct amount of adenine is available for DNA synthesis.
Anticonvulsant
A drug used to treat epileptic seizures.
Ataxia
This is a medical term for unsteadiness and may be due to impaired sensation in the feet (sensory ataxia) or disease in a part of the brain called the cerebellum (cerebellar ataxia).
ATPase genes
These mitochondrial DNA genes encode 2 subunits of the enzyme ATPase (Complex V) which utilises the proton gradient generated by the mitochondrial respiratory chain to form ATP.
Audiology
The scientific study of hearing, especially for the diagnosis and treatment of hearing defects.
Autosomal dominant
This describes the pattern of inheritance observed where a mutation need only be present in one copy of two inherited genes to cause disease.
Autosomal recessive
This describes the pattern of inheritance observed where a mutation must be present on both copies of two inherited genes for disease to occur.
Biochemical defect
This refers to the individual tests of function performed on mitochondria isolated from muscle. The defect referred to may be isolated to one complex (most commonly complex I) or involve multiple complexes.
Cardiomyopathy
A weakness of heart muscle leading to impaired function.
Cerebrospinal fluid (CSF)
This is the nutrient containing fluid that bathes the brain and spinal cord. Sampling of this fluid by lumbar puncture can be useful in the diagnosis of mitochondrial disease, particularly in children.
Chorionic Villous Biopsy (Sample)
A biopsy of tissue derived from the developing fetus taken after 9-12 weeks of pregnancy. Fetal DNA can be extracted from these cells and analysed for known mitochondrial DNA mutations. It is also possible for the cells to be cultured and analysed biochemically although considerable caution must be employed when interpreting these results.
Chromosome
One of 23 pairs of rod-like structures found in the cell nucleus and housing all of the nuclear genetic material
Chronic Progressive External Ophthalmoplegia (CPEO / CPEO +)
A longstanding impairment of eye movement in all directions, although there may often be relative sparing of downgaze.
Complex V
This enzyme facilitates the final step in the conversion of energy from foodstuffs into ATP. It consists of two major subunits and its structure is partly encoded in mitochondrial DNA (ATPase genes).
Computed Tomography (CT) scan
An X-ray based scan composed of multiple individual images. In many respects this type of scan has been superseded by magnetic resonance imaging.
Dementia
A degenerative process affecting higher brain function including memory and thought processing.
Developmental delay / regression
Failure to reach expected motor, social, visual or language skills, or in the case of regression to have previously attained these skills then lost one or more of them.
DGOUK
Mutations in the deoxyguanosine kinase gene cause a form of mitochondrial DNA depletion affecting brain and liver.
Diabetes
A disorder of glucose metabolism caused by either insufficiency of the regulatory hormone insulin (Type I) or resistance to its action (Type II).
Diabetes and Deafness
The association of these two conditions is one of the ways in which the 3243A>G mutation manifests disease.
Dietician
A healthcare professional who has received specialist training regarding diet and nutrition in relation to health and disease.
DNA
Deoxyribonucleic acid. This is a double-stranded helix of bases (adenine, guanine, cytosine and thymidine) that encodes our genetic blueprint, i.e. the information needed to make and maintain us.
DVLA
The Driver and Vehicle Licensing Agency an executive agency of the Department of Transport (UK Govt)
Echocardiogram (ECHO)
An ultrasound technique used to image the heart.
Electrocardiogram (ECG)
A recording of the electrical activity of the heart from leads applied across the chest wall.
Electroencephalogram (EEG)
A recording of brainwave activity obtained from electrodes applied to the surface of the scalp.
Embryo
The early stages of fetal growth from conception to the eighth week of pregnancy
Encephalomyopathic
A descriptive term for a disease process affecting both brain and muscle function so that sufferers may have both impaired awareness and muscle weakness.
Encephalopathy
A description of the impaired awareness, arousal or thought processing associated with many brain disorders including mitochondrial disease.
Epilepsy
A chronic neurological condition characterised by recurrent epileptic seizures
Epileptic seizures
Manifestation(s) of abnormal, usually excessive and self-limiting, activity of neurons in the brain. Epileptic seizures are common in some forms of mitochondrial disease, being particularly associated with MELAS and MERRF. Different types of seizure occur, some affecting part of the brain, some affecting the whole brain at once. They are treated with anti-epileptic drugs the same way as other patients with epilepsy.
Gene
A working subunit of DNA that contains the code for a specific product (this is usually a protein).
General Anaesthetic (GA)
A form of deep anaesthesia where the patient is rendered unconscious and is often employed for major surgical procedures.
Generalised Tonic-Clonic Seizures (GTCS)
An epileptic seizure with initial involvement of large areas of both halves of the brain.
Hepatocerebral
A process involving the liver and brain
Heteroplasmy
This term describes the situation where two (or more) different types of mitochondrial DNA coexist in the same cell or tissue.
Homoplasmy
A term used to describe the presence of only one type of mitochondrial DNA in all cells or in a whole tissue. This may be either wild-type or mutated mitochondrial DNA.
Insulin
A hormone produced by the pancreas and involved in the control of metabolism. In particular, insulin regulates the availability and storage of glucose. Diabetic patients may have to administer manufactured insulin several times each day.
Irritable Bowel Syndrome (IBS)
A condition characterised by alternating constipation, bloatedness, cramping abdominal pain and diarrhoea. This disorder is common in the general population and affects women more often than men.
In-vitro fertilisation (IVF)
This is the process of producing “test-tube babies” where the egg and sperm are brought together outside of the body and then re-introduced to the womb.
Kearns-Sayre Syndrome (KSS)
A disease that appears before the age of 20 years. It is characterised by progressive difficulty in moving the eyes, build up of pigment at the back of the eye, short stature and heart problems. It is usually caused by a large deletion or rearrangement of mitochondrial DNA.
Lactic acid (Lactate)
A chemical that builds up in cells when there is not enough oxygen to fully burn food energy. The burning pain that you feel in your muscles after a long sprint is because of lactic acid building up. Patients with mitochondrial disease produce more lactic acid than normal and hence tend to suffer muscle pain after less intense exercise.
Lactic acidosis
Lactic acid can leak into the blood making it more acidic. This has many effects including stimulating breathing in an attempt to get rid of the extra acid. Severe lactic acidosis can affect heart, liver and kidney function and can be dangerous.
Lamotrigine
A commonly used drug for the treatment of epilepsy
L-Arginine
An amino acid that helps blood vessels to relax. It has been tried as a treatment of stroke-like episodes. The idea is that these are caused when blood vessels in part of the brain narrow down and stop blood flowing. By giving L-arginine the hope is that these vessels will relax and restore the blood flow. At present this remains an experimental treatment and the results of clinical trials are not clear-cut.
Laxatives
These drugs encourage regular bowel evacuation.
Leber’s Hereditary Optic Neuropathy LHON
This is the commonest of the mitochondrial diseases. The disease primarily affects the optic nerves. Patients usually first notice problems with their vision in their twenties or thirties. The first symptoms are of blurring of central vision and loss of colour vision. Both eyes are usually affected. Eventually vision may be limited to being able to make out rough shapes or to count fingers only
Leigh disease (syndrome)
A severe form of mitochondrial disease that usually comes on in the first two years of life. The first signs are often the loss of motor skills, such as sucking and head control. Patients can also be irritable and have poor appetite with frequent vomiting.
The disease usually progresses over the next few years to include muscle weakness and episodes of lactic acidosis. Unfortunately, most patients die before reaching their teens, although a few cases have come on later and survived longer.
Levetiracetam
This newer anticonvulsant is now widely used in the treatment of epilepsy
Lipoma
A lump of fat storing cells found just under the skin. Rarely, patients with MERRF can develop multiple lipomas (Ekboms syndrome). These tend to grow slowly but can cause cosmetic problems.
Liver failure
The liver is crucial for making the proteins found in the blood and for breaking down waste products. It can be involved in mitochondrial disease, and if severely affected can be fatal.
Lumbar puncture
The brain and spinal cord sit in a fluid called cerebrospinal fluid. As this fluid surrounds the brain its composition gives important clues as to how the brain is functioning. A lumbar puncture involves placing a small needle under local anaesthetic into the small of the back in order to collect a very small volume of this fluid.
Magnetic Resonance Imaging (MRI) scan
A technique that produces highly detailed pictures of any part of the body. It involves lying still on a table that slides into a big doughnut shaped machine. The scan takes several minutes and can be quite claustrophobic. Because the scan uses very powerful magnets to produce the images it is very important that you tell the doctors if you have anything metal inside you. For example, cardiac pacemakers and some forms of surgical clips are not safe and if in doubt you should ask.
Maternal inheritance
This describes the situation where a genetic condition is passed on exclusively from mother to child.
MELAS
See text in relevant section.
MERRF
See text in relevant section.
Metformin
A drug used in the treatment of diabetes. Rarely it can cause lactic acidosis, and as this is also a potential problem in mitochondrial disease, this drug should be used with caution.
Mitochondria
Mitochondria are found in virtually every cell in the body. They are central to the conversion of food energy into ATP, which the cell then uses to power everything that it does.
Mitochondrial bottleneck (hyperlink to figure)
Eggs are formed from precursor cells in the mothers’ ovaries. In a mother carrying a heteroplasmic mtDNA mutation there will be a percentage of normal and abnormal mitochondria throughout her body, including in these precursor cells. The exact proportion will vary slightly between cells, but let’s say overall there is a 50:50 mix in the mother. Only a small fraction of the mitochondria present in the precursor cell survive in the egg. Let’s say for example that only ten survive, and by chance eight of these contain abnormal mtDNA. If that egg is fertilised, this high proportion of abnormal mitochondria will be passed on to the child. In this case, the child will be more severely affected than the mother. On the other hand, only one of the ten surviving mitochondria in another egg may be affected, in which case the child will be very mildly affected. We do not understand what controls the proportion of normal vs abnormal mtDNA in the egg and all of this means that it is very difficult to predict how a child will be affected, even if we know precisely what proportion of abnormal mtDNA the mother has.
Mitochondrial diseases
A broad group of diseases caused by abnormalities in both mitochondrial DNA and nuclear DNA. Most are inherited, but many arise for the first time in individuals.
Mitochondrial DNA (mtDNA)
A circular molecule of DNA which codes for several of the proteins found in mitochondria. Each mitochondrion contains several copies of mitochondrial DNA.
Mitochondrial myopathy
A weakness of muscles specifically due to mitochondrial dysfunction. This usually affects the large muscles around the hips and shoulders. See proximal myopathy.
Mitochondrial Respiratory Chain
Mitochondria convert food energy into ATP. To do this they use a series of enzymes called the mitochondrial respiratory chain. These pass food molecules one to the next and gradually extract the energy contained in them. Several mitochondrial diseases affect one or more members of the respiratory chain, reducing the ability of the mitochondria to work.
Muscle biopsy
Muscle cells are commonly affected in mitochondrial disease and as they are very rich in mitochondria they are a useful tissue to study. To do this a small piece of muscle is removed, usually from the thigh. In adult patients this is done under local anaesthetic and leaves only a very small scar on the leg. In children a general anaesthetic is preferred and an ‘open’ biopsy is performed by a paediatric surgeon. The scar from this procedure is also small. The piece of tissue removed (the biopsy) is then analysed in the lab to help with diagnosis.
Mutation
A change in the DNA sequence. It can refer to either the DNA in the cell nucleus or within the mitochondria. Usually it means that just one base pair (the building blocks of DNA) is changed, but it can also be used when large chunks of DNA are missing.
Myoclonic epilepsy
Forms of epilepsy in which myoclonic jerks are common, often along with other types of seizure.
Myoclonus
A sudden jerk of the muscles caused by cells in the brain or spinal cord firing off suddenly. Sometimes the whole body is affected and can be so severe as to cause the patient to fall over. They are a form of epileptic seizure and frequently occur in patients with MERRF.
Myopathy / Myopathic
Myopathy means disease of the muscles, usually causing weakness. Sometimes specific features of these diseases can be detected by electromyography and these changes are called myopathic.
Nerve conduction studies
These involve giving small electric shocks to the nerves in the hands and feet. The tests are a bit painful but give useful information on how well the nerves are responding.
Neuropathy
Damage to nerves in the arms and legs. Usually patients feel numbness and tingling in the hands and feet first, which can gradually spread to affect more central parts of the body.
Nuclear DNA
All cells in the body contain two sets of chromosomes housed in the nucleus. These control nearly all of the workings of the cell, the only exception being those that are controlled by the mitochondrial DNA.
Oocyte
The precursor cells in a womans’ ovaries from which her eggs develop.
Ophthalmoplegia
An inability to move the eyes in their sockets.
Optic nerve
The main nerve that travels from the eye to the brain and carries visual information.
Pearson’s syndrome
A disease of early childhood characterised by severe anaemia with failure of the pancreas. Patients often die within the first few years of life.
Percutaneous endoscopically-guided gastrostomy (PEG)
In patients who are unable to swallow safely it is sometimes necessary to use a PEG tube. This is a very fine tube that is pushed through the skin of the abdomen into the stomach. Liquid food can then be slowly passed through this tube directly into the stomach. Patients can continue to eat small amounts but the extra feed helps to maintain the body’s nutritional needs.
Point mutation
A single base pair change in either the nuclear or mitochondrial DNA molecules.
POLG1
A nuclear encoded enzyme involved in the repair of mitochondrial DNA. Patients usually develop an ophthalmoplegia and ptosis, but numerous other features have also been associated with mutations in this gene including Alpers’ disease.
Progressive Neuronal Degeneration of Childhood (PNDC)
A very severe mitochondrial disease that occurs in childhood. Also known as Alpers’ syndrome. Characterised by severe epileptic seizures, developmental delay and liver failure. Autosomal recessive inheritance.
Proximal myopathy
Weakness of the muscles around the shoulders and hips. This is the commonest pattern of muscle involvement in mitochondrial disease.
Ptosis
Drooping of the eyelids. Sometimes this is so severe as to cover the eye completely, in which case surgery may be needed to lift the eyelid back up again.
Riboflavine
A vitamin sometimes given to children with mitochondrial disease in an attempt to improve mitochondrial function. No large-scale trials have been conducted to demonstrate benefit.
Single deletion
Means that one particular piece of the mitochondrial DNA is missing.
Sodium Valproate
An anti-epileptic drug commonly used in children. It can very occasionally affect the liver and lead to lactic acidosis. As this is also a potential problem in mitochondrial disease sodium valproate should be used with caution in this group of patients.
Speech and language therapy
Health care professionals who specialise in the treatment of speech and swallowing problems.
Sporadic
Means that a change in the DNA has arisen for the first time in an individual, usually in the very early stages of development. This means that neither of the parents will be affected, nor will brothers or sisters of the patient. However, it is possible that the change will be passed on to children of the patient, depending on the nature of the mutation.
Stroke-like episode
Patients with MELAS are prone to stroke-like episodes. These often occur as a result of an infection and may start with a headache. This can then progress over several hours to weakness affecting the body. This can look similar to a stroke, but thankfully the weakness usually recovers more quickly. No specific treatment exists but it is important to keep well hydrated and to treat any other problems that may arise such as seizures. Patients who have many stroke-like episodes can suffer permanent disability.
SUCLA2
A nuclear encoded protein involved in the generation of ATP in mitochondria. Patients with mutations in this gene are usually affected by two years of age and show poor muscle strength and deafness. Autosomal recessive inheritance.
Thiamine
This is also known as vitamin B1 and is sometimes prescribed for children with mitochondrial disease, particularly those with pyruvate dehydrogenase deficiency where there has been some evidence of response to treatment.
Thymidine Phosphorylase
This is an enzyme. Mutations in this nuclear gene cause MNGIE
TK2
The thymidine kinase 2 gene is nuclear encoded and mutations are associated with depletion of mitochondrial DNA in muscle. The resulting clinical picture is one of myopathy in early childhood that progresses to involve respiratory muscles leading to severe breathing difficulties.
Trials
Formal and strictly controlled studies of a particular therapy (usually a drug) that involves both control and test groups of participants. The best trials are ‘double-blind’, where neither the person administering the drug nor the person taking it knows if it is placebo (fake) or active drug. A third person knows the code that will allow this to be discerned later.
Twinkle
The protein product of this nuclear gene is involved in mitochondrial DNA maintenance and mutations in the gene lead to multiple mitochondrial DNA deletions.
Ubiquinone
This compound is also known as co-enzyme Q10 (CoQ10). It is a key component of the mitochondrial respiratory chain and a frequently purchased vitamin supplement. However, evidence for its effectiveness in mitochondrial disorders is lacking. In one specific and very rare condition, ubiquinone deficiency, successful treatment has been possible with large replacement doses.
Valproic Acid
This is an alternative name for sodium valproate (see above).
Videofluoroscopy
This is an X-ray based imaging technique that allows speech and language therapists to assess swallowing.
Vitamins
The role of supplementary vitamins in the treatment of mitochondrial disease remains unproven.
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