Glossary of Terms

A

Amino acid – The ‘building blocks’ that make up proteins found in our body.

Ataxia – A lack of voluntary coordination of muscle movements which may affect balance, coordination and speech.

ATP (adenosine triphosphate) – The chemical that provides the energy used by the cells of the body.

Autosomal dominant – One copy of a faulty gene has been inherited (from the mother or the father) and caused a disease or trait.

Autosomal recessive – Two copies of a faulty gene have been inherited (usually one from the mother and one from the father) and caused a disease or trait.

B

Biomarker – A ‘biological marker’ that can be used to suggest a particular disease. Biomarkers include a broad range of medical indicators that can be accurately measured, such as pulse, blood pressure or levels of naturally occurring proteins in a blood sample.

C

Chromosomes – Thread-like structures made up of genetic information (DNA) found within the nucleus of cells. Each cell usually has 23 pairs of chromosomes.

Complexes – Components of the mitochondrial respiratory chain that are arranged into five different groups (Complex I to V).

COX (Cytochrome C Oxidase) – Complex IV of the mitochondrial respiratory chain. There are 14 COX subunits that are encoded by both the nuclear genome (11 subunits) and the mitochondrial genome (3 subunits).

Creatine kinase – An enzyme found in muscle and other tissues. It uses ATP to breakdown creatine. Patients with muscle disease often show elevated levels of CK in the blood.

CRISPR/Cas – A powerful technique that is used for gene editing.

Cristae – The folds of the inner mitochondrial membrane.

Cytoplasm – A jelly-like substance found within cells that contains many different structures, including mitochondria.

D

Deletion – Removal of a single chemical letter or a section of DNA. These deletions can occur in the nuclear DNA or the mitochondrial DNA. Mitochondrial DNA deletions are a common cause of mitochondrial disease in adult patients.

Depletion – A reduction in the amount of mitochondrial DNA within a cell or tissue. Mitochondrial DNA Depletion Syndrome (MDDS) is a group of autosomal recessive disorders that can lead to a significant reduction in the amount of mitochondrial DNA in affected tissues (e.g. muscle, liver, brain).

DNA (Deoxyribonucleic Acid) – The molecule that contains all the genetic information needed to make all living things. DNA contains four different chemicals represented by the letters A,T,C and G.

DNA sequence – The order of the chemical letters within DNA. The DNA sequence is unique to every person and makes us who we are.

Dysarthria – Difficult or unclear speech formation, usually related to changes in the brain, and not related language abilities

Dysphagia – A medical term used to describe swallowing difficulties.

Dysphasia – A language disorder due to brain disease resulting in difficulties understanding (receptive dysphasia) or putting words together (expressive dysphasia).

Dysphonia – Difficulty speaking due to physical problems with the mouth, tongue, throat or vocal cords.

Dystonia – A movement disorder that is common in mitochondrial disease. Symptoms can include uncontrolled muscle cramps, spasms and parts of the body twisting into unusual positions.

E

Electron Transport Chain (ETC) – Part of the energy chain that is responsible for generating energy within the mitochondria. The ETC is made up of four protein complexes (I-IV) that move electrons to power energy production. Complex V, also known as ATP synthase, uses the energy created by complexes I-IV to generate cellular energy in the form of ATP but is not strictly part of the ETC.

Exon – The part of your DNA sequence that contains the instruction to make a protein. A single gene can be made up of several exons separated by intervening DNA sequence that does not contain instructions to make a protein (known as an ‘intron’).

F

Fatigue – A subjective feeling of tiredness often alleviated by periods of rest.

Fibroblast – a type of connective tissue cell present in the body. Skin biopsies are often taken in order to culture fibroblasts and determine mitochondrial function.

Fibroblast Growth Factor (FGF) 21 – A metabolic hormone (protein) found in humans that may be useful as a biomarker of mitochondrial disease.

Fission – The process by which mitochondria split apart in the cell.

Free radicals – See reactive oxygen species.

Fusion – The process by which mitochondria come together in the cell.

G

Gene – Genetic ‘instructions’ within our DNA that produce the important building blocks (proteins) that make up our bodies. Genes are made up of exons and introns.

Gene editing – A technique that allows the order of the four chemical letters (A, T, C, G) that make up the DNA sequence to be changed. This can involve adding, replacing or removing a single letter or a section of DNA. The technique has the potential to correct a genetic ‘mistake’ (or mutation) within the DNA sequence that is causing a genetic disease.

Gene therapy – The introduction of normal genes into cells, to replace missing or defective ones, in order to correct a genetic disorder.

Genetic bottleneck – A process that explains how women with a mix of normal and faulty mitochondrial DNA (known as heteroplasmy) can have children with very different levels of faulty mitochondrial DNA. It happens because the number of mitochondria passed to the next generation is reduced when egg cells are being made (described as a ‘bottleneck’) meaning that some eggs may receive many copies of the faulty mitochondrial DNA and others may receive very few.

Genetic diagnosis – Identifying a mistake within a gene that is responsible for causing a genetic disease.

Genome – The complete set of genetic information needed to make and maintain all living things.

Genomics – The study of the genome. It includes investigating the order of chemical letters that make up the DNA sequence using powerful laboratory techniques.

Genotype – the set of genes carried by an individual; a mutation in a specific genotype may indicate a clinical disease.

H

Heteroplasmy / Heteroplasmic – a mix of normal and faulty mitochondrial DNA within a cell or tissue in the body.

Homoplasmy / Homoplasmic – the presence of only faulty mitochondrial DNA within a cell or tissue in the body.

I

Intron - a sequence of DNA that does not contain instructions to produce a protein and is found between exons.

L

Lactate – lactic acid (a chemical found in the body, often measured in blood or spinal fluid). Lactic acidosis is the build up of lactate in the body due to problems when the body’s metabolism. Patients with mitochondrial disease may experience lactic acidosis during times of metabolic stress e.g. illness, excessive exercise, dehydration.

Leigh Syndrome – the most common mitochondrial disease in children often associated with brain changes and developmental delay.

Leber’s Hereditary Optic Neuropathy (LHON) – a particular mitochondrial disease which is characterised by a rapid loss of sight in both eyes.

M

Maternal inheritance – Mitochondrial DNA is inherited from the mother only, referred to as ‘maternal inheritance’. This is different to nuclear DNA which is inherited from the mother and the father.

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) – the most common mitochondrial disease caused by a mutation in mitochondrial DNA.

Metabolic disorder – A condition that disrupts the normal process of making energy from the food we eat due to abnormal chemical reactions in the body.

Metabolism – Normal chemical processes that occur within the body in order to maintain life, such as energy production.

Metabolites – A substance that is formed during, or is necessary for, metabolism.

Metabolomics – The study of different metabolites found within the body.

MERRF (Myoclonic Epilepsy with Ragged Red Fibres) – A particular mitochondrial disease caused by a mutation in mitochondrial DNA.

Migraine – A recurring headache with associated sensory disturbances.

Mitochondria – Small structures found in nearly every cell of the body that have an important role in energy production.

Mitochondrial biogenesis – The production of new mitochondria within a cell.

Mitochondrial disease – A term that covers a wide range of different diseases characterised by faulty mitochondria.

Mitochondrial DNA (mtDNA) – The DNA found within mitochondria that contains 37 genes needed for the mitochondria to function. This is separate to the nuclear DNA, which contains the majority of genes needed for mitochondrial function. Genetic ‘mistakes’ (mutations) in the mtDNA can result in mitochondrial DNA disease.

Mitochondrial DNA disease - a term that covers a wide range of different diseases characterised by faulty mitochondria when the genetic mistake is found within the mtDNA.

Mitochondrial donation – An IVF-based treatment that can prevent mitochondrial DNA disease being passed from a mother to her child.

Mitochondrial dysfunction – A term used to describe faulty mitochondria, or mitochondria that are not working properly.

Mitochondrial membrane – Mitochondria consist of two mitochondrial membranes: the outer layer that surrounds the mitochondria and the inner layer within the mitochondria. The inner mitochondrial membrane is highly folded and is the site of energy production.

Mitochondrial respiratory chain - The complete energy chain (complexes I-V) that is responsible for generating energy within the mitochondria.

Muscle biopsy – A procedure that involves removing a small sample of muscle to help investigate or diagnose a mitochondrial disease.

Mutation – A genetic ‘mistake’ within the DNA sequence that can cause genetic disease.

Mutation load - The level of faulty mitochondrial DNA found within a cell or tissue. This is often expressed as a percentage.

Myopathy – A medical term used to describe muscle disease.

N

Neuropathy – Damage to the nerves. Peripheral neuropathy often causes numbness in your hands and/or feet, and can cause both weakness and pain.

Next generation sequencing (NGS) – A modern and highly sensitive genomic technique that allows the entire DNA sequence to be determined.

Nuclear DNA – Genetic information found in the nucleus of the cell that contains ~20,000 genes and determines characteristics such as height, eye colour etc. The majority of genes required for the mitochondria to function are found in the nuclear DNA (also known as the nuclear genome).

Nucleus – The part of the cell that contains the nuclear DNA and controls how the cell behaves.

O

Oocyte – Another word for an egg cell.

Ophthalmoplegia – Weakness or paralysis of one or more of the muscles within or around the eye responsible for eye movements.

Optic atrophy – A sign of damage to the optic nerve (the nerve which carries signals from the eye to the brain) which may result in visual loss. On examination, the back of the eye (optic disc) appears pale.

Oxidative phosphorylation – The biochemical process that takes place in the mitochondria and produces ATP.

Oxidative damage - Damage to cells when there are high levels of reactive oxygen species. This damage may contribute to some of the symptoms of mitochondrial disease.

P

Pathogenic – Disease-causing.

Phenotype – A set of physical characteristics or traits resulting from inherited genes.

Point mutation – A change in a single chemical letter of the DNA. These changes can occur in the nuclear DNA or the mitochondrial DNA and can both cause mitochondrial disease.

Preimplantation genetic diagnosis (PGD) – an IVF-based technique that involves testing early embryos in the lab to identify an embryo with a low risk of mitochondrial disease that can be transferred to the womb to try and establish a pregnancy.

Prenatal testing – A test performed on cells taken from an early pregnancy to determine the risk of mitochondrial disease in the developing baby.

Protein – The ‘building blocks’ that make up our body and are an essential part of all living things. Proteins are made of amino acids (see above) and the instructions to make these proteins are found within our DNA.

Proteomics – The study of proteins produced in the body.

Ptosis – Drooping (falling) of the upper eyelid which can happen in one or both eyes.

R

Reactive oxygen species (ROS) – Damaging chemicals that are produced by the mitochondria during normal energy production. These reactive oxygen species, also known as free radicals, may be found at higher levels within cells when the mitochondria don’t work properly.

Rearrangements – Partial deletions and partial duplications of mtDNA.

Respiratory chain complexes – see Complexes.

Ribonucleic acid (RNA) – A molecule that is very similar to DNA and is present in all living cells. Its main role is to act as a messenger and copy instructions contained in the DNA which can then be made into a protein.

S

Seizure – Sudden, abnormal electrical activity in the brain causing abnormal movements, loss of awareness or loss of consciousness.

Splicing – A molecular process in which introns are removed and exons are joined together.

Stem cell – A cell which is capable of giving rise to more cells that are the same or can become different cells of the body.

Stroke-like episode – An evolving neurological event occurring at any age, driven by seizure activity and supported by evidence of EEG and MRI brain changes. These episodes are most commonly associated with the m.3243A>G mutation and POLG.

T

Threshold effect – The level of faulty mitochondria (or 'mutation load') that must be reached within a cell or tissue for the clinical symptoms of mitochondrial DNA disease to occur. This can vary for mitochondrial DNA diseases caused by different genetic mistakes in the mtDNA, but usually ranges from 60-90% mutation.

Transcription – The process by which DNA is copied into RNA.

Transcriptomics – the study of RNA which is produced by the genome.

Translation – The process by which RNA is used to make protein.

W

Whole exome sequencing (WES) – A form of next generation sequencing that allows specific genes within the DNA to be sequenced.

Wild-type – The naturally occurring version of a gene that does not contain a mutation.

Z

Zygote – An egg just after it has been fertilised and before it divides into two cells.