Leigh's disease
Encyclopedia
Leigh's disease, also known as Subacute Necrotizing Encephalomyelopathy (SNEM), is a rare neurometabolic disorder that affects the central nervous system
. It is named after Denis Archibald Leigh, a British psychiatrist
who first described the condition in 1951.
s in mitochondrial DNA
(mtDNA) or in nuclear DNA
(gene SURF1
and some COX
assembly factors) cause degradation of motor skills and eventually death.
Mitochondria are an essential organelle
in eukaryotic
cells. Their function is to convert the potential energy of glucose
, amino acid
s, and fatty acid
s into adenosine triphosphate
(ATP). Mitochondria carry their own DNA
, called mitochondrial DNA [mtDNA]. The information stored in the mtDNA is used to produce several of the enzyme
s essential to the production of ATP.
Mutations in the mtDNA can cause mitochondria to fail or to function improperly. In the case of Leigh's disease, crucial cells in the brain stem
have mutated mtDNA, creating poorly functioning mitochondria. This causes a chronic lack of energy in the cells, which, in turn, affects the central nervous system and inhibits motor functions.
, occurring in 19 patients, was the most common movement disorder. The dystonia was usually multifocal at onset and showed progression in six patients. Rigidity, tremor, chorea, hypokinesia, myoclonus, and tics were also noted (Macaya et al.). As it progresses rapidly, the earliest signs may be poor sucking ability and loss of head control and motor skills. Other symptoms include loss of appetite, vomiting, irritability, continuous crying (in infants), and seizures. A later sign can also be episodes of lactic acidosis
, which can lead to impairment of respiratory and kidney function. Some children can present with loss of development skills or developmental regression and have often had investigations for failure to thrive. As the disease progresses in adults, it may also cause general weakness, kidney failure, and heart problems. Life expectancy is usually about a year within the onset of symptoms although both acute fulminating illness of a few days and prolonged survival have been reported.
may be recommended. Adults may have puffiness or swelling of the eye area and the hands. It is currently treated with thiamin (vitamin B1), but even with treatment, infants rarely live longer than two or three years after the onset of the disease. In cases of older people, the disease takes longer, but is still almost always fatal.
enzyme
s (which are on both the mtDNA and the nuclear DNA). The X-linked Leigh's disease is a mutation of a gene encoding PDHA1, part of the pyruvate dehydrogenase complex, located on the X chromosome
.
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. It is named after Denis Archibald Leigh, a British psychiatrist
Psychiatrist
A psychiatrist is a physician who specializes in the diagnosis and treatment of mental disorders. All psychiatrists are trained in diagnostic evaluation and in psychotherapy...
who first described the condition in 1951.
Causes
It is an inherited disorder that usually affects infants between the age of three months and two years, but, in rare cases, teenagers and adults as well. In the case of the disease, mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
(mtDNA) or in nuclear DNA
Nuclear DNA
Nuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
(gene SURF1
SURF1
Surfeit locus protein 1 is a protein that in humans is encoded by the SURF1 gene.-Further reading:...
and some COX
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
assembly factors) cause degradation of motor skills and eventually death.
Mitochondria are an essential organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
in eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cells. Their function is to convert the potential energy of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
, amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, and fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s into adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP). Mitochondria carry their own DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, called mitochondrial DNA [mtDNA]. The information stored in the mtDNA is used to produce several of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s essential to the production of ATP.
Mutations in the mtDNA can cause mitochondria to fail or to function improperly. In the case of Leigh's disease, crucial cells in the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
have mutated mtDNA, creating poorly functioning mitochondria. This causes a chronic lack of energy in the cells, which, in turn, affects the central nervous system and inhibits motor functions.
Signs and Symptoms
The disease is characterized by movement disorders. In one case review, 22 of 34 patients had evidence of a movement disorder. DystoniaDystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
, occurring in 19 patients, was the most common movement disorder. The dystonia was usually multifocal at onset and showed progression in six patients. Rigidity, tremor, chorea, hypokinesia, myoclonus, and tics were also noted (Macaya et al.). As it progresses rapidly, the earliest signs may be poor sucking ability and loss of head control and motor skills. Other symptoms include loss of appetite, vomiting, irritability, continuous crying (in infants), and seizures. A later sign can also be episodes of lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
, which can lead to impairment of respiratory and kidney function. Some children can present with loss of development skills or developmental regression and have often had investigations for failure to thrive. As the disease progresses in adults, it may also cause general weakness, kidney failure, and heart problems. Life expectancy is usually about a year within the onset of symptoms although both acute fulminating illness of a few days and prolonged survival have been reported.
Treatment
Leigh's disease is an extremely rare disorder. There is currently no cure or effective treatment. A high-fat, low-carbohydrate dietLow-carbohydrate diet
Low-carbohydrate diets or low-carb diets are dietary programs that restrict carbohydrate consumption usually for weight control or for the treatment of obesity. Foods high in digestible carbohydrates are limited or replaced with foods containing a higher percentage of proteins and fats...
may be recommended. Adults may have puffiness or swelling of the eye area and the hands. It is currently treated with thiamin (vitamin B1), but even with treatment, infants rarely live longer than two or three years after the onset of the disease. In cases of older people, the disease takes longer, but is still almost always fatal.
X-linked Leigh's disease
There is another form of this disease called the X-linked Leigh's syndrome (OMIM 308930), which is a mutation in the oxidative phosphorylationOxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s (which are on both the mtDNA and the nuclear DNA). The X-linked Leigh's disease is a mutation of a gene encoding PDHA1, part of the pyruvate dehydrogenase complex, located on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
.