MELAS
Encyclopedia
Mitochondrial encephalomyopathy, lactic acidosis
, and stroke
-like episodes – abbreviated to MELAS – is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's hereditary optic neuropathy
. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome
which is inherited purely from the female parent. The disease can manifest in both sexes.
Most people with MELAS have a buildup of lactic acid
in their bodies, a condition called lactic acidosis
. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia
), hearing loss, heart and kidney problems, diabetes, Epilepsy, and hormonal imbalances.
The presentation of some cases is similar to that of Kearns-Sayre syndrome
.
, MT-ND5
) related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex (NADH dehydrogenase
, also called complex I) in mitochondria that helps convert oxygen and simple sugars to energy.
, MT-TL1
, and MT-TV
) associated with this disorder provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.
Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.
s, amino acids, antioxidant
s and vitamin
s have been used, but there have been no consistent successes reported.
Although there have been no controlled trials on long-term benefits of dietary manipulations, the following supplements have shown promise and given hope to MELAS patients.
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...
, and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
-like episodes – abbreviated to MELAS – is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's hereditary optic neuropathy
Leber's hereditary optic neuropathy
Leber’s hereditary optic neuropathy or Leber optic atrophy is a mitochondrially inherited degeneration of retinal ganglion cells and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males...
. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
which is inherited purely from the female parent. The disease can manifest in both sexes.
Presentation
MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).Most people with MELAS have a buildup of lactic acid
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
in their bodies, a condition called 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...
. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
), hearing loss, heart and kidney problems, diabetes, Epilepsy, and hormonal imbalances.
The presentation of some cases is similar to that of Kearns-Sayre syndrome
Kearns-Sayre syndrome
Kearns–Sayre syndrome also known as oculocraniosomatic disease or Oculocraniosomatic neuromuscular disease with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age...
.
Genetics
MELAS is caused by mutations in the genes in mitochondrial DNA.NADH dehydrogenase
Some of the genes (MT-ND1MT-ND1
MT-ND1 is a mitochondrial gene. It is associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.-External links:*...
, MT-ND5
MT-ND5
MT-ND5 is a mitochondrial gene. It is associated with MELAS or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.-External links:*...
) related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex (NADH dehydrogenase
NADH dehydrogenase
NADH dehydrogenase is an enzyme located in the inner mitochondrial membrane that catalyzes the transfer of electrons from NADH to coenzyme Q...
, also called complex I) in mitochondria that helps convert oxygen and simple sugars to energy.
Transfer RNAs
Other genes (MT-THMT-TH
Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.-Function:...
, MT-TL1
MT-TL1
Mitochondrially encoded tRNA leucine 1 also known as MT-TL1 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL1 gene.-Function:...
, and MT-TV
MT-TV (mitochondrial)
Mitochondrially encoded tRNA valine also known as MT-TV is a transfer RNA which in humans is encoded by the mitochondrial MT-TV gene....
) associated with this disorder provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.
Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.
Inheritance
This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.Prognosis
There is no known treatment for the underlying disease, which is progressive and fatal. Patients are managed according to what areas of the body are affected at a particular time. EnzymeEnzyme
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, amino acids, antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
s and vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s have been used, but there have been no consistent successes reported.
Although there have been no controlled trials on long-term benefits of dietary manipulations, the following supplements have shown promise and given hope to MELAS patients.
- CoQ10 has been helpful for some MELAS patients. NicotinamideNicotinamideNicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...
has been used because complex l accepts electrons from NADH and ultimately transfers electrons to CoQ10.
- RiboflavinRiboflavinRiboflavin, also known as vitamin B2 or additive E101, is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors FAD and FMN, and is therefore required by all flavoproteins. As such, vitamin B2 is required for a...
has been reported to improve the function of a patient with complex l deficiency and the 3250T-C mutation.
- The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impaired vasodilation in intracerebral arteries owing to nitric oxideNitric oxideNitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
depletion.
- There is evidence from animal studies that resveratrolResveratrolResveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
and other SIRT1 activators may be used to treat MELAS by increasing mitochondrial biogenesis and function. Sirtris PharmaceuticalsSirtris PharmaceuticalsSirtris Pharmaceuticals, Inc. is a biotechnology company based in Cambridge, MA that is developing therapies for type 2 diabetes, cancer, and other diseases. Founded in 2004 by a Harvard University biologist, Drs. David Sinclair, and venture capitalist Christoph Westphal, the company went public in...
, a GlaxoSmithKline company based in Cambridge, MA, is developing a proprietary formulation of resveratrol (called SRT-501) for the treatment of MELAS under Orphan DrugOrphan drugAn orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
Designation from the U.S. Food and Drug Administration. Results from this phase 1b trial are expected in the first half of 2009.
- There is also a case report where succinate was successfully used to treat uncontrolled convulsions in MELAS patients, although this treatment modality is yet to be thoroughly investigated or widely recommended.