Leukoencephalopathy with vanishing white matter
Encyclopedia
Leukoencephalopathy with vanishing white matter (VWM disease) is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 gene
s encoding subunits of the translation initiation factor EIF-2B: EIF2B1
, EIF2B2
, EIF2B3
, EIF2B4
, or EIF2B5
. The disease belongs to a family of conditions called the Leukodystrophies.
, occurred when she was 31 years old. Throughout the duration of her life, she experienced chronic episodes with extensive deterioration of her brain following minor physical trauma. Upon death, autopsy was performed in which the cerebral white matter displayed dispersed cystic areas. These areas were surrounded by a dense net of oligodendrocytes in which only mild fibrillary astrocytes and scant sudanophilic lipids were found.
As the years progressed, more accounts of similar patients with similar symptoms were documented; however no one classified all the accounts as the same disease. It was not until 1993-94 when Dr. Hanefeld and Dr. Schiffmann and their colleagues identified the disease as childhood-onset progressive leukoencephalopathy
. They determined it was autosomal recessive. They too saw that head trauma was a trigger for the onset of VWM. The key factor which allowed them to connect these patients together was the results of the magnetic-resonance spectroscopy in which the normal white matter
signals were gone and often replaced with resonances indicative of lactate
and glucose
. They determined the cause was hypomyelination. It was in 1997-98 when the name vanishing white matter came to be. Dr. van der Knaap and colleagues saw the same characteristics in another set of patients, but these patients also expressed fibrile infections. Dr. van der Knaap used MRI as well as magnetic-resonance spectroscopy and determined that ongoing cystic degeneration of the cerebral white matter and matter rarefaction
was more descriptive of the disease rather than hypomyelination and proposed the name vanishing white matter. The name proposed by Dr. Schiffmann in 1994, childhood ataxia with central hypomyelination (CACH) is another commonly accepted name.
in eIF2B, slight increases in the amount of stress these cells encounter occur, making them more susceptible to failure due to stress. The large amount of oligodendrocytes which display apoptotic characteristics and express apoptotic proteins suggests cell number reduction in the early stages of the disease. Premature ovarian failure
has also been associated with diminishing white matter. However through an intensive survey, it was determined that even if an individual has premature ovarian failure, she does not necessarily have VWM.
eIF2B is the guanine nucleotide-exchange factor for eIF2, and is composed of 5 subunits. The largest subunit, eIF2B5 contains the most mutations for VWM. eIF2B is a complex which is very involved with the regulation of in the translation of mRNA into proteins. eIF2B is essential for the exchange of guanosine diphosphate
(GDP) for guanosine-5'-triphosphate(GTP) in the initiation of translation via eIF2, because eIF2 is regenerated through this exchange. A decrease in eIF2B activity has been correlated with the onset of VWM. A common factor among VWM patients is mutations in the five subunits of eIF2B (21 discovered thus far), expressed in over 60% of the patients. These mutations lead to the decreased activity of eIF2B. The most common mutation is R113H, which is the mutation of histidine
to arginine
. The homozygous form of the mutation is the least severe form. This mutation has also been documented in rodents, but they do not acquire VWM, while humans do. Another common mutation is G584A found in the eIF2B5 subunit. A correlation with stress has also been made, as eIF2B plays a central role in stress management – it is essential in down regulation protein synthesis in different stress conditions – and VWM patients are highly sensitive to stress. Protein eIF2B exists in all cells, and if this protein is reduced enough the cell will be negatively affected, and if it is reduced to zero, the cell will die. In affected cells, the protein is reduced to about 50%, which is acceptable for functionality in most cells, but not in glial cells since they synthesize a large amount of proteins constantly and need as many functioning proteins within them as possible. This would lower the baseline of the amount of stress a cell can handle, and thus in a stressed environment, it would have detrimental effects on these cells. Mutations in three of the subunits of eIF2B (2,4,&5) has been seen in both VWM and premature ovarian failure. The North American Cree
population has also been found to have a distinctive mutation, R195H, which can lead to VWM. All patients who have been studied only have one mutation present in the gene, causing the eIF2B to still be active, which leads to VWM. If two mutations occurred, then eIF2B activity would be stopped by the body.
, optic atrophy, epilepsy
, loss of motor functions, irritability, vomiting, coma, and even fever has been tied to VWM. The neurological disorders and symptoms which occur with VWM are not specific to countries, they are the same all over the world. Neurological abnormalities may not always be present in those who experience onset as adults.
, delusions, and imperative commenting. He showed very minimal physical impairments, commonly seen in child-onsets. However, his MRI showed characteristic signs of VWM disease.
(T2-weighted), proton density, and Fluid attenuated inversion recovery
(FLAIR) images are the best approach. T2-weighted images are also ideal for displaying cerebrospinal fluid and rarefied/cystic white matter. To view the remaining tissue, and get perspective on the damage done (also helpful in determining the rate of deterioration) spin-lattice relaxation time
(T1-weighted), proton density, and FLAIR images are ideal as they show radiating stripe patterns in the degenerating white matter. By being able to identify these criteria, it is very easy to diagnose patients with VWM through MRI. A failure of MRI images is their ineffectiveness and difficulty in interpretation in infants since the brain has not fully developed yet. Though some patterns and signs may be visible, it is still difficult to conclusively diagnose. This often leads to misdiagnosis in infants particularly if the MRI results in equivocal patterns or because of the high water content in infants' brains. The easiest way to fix this problem is a follow-up MRI in the following weeks.
and may be hard to differentiate from schizophrenia
. Common misdiagnosis from misinterpreting the MRI include asphyxia
, congential infections, metabolic diseases.
Multiple Sclerosis
is often a misdiagnosis, but only in children due to its neurological characteristics, onset in early years, and MRI abnormalities. However, there are many differences between the two diseases. The glial cells express a loss of myelin. This loss of myelin is different from that seen in other diseases where hypomyelination occurs. In VWM, the cells never produce the normal amounts, whereas with diseases like MS, the cells' normal amounts are deteriorated. Also, with MS, the demyelination occurs due to inflammation
, which is not the case in VWM. Cell differences include a lower penetration of the macrophages and microglia
, as well as the lack of T cells and B cells in VWM. Finally, patients with MS have widespread demyelination, but those with VWM only express demyelination in a localized area.
gene were found. No effective systemic studies have been conducted to determine the incidence around the world, but through the studies conducted thus far, it appears to be more prevalent in the white populations. VWM appears to have a lower number of cases in the Middle East, and Turkey has not yet had a reported case. Its prevalence is only limited by the physician’s ability to identify the disease. As of 2006, more than 200 people have been identified with VWM, many of whom were originally diagnosed with an unclassified leukodystrophy.
has been shown to provide cytoprotective traits to glial cells exposed to stressors such as excitotoxicity
and oxidative stress
. These stressors would be detrimental to cells with a genetically reduced activity of protein eIF2B. However, research connecting these ideas have not been conducted yet.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s encoding subunits of the translation initiation factor EIF-2B: EIF2B1
EIF2B1
Translation initiation factor eIF-2B subunit alpha is a protein that in humans is encoded by the EIF2B1 gene.-Further reading:...
, EIF2B2
EIF2B2
Translation initiation factor eIF-2B subunit beta is a protein that in humans is encoded by the EIF2B2 gene.-Interactions:EIF2B2 has been shown to interact with EIF2B5 and NCK1.-Further reading:...
, EIF2B3
EIF2B3
Translation initiation factor eIF-2B subunit gamma is a protein that in humans is encoded by the EIF2B3 gene.-Further reading:...
, EIF2B4
EIF2B4
Translation initiation factor eIF-2B subunit delta is a protein that in humans is encoded by the EIF2B4 gene.-Further reading:...
, or EIF2B5
EIF2B5
Translation initiation factor eIF-2B subunit epsilon is a protein that in humans is encoded by the EIF2B5 gene.-Interactions:EIF2B5 has been shown to interact with EIF2B2 and EIF2B1.-Further reading:...
. The disease belongs to a family of conditions called the Leukodystrophies.
Synonyms
- childhood ataxiaAtaxiaAtaxia 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...
with central nervous system hypomyelinization; CACH - vanishing white matter leukodystrophy
- creeCreeThe Cree are one of the largest groups of First Nations / Native Americans in North America, with 200,000 members living in Canada. In Canada, the major proportion of Cree live north and west of Lake Superior, in Ontario, Manitoba, Saskatchewan, Alberta and the Northwest Territories, although...
leukoencephalopathy; CLE - vanishing white matter leukodystrophyLeukodystrophyLeukodystrophy refers to a group of disorders characterized by dysfunction of the white matter of the brain. The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers...
with ovarian failure, included - ovarioleukodystrophy, included
- myelinopathia centralis diffusa
History
The first time this disease was documented was in 1962 when Eickle studied a 36 year old woman. Her first symptoms, gait difficulties and secondary amenorrhoeaAmenorrhoea
Amenorrhoea , amenorrhea , or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation , the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method...
, occurred when she was 31 years old. Throughout the duration of her life, she experienced chronic episodes with extensive deterioration of her brain following minor physical trauma. Upon death, autopsy was performed in which the cerebral white matter displayed dispersed cystic areas. These areas were surrounded by a dense net of oligodendrocytes in which only mild fibrillary astrocytes and scant sudanophilic lipids were found.
As the years progressed, more accounts of similar patients with similar symptoms were documented; however no one classified all the accounts as the same disease. It was not until 1993-94 when Dr. Hanefeld and Dr. Schiffmann and their colleagues identified the disease as childhood-onset progressive leukoencephalopathy
Leukoencephalopathy
The term Leukoencephalopathy is a broad term for leukodystrophy-like diseases . It is applied to all brain white matter diseases, whether their molecular cause is known or not...
. They determined it was autosomal recessive. They too saw that head trauma was a trigger for the onset of VWM. The key factor which allowed them to connect these patients together was the results of the magnetic-resonance spectroscopy in which the normal white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
signals were gone and often replaced with resonances indicative of lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
and 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...
. They determined the cause was hypomyelination. It was in 1997-98 when the name vanishing white matter came to be. Dr. van der Knaap and colleagues saw the same characteristics in another set of patients, but these patients also expressed fibrile infections. Dr. van der Knaap used MRI as well as magnetic-resonance spectroscopy and determined that ongoing cystic degeneration of the cerebral white matter and matter rarefaction
Rarefaction
Rarefaction is the reduction of a medium's density, or the opposite of compression.A natural example of this is as a phase in a sound wave or phonon. Half of a sound wave is made up of the compression of the medium, and the other half is the decompression or rarefaction of the medium.Another...
was more descriptive of the disease rather than hypomyelination and proposed the name vanishing white matter. The name proposed by Dr. Schiffmann in 1994, childhood ataxia with central hypomyelination (CACH) is another commonly accepted name.
Causes/Description
VWM is a leukodystrophy which has unique biochemical abnormalities. A unique characteristic of VWM is that only oligodendrocytes and astrocytes are negatively affected while other glial cells and neurons seem to be unaffected. This is the central question behind VWM. The real reasons behind this behavior are unknown since the cells are in the brain and have been rarely studied. However there is a theory which is generally accepted by most experts in the field. The main characteristic of these cells is the fact that they synthesize a lot of proteins. These cells produce a large amount of proteins from a small amount of precursors and so are constantly working and under a reasonable amount of stress. So with a 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...
in eIF2B, slight increases in the amount of stress these cells encounter occur, making them more susceptible to failure due to stress. The large amount of oligodendrocytes which display apoptotic characteristics and express apoptotic proteins suggests cell number reduction in the early stages of the disease. Premature ovarian failure
Premature ovarian failure
Premature Ovarian Failure , also known as premature ovarian insufficiency, primary ovarian insufficiency , premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40...
has also been associated with diminishing white matter. However through an intensive survey, it was determined that even if an individual has premature ovarian failure, she does not necessarily have VWM.
eIF2B’s role
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
(GDP) for guanosine-5'-triphosphate(GTP) in the initiation of translation via eIF2, because eIF2 is regenerated through this exchange. A decrease in eIF2B activity has been correlated with the onset of VWM. A common factor among VWM patients is mutations in the five subunits of eIF2B (21 discovered thus far), expressed in over 60% of the patients. These mutations lead to the decreased activity of eIF2B. The most common mutation is R113H, which is the mutation of histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
to arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
. The homozygous form of the mutation is the least severe form. This mutation has also been documented in rodents, but they do not acquire VWM, while humans do. Another common mutation is G584A found in the eIF2B5 subunit. A correlation with stress has also been made, as eIF2B plays a central role in stress management – it is essential in down regulation protein synthesis in different stress conditions – and VWM patients are highly sensitive to stress. Protein eIF2B exists in all cells, and if this protein is reduced enough the cell will be negatively affected, and if it is reduced to zero, the cell will die. In affected cells, the protein is reduced to about 50%, which is acceptable for functionality in most cells, but not in glial cells since they synthesize a large amount of proteins constantly and need as many functioning proteins within them as possible. This would lower the baseline of the amount of stress a cell can handle, and thus in a stressed environment, it would have detrimental effects on these cells. Mutations in three of the subunits of eIF2B (2,4,&5) has been seen in both VWM and premature ovarian failure. The North American Cree
Cree
The Cree are one of the largest groups of First Nations / Native Americans in North America, with 200,000 members living in Canada. In Canada, the major proportion of Cree live north and west of Lake Superior, in Ontario, Manitoba, Saskatchewan, Alberta and the Northwest Territories, although...
population has also been found to have a distinctive mutation, R195H, which can lead to VWM. All patients who have been studied only have one mutation present in the gene, causing the eIF2B to still be active, which leads to VWM. If two mutations occurred, then eIF2B activity would be stopped by the body.
Symptoms
Onset usually occurs in childhood, however some adult cases have been found. Generally, physicians look for the symptoms in children. Symptoms include cerebellar ataxia, spasticitySpasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
, optic atrophy, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, loss of motor functions, irritability, vomiting, coma, and even fever has been tied to VWM. The neurological disorders and symptoms which occur with VWM are not specific to countries, they are the same all over the world. Neurological abnormalities may not always be present in those who experience onset as adults.
Neuropathology
VWM has a greater affect in the brain. Upon autopsy, the full effect of VWM has been documented. The gray matter remains normal in all characteristics while the white matter changes texture, becoming soft and gelatinous. Rarefaction of the white matter is seen through light microscopy and the small number of axons and U-fibers that were affected can also be seen. Numerous small cavities in the white matter are also apparent. The key characteristic that sets VWM apart from the other leukodystrophies is the presence of foamy oligodendrocytes. These foamy oligodendrocytes tend to have increased cytoplasmic structures, a greater number of irregular mitochondria and a higher rate of apoptosis. Abnormally shaped astrocytes with fibrile infections are very prevalent throughout the capillaries in the brain. Strangely, astrocytes are affected more than oligodendrocytes; there is even a reduction in the astrocyte progenitors, yet axons remain relatively unharmed.Diagnosis
Most diagnosis occurs in the early years of life around 2 to 6 years old. There have been cases in which onset and diagnosis have occurred late into adulthood. Those with onset at this time have different signs, particularly the lack of cognitive deterioration. Overall, detection of adult forms of VWM is difficult as MRI was not a common tool when they were diagnosed. Common signs to look for include chronic progressive neurological deterioration with cerebellar ataxia, spasticity, mental decline, decline of vision, mild epilepsy, rapid deterioration and fibrile infections following head trauma or fright, lose of motor functions, irritability, vomiting, and even coma. Those who go into coma, if they do come out usually die within a few years. The diagnosis can be difficult if the physician does not take an MRI.Case report on diagnosis of adult-onset VWM
The individual was examined at age 32, but he stated that he started noting differences 5 years before. He noticed sexual impotency, social isolation, unexplained aggression and sadness, loss of motivation, inert laughs, auditory hallucinations, thought insertionThought insertion
Thought insertion is the idea that another thinks through the mind of the patient. The patient may sometimes be unable to distinguish between their own thoughts and those inserted into their minds. A patient who is diagnosed with this disorder is found to be convinced of their beliefs and...
, delusions, and imperative commenting. He showed very minimal physical impairments, commonly seen in child-onsets. However, his MRI showed characteristic signs of VWM disease.
MRI
If an MRI is performed, the disorder is exceptionally easy to diagnose. The MRI of patients with VWM is very distinct, showing a well defined leukodystrophy. With many experienced physicians, an MRI is sufficient to diagnose a patient with VWM, they would not even have to see the patient to view their symptoms. These MRIs display a very characteristic reversal of signal intensity of the white matter in the brain. Recovery sequences and holes in the white matter are also visible. Over time, the MRI is excellent at showing rarefaction and cystic degeneration of the white matter as it is replaced by fluid. To show this change, displaying white matter as a high signal, spin-spin relaxation timeSpin-spin relaxation time
thumb|right|T2 relaxation curveSpin–spin relaxation is the mechanism by which Mxy, the transverse component of the magnetization vector, exponentially decays towards its equilibrium value of zero, in nuclear magnetic resonance and magnetic resonance imaging...
(T2-weighted), proton density, and Fluid attenuated inversion recovery
Fluid attenuated inversion recovery
Fluid attenuated inversion recovery is a pulse sequence used in magnetic resonance imaging which was invented by Dr. Graeme Bydder. FLAIR can be used with both three dimensional imaging or two dimensional imaging ....
(FLAIR) images are the best approach. T2-weighted images are also ideal for displaying cerebrospinal fluid and rarefied/cystic white matter. To view the remaining tissue, and get perspective on the damage done (also helpful in determining the rate of deterioration) spin-lattice relaxation time
Spin-lattice relaxation time
Spin–lattice relaxation is the mechanism by which the z component of the magnetization vector comes into thermodynamic equilibrium with its surroundings in nuclear magnetic resonance and magnetic resonance imaging. It is characterized by the spin–lattice relaxation time, a time constant known as T1...
(T1-weighted), proton density, and FLAIR images are ideal as they show radiating stripe patterns in the degenerating white matter. By being able to identify these criteria, it is very easy to diagnose patients with VWM through MRI. A failure of MRI images is their ineffectiveness and difficulty in interpretation in infants since the brain has not fully developed yet. Though some patterns and signs may be visible, it is still difficult to conclusively diagnose. This often leads to misdiagnosis in infants particularly if the MRI results in equivocal patterns or because of the high water content in infants' brains. The easiest way to fix this problem is a follow-up MRI in the following weeks.
Common misdiagnosis
Often with VWM, the lack of knowledge of the disease causes a misdiagnosis among physicians. As VWM is a member of the large group of leukodystrophy syndromes, it is often misdiagnosed as another type such as metachromatic leukodystrophy. More often than not, it is simply classified as a non-specific leukodystrophy. The characteristics of the brain upon autopsy are often very similar to atypical diffuse sclerosis, such as the presence of fibrillary astrocytes and scant sudanophilic lipids. Adult-onset VWM disease can present with psychosisPsychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
and may be hard to differentiate from schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. Common misdiagnosis from misinterpreting the MRI include asphyxia
Asphyxia
Asphyxia or asphyxiation is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. An example of asphyxia is choking. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs...
, congential infections, metabolic diseases.
Multiple Sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
is often a misdiagnosis, but only in children due to its neurological characteristics, onset in early years, and MRI abnormalities. However, there are many differences between the two diseases. The glial cells express a loss of myelin. This loss of myelin is different from that seen in other diseases where hypomyelination occurs. In VWM, the cells never produce the normal amounts, whereas with diseases like MS, the cells' normal amounts are deteriorated. Also, with MS, the demyelination occurs due to inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, which is not the case in VWM. Cell differences include a lower penetration of the macrophages and microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
, as well as the lack of T cells and B cells in VWM. Finally, patients with MS have widespread demyelination, but those with VWM only express demyelination in a localized area.
Epidemiology
Extensive pathological and biochemical tests were performed, however the cause was found by studying a small population in which mutations in the eIF2BEIF2B
eIF2B is a protein found in eukaryotes. It is the guanine nucleotide exchange factor for the eukaryotic initiation factor 2 and therefore converts the inactive eIF2-GDP to the active eIF2-GTP...
gene were found. No effective systemic studies have been conducted to determine the incidence around the world, but through the studies conducted thus far, it appears to be more prevalent in the white populations. VWM appears to have a lower number of cases in the Middle East, and Turkey has not yet had a reported case. Its prevalence is only limited by the physician’s ability to identify the disease. As of 2006, more than 200 people have been identified with VWM, many of whom were originally diagnosed with an unclassified leukodystrophy.
Treatment
There are no real treatments, only precautions which can be taken, mainly to reduce trauma to the head and avoiding physiological stress. MelatoninMelatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
has been shown to provide cytoprotective traits to glial cells exposed to stressors such as excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
and oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. These stressors would be detrimental to cells with a genetically reduced activity of protein eIF2B. However, research connecting these ideas have not been conducted yet.
See also
- The Stennis FoundationThe Stennis FoundationThe Stennis Foundation is a registered nonprofit organization based in the U.S. The Foundation is primarily a fundraising organization, raising money, and then sending it to various research projects...
- CADASILCADASILCADASIL is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19. The disease belongs to a family of disorders called the Leukodystrophies...
(Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) - Progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
- Metachromatic leukodystrophyMetachromatic leukodystrophyMetachromatic leukodystrophy is a lysosomal storage disease which is commonly listed in the family of leukodystrophies. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous...
External links
- GeneReviews/NCBI/NIH/UW entry on CARASIL Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, Maeda Syndrome
- OMIM entries on CARASIL
- Leukoencephalopathy with vanishing white matter
- The Stennis Foundation
- GeneReviews/NCBI/NIH/UW entry on Childhood Ataxia with Central Nervous System Hypomylenation/Vanishing White Matter
- OMIM entries on CACH/VWM
- GeneReviews/NCBI/NIH/UW entry on CADASIL
- OMIM entries on CADASIL