Leukodystrophy, Globoid Cell
Galactosylceramidase
Leukodystrophy, Metachromatic
Psychosine
Cerebroside-Sulfatase
Diffuse Cerebral Sclerosis of Schilder
Cerebrosides
Galactosidases
Glucose Transporter Type 5
Hereditary Central Nervous System Demyelinating Diseases
Sulfoglycosphingolipids
Pelizaeus-Merzbacher Disease
Brain
Saposins
Sulfatases
Disease Models, Animal
Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method. (1/117)
BACKGROUND AND PURPOSE: Our purpose was to determine the characteristic MR features of early-onset (before age 2 years) versus late-onset (after age 2 years) globoid cell leukodystrophy (GLD). METHODS: Thirty-four brain MR images in 22 patients with GLD were reviewed. A severity score (0 to 32), based on a point system derived from the location and extent of disease and the presence of focal and/or global atrophy, was calculated for each examination. RESULTS: Of the 22 patients, three were asymptomatic and 19 were symptomatic. Ten patients had early-onset disease, whereas nine had late-onset disease. MR images of all patients showed abnormalities. In the early-onset group (n = 10; mean maximum MR score, 8.1; range, 3-18), 90% had pyramidal tract involvement, 80% had cerebellar white matter involvement, 70% had deep gray matter involvement, 60% had posterior corpus callosal involvement, 50% had parietooccipital white matter involvement, and 40% had cerebral atrophy. Serial MR imaging in four of these patients revealed progressive disease. In the late-onset group (n = 9; mean maximum MR score, 5.6; range, 4-10), 100% had pyramidal tract involvement, 100% had parietooccipital white matter involvement, 89% had posterior corpus callosal involvement, and none had cerebellar white matter involvement, deep gray matter involvement, or cerebral atrophy. Serial MR imaging in one patient with late-onset GLD did not reveal any change. A spectrum of findings was observed in the three patients who were asymptomatic. CONCLUSION: Cerebellar white matter and deep gray matter involvement are present only in early-onset GLD. Pyramidal tract involvement is a characteristic finding in both early- and late-onset GLD. This scoring method for brain MR observations will assist in the objective assessment of the impact of hematopoietic stem cell transplantation in patients with GLD. (+info)Optic nerve enlargement in Krabbe's disease. (2/117)
We report imaging and gross pathologic findings from two cases of Krabbe disease in which there was marked enlargement of the intracranial optic nerves. Numerous globoid cells were observed in the optic nerves at autopsy in one case. Krabbe disease should be included in the differential diagnosis of children with enlargement of the optic nerves. (+info)Inhibition of cytokinesis by a lipid metabolite, psychosine. (3/117)
Although a number of cellular components of cytokinesis have been identified, little is known about the detailed mechanisms underlying this process. Here, we report that the lipid metabolite psychosine (galactosylsphingosine), derived from galactosylceramide, induced formation of multinuclear cells from a variety of nonadherent and adherent cells due to inhibition of cytokinesis. When psychosine was added to the human myelomonocyte cell line U937, which was the most sensitive among the cell lines tested, cleavage furrow formed either incompletely or almost completely. However, abnormal contractile movement was detected in which the cellular contents of one of the hemispheres of the contracting cell were transferred into its counterpart. Finally, the cleavage furrow disappeared and cytokinesis was reversed. Psychosine treatment also induced giant clots of actin filaments in the cells that probably consisted of small vacuoles with filamentous structures, suggesting that psychosine affected actin reorganization. These observations could account for the formation of multinuclear globoid cells in the brains of patients with globoid cell leukodystrophy, a neurological disorder characterized by the accumulation of psychosine due to galactosylceramidase deficiency. (+info)MR imaging and proton MR spectroscopy in adult Krabbe disease. (4/117)
We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement. (+info)Globoid cell leukodystrophy: the first case with antemortem diagnosis in Japan. (5/117)
A Japanese boy was diagnosed as globoid cell leukodystrophy on the basis of a marked decrease in the galactocerebroside beta-galactosidase activity in the leukocytes and the serum when one year and two months old. At autopsy when 1 year and 10 months, microscopic findings were characteristic for those of globoid cell leukodystrophy. Galactocerebroside beta-galactosidase activities of leukocytes and sera of his father and mother were found to be half those of control subjects, thus it suggested the parents being heterozygotes of the disease. (+info)Electroencephalographic findings in a case of globoid cell leukodystrophy. (6/117)
An increased slow wave pattern of the EEG basic waves without epileptogenic discharges was observed in an early stage of a case of Krabbe's disease. In the later stage of the illness, spikes and sharp waves were mixed with. The peculiar runs of fast activity which were described by Kliemann et al. (1969) were not observed during the course of our patient. (+info)Identification of a molecular target of psychosine and its role in globoid cell formation. (7/117)
Globoid cell leukodystrophy (GLD) is characterized histopathologically by apoptosis of oligodendrocytes, progressive demyelination, and the existence of large, multinuclear (globoid) cells derived from perivascular microglia. The glycosphingolipid, psychosine (d-galactosyl-beta-1,1' sphingosine), accumulates to micromolar levels in GLD patients who lack the degradative enzyme galactosyl ceramidase. Here we document that an orphan G protein-coupled receptor, T cell death-associated gene 8, is a specific psychosine receptor. Treatment of cultured cells expressing this receptor with psychosine or structurally related glycosphingolipids results in the formation of globoid, multinuclear cells. Our discovery of a molecular target for psychosine suggests a mechanism for the globoid cell histology characteristic of GLD, provides a tool with which to explore the disjunction of mitosis and cytokinesis in cell cultures, and provides a platform for developing a medicinal chemistry for psychosine. (+info)Quantification of cellular acid sphingomyelinase and galactocerebroside beta-galactosidase activities by electrospray ionization mass spectrometry. (8/117)
BACKGROUND: Diagnosis of Niemann-Pick (A and B) and Krabbe diseases is achieved by measurement of the lysosomal enzymes acid sphingomyelinase (ASM) and galactocerebroside beta-galactosidase (GCG), respectively. Conventional assays use radiolabeled or fluorescent substrates and do not allow simultaneous determination of two or more enzymes in the sample. METHODS: We developed a sensitive and specific method to assay ASM and GCG in skin fibroblast homogenates using biotinylated substrate conjugates. The products were purified by bioaffinity capture on streptavidin-agarose beads and, following release, were analyzed by electrospray ionization mass spectrometry. Quantification was achieved using stable-isotope-labeled internal standards that were chemically identical to the products of the enzymatic reactions. RESULTS: The method demonstrated excellent linearity of ASM and GCG enzymatic product formation with the amount of cellular protein and incubation time. The range of ASM activities in fibroblast lysates from six healthy patients was 39-70 nmol. mg(-1). h(-1) compared with 3.7-5.1 nmol. mg(-1). h(-1) in cell lysates from two patients affected with Niemann-Pick A disease. The GCG activities toward the corresponding substrate conjugate were 4.0-6.8 nmol. mg(-1). h(-1) in cell lysates from healthy patients compared with 0.1-0.2 nmol. mg(-1). h(-1) in cell lysates from two patients affected with Krabbe disease. The amounts of substrate conjugates needed per analysis were 15 nmol (14 microg) for both ASM and GCG. CONCLUSIONS: Electrospray mass spectrometry combined with the use of biotinylated substrate conjugates and bioaffinity purification represents a new approach for the diagnosis of lysosomal storage diseases as demonstrated for Niemann-Pick A and Krabbe diseases. No radioactive substrates are used, and the method uses a single instrumental platform to determine both ASM and GCG in one cell sample. (+info)Globoid cell leukodystrophy, also known as Krabbe disease, is a rare inherited disorder that affects the nervous system. It is characterized by the accumulation of abnormal quantities of a protein called psychosine in the brain's nerve cells, leading to their destruction and progressive damage to the protective sheath (myelin) that covers the nerves.
The term "leukodystrophy" refers to a group of disorders that affect the white matter of the brain, which is primarily composed of myelin. In globoid cell leukodystrophy, the accumulation of psychosine in the brain's nerve cells, particularly in macrophages (which are then referred to as "globoid cells"), results in progressive demyelination and severe neurological symptoms.
Early-onset forms of Krabbe disease typically present within the first six months of life, with symptoms such as irritability, feeding difficulties, muscle weakness, and developmental delays. Late-onset forms may not become apparent until later in childhood or even adulthood, with symptoms that can include vision loss, hearing impairment, muscle stiffness, and difficulty coordinating movements. The progression of the disease is often rapid, leading to severe disability and a shortened lifespan.
There is currently no cure for globoid cell leukodystrophy, but various treatments, such as bone marrow transplantation and enzyme replacement therapy, are being investigated to help manage the symptoms and slow down the progression of the disease.
Galactosylceramidase (galactocerebrosidase) is an enzyme that breaks down a fatty substance called galactosylceramide, which is found in myelin – the protective covering of nerve fibers in the brain. This enzyme plays a crucial role in the maintenance and functioning of the nervous system.
Deficiency of galactosylceramidase leads to the accumulation of galactosylceramide in the lysosomes (membrane-bound organelles responsible for breaking down waste materials within cells), resulting in an inherited metabolic disorder known as Krabbe disease or globoid cell leukodystrophy. This rare and progressive neurological condition affects the development and maintenance of myelin, causing severe damage to the nervous system and leading to motor, cognitive, and sensory impairments, ultimately resulting in early death if left untreated.
Metachromatic leukodystrophy (MLD) is a genetic disorder that affects the nervous system's white matter. It is caused by mutations in the arylsulfatase A (ARSA) gene, which leads to an accumulation of sulfatides in the brain and peripheral nerves. This accumulation results in progressive damage to the protective sheath (myelin) that covers nerve fibers, impairing the transmission of nerve impulses and leading to neurological symptoms.
The clinical presentation of MLD varies depending on the age of onset. The late-infantile form is the most common and typically appears between ages 1 and 2. Symptoms include developmental regression, motor difficulties, muscle weakness, and loss of vision and hearing. The juvenile form usually begins between ages 4 and 6, while the adult form can manifest anytime after age 16. These later-onset forms tend to have a slower progression but still result in significant neurological impairment over time.
Currently, there is no cure for MLD, and treatment focuses on managing symptoms and slowing disease progression. Bone marrow transplantation or stem cell transplantation may be beneficial if performed early in the course of the disease.
I'm sorry for any confusion, but "psychosine" is not a commonly used term in medicine or psychology. It is a lipid molecule that has been researched in the context of certain neurological conditions, particularly Krabbe disease, which is a rare and fatal genetic disorder affecting the nervous system.
In Krabbe disease, psychosine accumulates in the body due to a deficiency of an enzyme called galactocerebrosidase. This buildup of psychosine is thought to contribute to the damage and destruction of nerve cells, leading to the symptoms of the disease. However, it's important to note that this is still an area of ongoing research, and there is no medical definition for "psychosine" in a general sense.
Cerebroside-sulfatase is an enzyme that plays a crucial role in the breakdown and recycling of lipids within the body, particularly in the brain. Its primary function is to break down a type of lipid called cerebroside sulfate, which is a major component of the myelin sheath that surrounds and insulates nerve fibers in the brain and nervous system.
Cerebroside-sulfatase deficiency can lead to a group of genetic disorders known as the mucopolysaccharidoses (MPS), specifically MPS IIIB or Sanfilippo syndrome B. In this condition, the lack of cerebroside-sulfatase activity leads to an accumulation of cerebroside sulfate in the lysosomes of cells, resulting in progressive neurological deterioration and developmental delays.
Neurologic mutant mice are genetically engineered or spontaneously mutated rodents that are used as models to study various neurological disorders and conditions. These mice have specific genetic modifications or mutations that affect their nervous system, leading to phenotypes that resemble human neurological diseases.
Some examples of neurologic mutant mice include:
1. Alzheimer's disease models: Mice that overexpress genes associated with Alzheimer's disease, such as the amyloid precursor protein (APP) or presenilin 1 (PS1), to study the pathogenesis and potential treatments of this disorder.
2. Parkinson's disease models: Mice that have genetic mutations in genes associated with Parkinson's disease, such as alpha-synuclein or parkin, to investigate the mechanisms underlying this condition and develop new therapies.
3. Huntington's disease models: Mice that carry an expanded CAG repeat in the huntingtin gene to replicate the genetic defect seen in humans with Huntington's disease and study disease progression and treatment strategies.
4. Epilepsy models: Mice with genetic mutations that cause spontaneous seizures or increased susceptibility to seizures, used to investigate the underlying mechanisms of epilepsy and develop new treatments.
5. Stroke models: Mice that have surgical induction of stroke or genetic modifications that increase the risk of stroke, used to study the pathophysiology of stroke and identify potential therapeutic targets.
Neurologic mutant mice are essential tools in biomedical research, allowing scientists to investigate the complex interactions between genes and the environment that contribute to neurological disorders. These models help researchers better understand disease mechanisms, develop new therapies, and test their safety and efficacy before moving on to clinical trials in humans.
Diffuse cerebral sclerosis of Schilder, also known as Schilder's disease, is a rare inflammatory demyelinating disorder of the central nervous system. It primarily affects children and young adults, but can occur at any age. The condition is characterized by widespread destruction of the myelin sheath, which surrounds and protects nerve fibers in the brain.
The hallmark feature of Schilder's disease is the presence of multiple, large, symmetrical lesions in the white matter of both cerebral hemispheres. These lesions are typically located in the parieto-occipital regions of the brain and can extend to involve other areas as well.
The symptoms of Schilder's disease vary depending on the location and extent of the lesions, but may include:
* Progressive intellectual decline
* Seizures
* Visual disturbances
* Weakness or paralysis on one side of the body (hemiparesis)
* Loss of sensation in various parts of the body
* Speech difficulties
* Behavioral changes, such as irritability, mood swings, and depression
The exact cause of Schilder's disease is not known, but it is believed to be an autoimmune disorder, in which the body's own immune system mistakenly attacks the myelin sheath. There is no cure for Schilder's disease, and treatment typically involves corticosteroids or other immunosuppressive therapies to reduce inflammation and slow the progression of the disease. Despite treatment, many patients with Schilder's disease experience significant disability and may require long-term care.
Cerebrosides are a type of sphingolipid, which are lipids that contain sphingosine. They are major components of the outer layer of cell membranes and are particularly abundant in the nervous system. Cerebrosides are composed of a ceramide molecule (a fatty acid attached to sphingosine) and a sugar molecule, usually either glucose or galactose.
Glycosphingolipids that contain a ceramide with a single sugar residue are called cerebrosides. Those that contain more complex oligosaccharide chains are called gangliosides. Cerebrosides play important roles in cell recognition, signal transduction, and cell adhesion.
Abnormalities in the metabolism of cerebrosides can lead to various genetic disorders, such as Gaucher's disease, Krabbe disease, and Fabry disease. These conditions are characterized by the accumulation of cerebrosides or their breakdown products in various tissues, leading to progressive damage and dysfunction.
Galactosidases are a group of enzymes that catalyze the hydrolysis of galactose-containing sugars, specifically at the beta-glycosidic bond. There are several types of galactosidases, including:
1. Beta-galactosidase: This is the most well-known type of galactosidase and it catalyzes the hydrolysis of lactose into glucose and galactose. It has important roles in various biological processes, such as lactose metabolism in animals and cell wall biosynthesis in plants.
2. Alpha-galactosidase: This enzyme catalyzes the hydrolysis of alpha-galactosides, which are found in certain plant-derived foods like legumes. A deficiency in this enzyme can lead to a genetic disorder called Fabry disease.
3. N-acetyl-beta-glucosaminidase: This enzyme is also known as hexosaminidase and it catalyzes the hydrolysis of N-acetyl-beta-D-glucosamine residues from glycoproteins, glycolipids, and other complex carbohydrates.
Galactosidases are widely used in various industrial applications, such as food processing, biotechnology, and biofuel production. They also have potential therapeutic uses, such as in the treatment of lysosomal storage disorders like Fabry disease.
Glucose Transporter Type 5 (GLUT5) is a specific type of glucose transporter protein that facilitates the transport of fructose across biological membranes. It is a member of the solute carrier 2 family, also known as SLC2A5. GLUT5 is primarily expressed in the small intestine, where it absorbs dietary fructose from the lumen into the enterocytes, and in the kidney, where it reabsorbs fructose from the glomerular filtrate back into the bloodstream.
Unlike other GLUT family members that transport glucose using a facilitated diffusion mechanism, GLUT5 is unique because it transports fructose via a similar mechanism but with higher affinity and specificity for fructose. The gene encoding GLUT5 is located on chromosome 1 (1p34.2-p36.1) and consists of nine exons and eight introns.
Mutations in the GLUT5 gene have been associated with essential fructosuria, a rare autosomal recessive disorder characterized by an inability to metabolize fructose due to deficient intestinal absorption and renal reabsorption of fructose. However, this condition is benign and does not cause any significant health problems.
Hereditary Central Nervous System (CNS) Demyelinating Diseases are a group of rare, inherited genetic disorders that affect the nervous system. These diseases are characterized by damage to the myelin sheath, which is the protective covering surrounding nerve fibers in the CNS (brain and spinal cord). The damage to the myelin sheath results in disrupted communication between the brain and other parts of the body, leading to various neurological symptoms.
Examples of Hereditary CNS Demyelinating Diseases include:
1. Leukodystrophies - A group of genetic disorders that affect the white matter (myelin) in the brain. Examples include Pelizaeus-Merzbacher disease, Krabbe disease, and Metachromatic leukodystrophy.
2. Hereditary Spastic Paraplegias (HSPs) - A group of inherited disorders that cause progressive stiffness and weakness in the legs due to damage to the nerve fibers in the spinal cord. Some forms of HSP can also involve CNS demyelination.
3. Neurodegenerative disorders with brain iron accumulation (NBIA) - A group of rare genetic disorders characterized by abnormal accumulation of iron in the brain, which can lead to damage to the myelin sheath and other structures in the brain. Examples include Pantothenate kinase-associated neurodegeneration (PKAN) and Neuroferritinopathy.
4. Cerebrotendinous xanthomatosis - A rare inherited disorder of bile acid metabolism that can lead to progressive neurological symptoms, including demyelination in the brain and spinal cord.
These disorders are typically diagnosed through genetic testing, medical history, physical examination, and imaging studies such as MRI. Treatment is focused on managing symptoms and slowing disease progression, and may include medications, physical therapy, and other supportive care measures.
Sulfoglycosphingolipids are a type of glycosphingolipid that contain a sulfate ester group in their carbohydrate moiety. They are important components of animal cell membranes and play a role in various biological processes, including cell recognition, signal transduction, and cell adhesion.
The most well-known sulfoglycosphingolipids are the sulfatides, which contain a 3'-sulfate ester on the galactose residue of the glycosphingolipid GalCer (galactosylceramide). Sulfatides are abundant in the nervous system and have been implicated in various neurological disorders.
Other sulfoglycosphingolipids include the seminolipids, which contain a 3'-sulfate ester on the galactose residue of lactosylceramide (Galβ1-4Glcβ1-Cer), and are found in high concentrations in the testis.
Abnormalities in sulfoglycosphingolipid metabolism have been associated with several genetic disorders, such as metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD), which are characterized by progressive neurological deterioration.
Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive genetic disorder affecting the nervous system. It is caused by mutations in the PLP1 gene, which provides instructions for making proteins that are important for the formation and maintenance of the myelin sheath, the protective covering that wraps around nerve cell fibers (axons) in the brain and spinal cord to ensure efficient transmission of electrical signals.
In individuals with PMD, the myelin sheath is either partially or completely absent, leading to progressive neurological symptoms. The classic form of PMD is characterized by early onset of nystagmus (involuntary eye movements), ataxia (loss of muscle coordination and balance), and intellectual disability. Other features may include hypotonia (low muscle tone), spasticity (stiff or rigid muscles), and seizures. The severity and progression of the disease can vary widely among affected individuals, ranging from a severe, lethal form to a milder form with a slower disease course.
Currently, there is no cure for PMD, and treatment is focused on managing symptoms and improving quality of life.
The brain is the central organ of the nervous system, responsible for receiving and processing sensory information, regulating vital functions, and controlling behavior, movement, and cognition. It is divided into several distinct regions, each with specific functions:
1. Cerebrum: The largest part of the brain, responsible for higher cognitive functions such as thinking, learning, memory, language, and perception. It is divided into two hemispheres, each controlling the opposite side of the body.
2. Cerebellum: Located at the back of the brain, it is responsible for coordinating muscle movements, maintaining balance, and fine-tuning motor skills.
3. Brainstem: Connects the cerebrum and cerebellum to the spinal cord, controlling vital functions such as breathing, heart rate, and blood pressure. It also serves as a relay center for sensory information and motor commands between the brain and the rest of the body.
4. Diencephalon: A region that includes the thalamus (a major sensory relay station) and hypothalamus (regulates hormones, temperature, hunger, thirst, and sleep).
5. Limbic system: A group of structures involved in emotional processing, memory formation, and motivation, including the hippocampus, amygdala, and cingulate gyrus.
The brain is composed of billions of interconnected neurons that communicate through electrical and chemical signals. It is protected by the skull and surrounded by three layers of membranes called meninges, as well as cerebrospinal fluid that provides cushioning and nutrients.
Saposins are a group of naturally occurring lipid-binding proteins that play an essential role in the metabolism of lipids within cells. They are named after a skin disease called "Niemann-Pick disease," where defects in saposin function lead to an accumulation of lipids in various tissues, including the brain.
There are four types of saposins (SapA, SapB, SapC, and SapD) that are produced by the cleavage of a larger precursor protein called prosaposin. These proteins help to facilitate the breakdown of lipids in lysosomes, which are specialized organelles within cells that break down and recycle various materials.
Saposins play an important role in activating certain enzymes that are involved in breaking down lipids, such as sphingolipids and gangliosides. They do this by binding to these enzymes and presenting them with their lipid substrates in a way that allows the enzymes to efficiently break them down.
Defects in saposin function can lead to a variety of diseases, including Niemann-Pick disease, Gaucher disease, and Krabbe disease, which are characterized by an accumulation of lipids in various tissues and neurological symptoms.
Sulfatases are a group of enzymes that play a crucial role in the metabolism of sulfated steroids, glycosaminoglycans (GAGs), and other sulfated molecules. These enzymes catalyze the hydrolysis of sulfate groups from these substrates, converting them into their respective unsulfated forms.
The human genome encodes for several different sulfatases, each with specificity towards particular types of sulfated substrates. For instance, some sulfatases are responsible for removing sulfate groups from steroid hormones and neurotransmitters, while others target GAGs like heparan sulfate, dermatan sulfate, and keratan sulfate.
Defects in sulfatase enzymes can lead to various genetic disorders, such as multiple sulfatase deficiency (MSD), X-linked ichthyosis, and mucopolysaccharidosis (MPS) type IIIC (Sanfilippo syndrome type C). These conditions are characterized by the accumulation of sulfated molecules in different tissues, resulting in progressive damage to multiple organs and systems.
Animal disease models are specialized animals, typically rodents such as mice or rats, that have been genetically engineered or exposed to certain conditions to develop symptoms and physiological changes similar to those seen in human diseases. These models are used in medical research to study the pathophysiology of diseases, identify potential therapeutic targets, test drug efficacy and safety, and understand disease mechanisms.
The genetic modifications can include knockout or knock-in mutations, transgenic expression of specific genes, or RNA interference techniques. The animals may also be exposed to environmental factors such as chemicals, radiation, or infectious agents to induce the disease state.
Examples of animal disease models include:
1. Mouse models of cancer: Genetically engineered mice that develop various types of tumors, allowing researchers to study cancer initiation, progression, and metastasis.
2. Alzheimer's disease models: Transgenic mice expressing mutant human genes associated with Alzheimer's disease, which exhibit amyloid plaque formation and cognitive decline.
3. Diabetes models: Obese and diabetic mouse strains like the NOD (non-obese diabetic) or db/db mice, used to study the development of type 1 and type 2 diabetes, respectively.
4. Cardiovascular disease models: Atherosclerosis-prone mice, such as ApoE-deficient or LDLR-deficient mice, that develop plaque buildup in their arteries when fed a high-fat diet.
5. Inflammatory bowel disease models: Mice with genetic mutations affecting intestinal barrier function and immune response, such as IL-10 knockout or SAMP1/YitFc mice, which develop colitis.
Animal disease models are essential tools in preclinical research, but it is important to recognize their limitations. Differences between species can affect the translatability of results from animal studies to human patients. Therefore, researchers must carefully consider the choice of model and interpret findings cautiously when applying them to human diseases.
Sphingolipid activator proteins (SAPs), also known as saposins, are a group of small proteins that play a crucial role in the metabolism of sphingolipids, a class of lipids found in cell membranes. These proteins are produced by the cleavage of a precursor protein called prosaposin.
SAPs facilitate the hydrolysis of sphingolipids by activating specific lysosomal hydrolases, enzymes that break down these lipids into simpler molecules. Each SAP has a unique structure and function, and they are named SapA, SapB, SapC, and SapD.
SapA and SapB activate the enzyme glucocerebrosidase, which breaks down glucosylceramide into glucose and ceramide. SapC activates the enzyme galactocerebrosidase, which breaks down galactosylceramide into galactose and ceramide. SapD has multiple functions, including activating the enzyme acid sphingomyelinase, which breaks down sphingomyelin into ceramide and phosphorylcholine.
Deficiencies in SAPs can lead to lysosomal storage disorders, such as Gaucher disease (caused by a deficiency in glucocerebrosidase) and Krabbe disease (caused by a deficiency in galactocerebrosidase). These disorders are characterized by the accumulation of undigested sphingolipids in various tissues, leading to cell dysfunction and tissue damage.
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Psychosine
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Jim Kelly
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Krabbe Disease9
- Globoid cellular leukodystrophy (Krabbe disease) is a metabolic disease. (slovgen.sk)
- Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is an autosomal-recessive sphingolipidosis caused by deficient activity of the lysosomal hydrolase galactosylceramide beta-galactosidase (GALC). (medscape.com)
- This accumulation causes formation of globoid cells (hematogenous often-multinucleated macrophages containing undigested galactosylceramide), which is the histologic hallmark of Krabbe disease. (medscape.com)
- Krabbe disease , also known as globoid cell leukodystrophy , is an autosomal recessive lysosomal storage disorder resulting in damage to cells involved in myelin turnover. (radiopaedia.org)
- Krabbe disease is a rare, inherited condition that affects the myelin that covers and protects your nerve cells, causing neurological issues. (disabled-world.com)
- krabbe disease (Globoid Cell Leukodystrophy) mini factsheets NINDS. (geometry.net)
- Several reports have shown that various late-onset leukodystrophies, such as X-linked adrenoleukodystrophy (ALD) and Krabbe disease (KD), may present as spastic paraplegia (SP) without leukodystrophy on neuroimaging and be easily misdiagnosed as hereditary spastic paraplegia (HSP) on clinical grounds. (dovepress.com)
- Diagnosis of Krabbe disease is by DNA analysis and/or detecting enzyme deficiency in white blood cells or cultured skin fibroblasts. (msdmanuals.com)
- Krabbe Disease (KD), also known as globoid cell Leukodystrophy, is a fatal neurodegenerative lysosomal storage disorder caused by deficiency of galactosylceramidase (GALC) that affects both central and peripheral nervous systems. (buffalo.edu)
Metachromatic leukodystrophy2
- The differential diagnosis is largely that of other leukodystrophies , mainly metachromatic leukodystrophy 12 . (radiopaedia.org)
- Any disease (such as globoid cell leukodystrophy, adrenoleukodystrophy, or metachromatic leukodystrophy) whose hallmarks are metabolic defects in the formation of myelin. (tabers.com)
Galactosylceramidase2
- GLS is caused by loss-of-function mutations in the galactosylceramidase (galc) gene, but several neuropathological data have suggested a relevant role of adaptive immunity and CD8+ T cells in GLD. (aini.it)
- Galactosylceramidase (Galc) is a lysosomal enzyme involved in the catabolism of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. (ptglab.com)
Disorders8
- Leukodystrophies are a group of rare genetic disorders that affect the central nervous system (CNS). (medlineplus.gov)
- Most metabolic disorders are inherited from one or both parents who carry a defective gene that regulates a particular protein in a class of the body's cells. (newworldencyclopedia.org)
- It is one of a group of genetic disorders called leukodystrophies. (disabled-world.com)
- Lipid storage diseases (also known as lipidoses) are a group of inherited metabolic disorders in which harmful amounts of fatty materials (lipids) accumulate in various cells and tissues in the body. (nih.gov)
- Niemann-Pick disease is a group of autosomal recessive disorders caused by an accumulation of fat and cholesterol in cells of the liver, spleen, bone marrow, lungs, and, in some instances, brain. (nih.gov)
- Leukodystrophies are frequently regarded as childhood disorders, but they can occur at any age, and the clinical and imaging patterns of the adult-onset form are usually different from the better-known childhood variants. (dovepress.com)
- The resulting stem cells are known as hematopoietic or blood-forming stem cells because they are similar to bone marrow cells, which have been widely used in the treatment of a variety of genetic disorders, blood diseases, and autoimmune diseases such as lupus, diabetes , and kidney disease , as well as in post-cancer therapies. (stemcellcareindia.com)
- Today, Umbilical Cord Blood (UCB) stem cells are used in the treatment of over 105 ailments in Thailand, including cardiovascular disease, cancer, hereditary/genetic diseases, and blood disorders such as sickle cell anaemia. (stemcellcareindia.com)
GALC4
- As a result of insufficient GALC function, galactosylceramide is not properly degraded and accumulates in myelin-producing cells. (slovgen.sk)
- Immunofluorescent analysis of (4% PFA) fixed SH-SY5Y cells using 51051-2-AP (GALC antibody) at dilution of 1:50 and Alexa Fluor 488-conjugated AffiniPure Goat Anti-Rabbit IgG(H+L). (ptglab.com)
- Hematopoietic stem cell transplantation (HSCT) partially attenuates the course of KD only if performed before the onset of symptoms, presumably because stem cell derivatives secrete GALC that is uptaken by myelinating glia via the mannose-6-phosphate receptor, so called cross-correction. (buffalo.edu)
- and 3) GALC uptake is less efficient in Galc-null cells in vitro, and surrounding WT cells provides minimal GALC to Galc-deficient OLs in vivo, indicating inefficient cross-correction of GALC. (buffalo.edu)
Late-onset forms1
- Studies indicate that early unrelated hematopoietic stem cell transplantation in both the infantile and late-onset forms is associated with at least short-term benefits on neurocognitive parameters, lifespan, and quality of life. (medscape.com)
Diffuse1
- None of the patients had evidence of diffuse leukodystrophy on neuroimaging. (dovepress.com)
Mutations1
- These severe mutations are believed to result in misfolding of the newly synthesized protein, which then accumulates in the endoplasmic reticulum and triggers apoptosis, or programmed cell death. (medscape.com)
Galactocerebrosidase1
- Deficiency of galactocerebrosidase results in the accumulation of galactosylceramide within the lysosomes of Schwann cells and oligodendrocytes which eventually results in apoptosis with secondary abnormal activation of microglia and macrophages with subsequent demyelination and gliosis 2,9,10 . (radiopaedia.org)
Murine1
- METHODS: We longitudinal monitored visual evoked potentials after the orthotopic implant of murine glioma cells into the mouse occipital cortex. (bvsalud.org)
Enzymes2
- The instructions for building nearly all the enzymes involved in metabolism are stored as deoxyribonucleic acid (DNA) in the nucleus of the cell. (newworldencyclopedia.org)
- Sphingolipidoses Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. (msdmanuals.com)
Metabolic1
- A metabolic disorder is any disease or disorder that negatively affects the biochemical reactions through which individual animal cells process nutrient molecules (such as the components of carbohydrates , proteins , and fats ) to yield energy or perform the functions necessary to sustain life (such as building complex molecules and creating cellular structure). (newworldencyclopedia.org)
Macrophages1
- The multinucleated macrophages are known as globoid cells 10 . (radiopaedia.org)
Pediatric2
- Domen J, Gandy K, Dalal J. Emerging uses for pediatric hematopoietic stem cells. (bethematchclinical.org)
- She is currently completing her graduate thesis research in the Crocker neuroscience lab, where she has been investigating the role of T-cells in Globoid Cell Leukodystrophy, a rare pediatric neurological disease. (jointmeeting.org)
Hereditary1
- We performed genetic analysis using a custom-designed gene panel for leukodystrophies in 112 hereditary spastic paraplegia-like patients. (dovepress.com)
Apoptosis2
- PKC is an important signaling molecule in numerous cell pathways, including cell differentiation, proliferation and apoptosis. (medscape.com)
- PKC isozymes are LR-dependent molecules that link psychosine-induced LR disruption to reduced PKC function and altered cell signaling activity, possibly driving demyelination and apoptosis in oligodendrocytes and Schwann cells. (medscape.com)
Hematopoietic cell transplantation2
- 1,2] Allogeneic hematopoietic cell transplantation (HCT) can prevent this progressive deterioration by introducing enzyme-producing cells that can cross the blood-brain barrier. (bethematchclinical.org)
- Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. (bethematchclinical.org)
Symptoms4
- What are the symptoms of leukodystrophies? (medlineplus.gov)
- Leukodystrophies can be hard to diagnose because there are so many different types which can have different symptoms. (medlineplus.gov)
- For pre-symptomatic infants and older individuals with mild symptoms, hematopoietic stem cell transplantation (HSCT) with cord blood is beneficial over symptomatic treatment only. (disabled-world.com)
- Patients with late-onset spastic paraplegia should be screened for underlying leukodystrophies, irrespective of the presence of additional complicating symptoms and neuroimaging abnormalities. (dovepress.com)
Umbilical cord1
- Prognosis may be significantly better for children who receive umbilical cord blood stem cells before disease onset or early bone marrow transplantation. (disabled-world.com)
Accumulation1
- As myelin forms a protective sheath around nerve cells and ensures the rapid transmission of nerve impulses, its deficit caused by the accumulation of galactosylceramide leads to damage of the nervous system. (slovgen.sk)
Lipids2
- Lipids are fat-like substances that are important parts of the membranes found within and between cells and in the myelin sheath that coats and protects the nerves. (nih.gov)
- Tiny bodies within cells called lysosomes regularly convert, or metabolize, the lipids and proteins into smaller components to provide energy for the body. (nih.gov)
Body's cells1
- These fatty materials are stored naturally in the body's cells, organs, and tissues. (nih.gov)
Affects2
- It thus affects both the peripheral nervous system and the central nervous system (manifesting as a leukodystrophy ). (radiopaedia.org)
- Each of the leukodystrophies affects one (and only one) of these substances. (disabled-world.com)
Type2
- One type of leukodystrophy, CTX, is treatable if it is diagnosed early. (medlineplus.gov)
- When a stem cell divides, the resultant cell has the option of remaining the same or converting into a different type with a different purpose. (stemcellcareindia.com)
Injections1
- Donors of blood, on the other hand, will have to go through multiple tests for clearance before receiving a series of GSF injections to encourage the release of cells from the bone marrow into the blood. (stemcellcareindia.com)
Transplantation3
- Stem cell or bone marrow transplantation can be helpful for a few types of leukodystrophy. (medlineplus.gov)
- Therapy primarily centers on hematopoietic stem cell transplantation which can delay disease progression 11 . (radiopaedia.org)
- Hematopoietic stem cell transplantation for patients with mucopolysaccharidosis II. (bethematchclinical.org)
Patients1
- The objective of this study was to investigate the frequency of late-onset leukodystrophies in patients with spastic paraplegia. (dovepress.com)
Syndrome1
- Zellweger Syndrome Central Nervous System Diseases Nerve Cells [Lodish et al. (geometry.net)
Differentiation1
- This process is known as differentiation, and it serves as the foundation for cell treatment in Delhi NCR. (stemcellcareindia.com)
Schwann1
- A study by White et al (2009) found that psychosine's cytotoxic effects on oligodendroglia and Schwann cells was mediated through disruption of the architecture and composition of lipid rafts (cell membrane regions characterized by high cholesterol and sphingolipid concentration), followed by altered protein kinase C (PKC) function. (medscape.com)
Bone1
- Stem cells are nature's pharmacy and can be found in everyone's bone marrow, adipose fat, tooth pulp derived or peripheral blood. (stemcellcareindia.com)
Germ1
- if the germ cells are affected, this damage can be inherited . (newworldencyclopedia.org)
Disease progression1
- studied the role of cytotoxic CD8+ T lymphocytes in a mouse model of GLD, showing that the influx of highly activated CD8+ T cells correlates with disease progression. (aini.it)
Adult Stem1
- Cord blood contains unusually high quantities of adult stem cells, which eventually grow into hematopoietic blood cells. (stemcellcareindia.com)
Immune1
- On the other hand, Ad vectors also have a number of disadvantages, including their low transduction efficiency in cells lacking coxsackievirus-adenovirus receptor (CAR) and their induction of innate immune responses. (hindawi.com)
Nerve2
- It also helps speed up signals between the nerve cells. (medlineplus.gov)
- When the white matter is damaged, it can slow down or block the signals between nerve cells. (medlineplus.gov)