Mucopolysaccharidoses VII - SLY syndrome

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To a bitter understanding of mucopolysaccharidoses VII a life threatening disease also known as SLY sydrome (after Dr. William Sly who originally described the condition in 1972).

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Prepared by Student: B. A. El-Dabour IUGAZA

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Mucopolysaccharides are long chains of sugar molecule used in the building of connective tissues in the body. "saccharide" is a general term for a sugar molecule (think of saccharin) "poly" means many "muco" refers to the thick jelly-like consistency of the molecules (they are found in mucus). They are formed almost entirely of polysaccharides with a little amount of proteins which gives them the name proteoglycans. (note the difference between glycoproteins and proteoglycans) Also known as glycosaminoglycans “GAGs”

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importance:  - they help build  bone,  cartilage,  tendons,  skin  and connective tissue. Glycosaminoglycans (formerly called mucopolysaccharides ) are also found in the fluid that lubricates our synovial joints. GAGs in the ECM of connective tissue

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Production: Protein cores made in the rough endoplasmic reticulum are posttranslationally modified by glycosyltransferases in the Golgi apparatus, where GAG disaccharides are added to protein cores to yield proteoglycans. Degradation: different GAGs are degradated in in cellular lysosomes by a group of specialized enzymes.

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Mucopolysaccharidosis The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans. Main mucopolysaccharidoses : 1-MPS I :Hurler syndrome – deficiency of alpha-L-iduronidase 2-MPS II :Hunter syndrome – deficiency of iduronate sulfatase (similar, but milder, symptoms to Hurler syndrome). 3-MPS IV Morquio syndrome– deficiency of Galactose 6-sulfatase. 4-MPS VII : Sly syndrome ß Glucoronidase. ( rarest disorder)

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Mucopolysaccharidosis type VII (MPS VII) is a very rare lysosomal storage disease (is estimated to occur in fewer than one in 250,000 births). Sly syndrome is caused by deficiency of the enzyme ß -glucuronidase. Pathophysiology: In MPS VII the molecular defect on the gene that encodes ß-glucuronidase protein (GUSB) leads to deficiency of the enzyme ß-glucuronidase. This enzyme is required for the breakdown of several GAGs, including dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS). Accumulation of DS, HS, and CS takes place in the lysosome of many systems and tissues, including the CNS. Note:The GAG itself is not toxic but It’s accomulation is dangerous.

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Heparan sulfate: Heparan sulfate (HS) is a linear polysaccharide  found in all animal tissues. It occurs as a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. It is in this form that HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation  and tumour metastasis. Dermatan sulfate: Dermatan sulfate is a GAG found mostly in skin , but also in blood vessels , heart valves, tendons , and lungs . Dermatan sulfate Heparan sulfate

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Genetics: The GUSB is located on chromosome 7 and contains 12 exons. The defect in GUSB is responsible for Sly syndrome. More than 45 mutation different mutations have been identified, approximately 90% of which were point mutations. Sex: Males and females are affected in equal numbers. Which indicates that this is not X-linked mutation.

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Age: As a point of emphasis, Sly syndrome is one of the few MPSs and lysosomal storage diseases that may be clinically evident at birth, and even the most severe defects may appear prenatally. In other forms, defects may present during the first years of life. In the milder forms, clinical features may not be evident until later. How is MPS VII inherited? MPS VII is a genetic recessive disease; which means that both parents have to be carriers of the defective gene. This way,they will always have a 25% of having a sick child. All mucopolysaccharidises are autosomal except for MPS II or Hunter syndrome, which is transmitted as a sex-linked recessive trait.

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Clinical problems in MPS VII: Growth: Growth in height is usually significantly less than normal but varies according to the severity of the disease. Intelligence: Individuals with the severe form of MPS VII experience progressive storage of GAG in the brain that is primarily responsible for the slowing of development by 1–3 years of age, followed by a progressive regression in skills until death.

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Nose, throat, chest and ear problems: Nose: Individuals with MPS VII may have chronic discharge of thick mucus from the nose (rhinorrhea) and chronic ear and sinus infections. Throat: The tonsils and adenoids often become enlarged and partly block the airway. The windpipe (trachea) becomes narrowed by storage material and may be floppy or softer than usual due to abnormal cartilage rings in the trachea. Chest: The shape of the chest is frequently abnormal and the junction between the ribs and the breastbone (sternum) is not as flexible as it should be. The chest is therefore rigid and cannot move freely to allow the lungs to take in a large volume of air.

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The result: Breathing difficulties

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Mouth: Individuals with MPS VII generally have thick lips and an enlarged tongue. Heart: Heart disease is common in individuals with the severe form of MPS VII, but may not develop or cause any real problems until later in the individual’s life. Coronary artery disease caused by GAG storage in the heart blood vessels may occur and can lead to death.

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Liver and spleen: In individuals with MPS VII, both liver and spleen become enlarged (hepatosplenomegaly) by accumulation of GAG. The large liver does not usually cause liver problems, but it can interfere with eating and breathing and the proper fitting of clothes.

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Abdomen hernias are also common. Corneal clouding

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How is MPS VII diagnosed? -Doctors may consider testing for MPS VII when signs and symptoms of the disease are present and are not explained by other causes. -To diagnose MPS VII, the doctor will typically first do a urine test to look for levels of GAG that are higher than normal. -A urine test is only one of the first steps in diagnosing MPS VII; a clear diagnosis requires a test to measure levels of enzyme activity in the blood or skin cells. In healthy individuals, the tests show white blood cells, serum and skin cells that contain normal levels of enzyme activity. In individuals with MPS VII, the enzyme activity levels are much lower or absent. Early diagnosis of MPS VII is critical. The earlier MPS VII is diagnosed, the sooner potential treatment options can be explored and supportive care may be started to help you or your loved one and potentially prevent some of the permanent damage that may be caused by the disease.

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General treatment and “Management”

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The goals of managing MPS VII are to improve quality of life, to slow down the progression of the disease, to prevent permanent tissue and organ damage. Currently there is no cure for MPS VII. However, early intervention may help prevent irreversible damage.

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Diet: There is no scientific evidence that a particular diet has any helpfull effect on individuals with MPS VII, and symptoms such as diarrhea tend to come and go naturally. Some parents find that a change in their child’s diet can ease problems such as excessive mucus, diarrhea or hyperactivity. Reducing intake of milk, dairy products and sugar, as well as avoiding foods with too many additives and coloring, have helped some individuals.

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Physical therapy/sports Joint stiffness is a common feature ofMPS VII. Limitation of motion and joint stiffness can cause significant loss of function. Range-of-motion exercises (passive stretching and bending of the limbs) may offer some benefits in preserving joint function, and should be started early. Individuals with MPS VII should be as active as possible to maintain their joint function and improve their general health. However, competitive sports should be avoided.

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Specific treatment of MPS VII 1-Hematopoietic Stem Cell Transplant (HSCT). 2-enzyme replacement . 3-gene therapy.

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Hematopoietic Stem Cell Transplant: The goal of HSCT for MPS VII is to restore the activity of the deficient enzyme, ß-glucuronidase, which may improve such symptoms as enlarged liver and spleen, joint stiffness, sleep apnea, heart disease. In this scenario, the blood cells circulating through the child’s body are from the normal donor and, therefore, have normal levels of the deficient lysosomal enzyme. As the cells circulate they can secrete some of their enzymes and potentially correct the defect in some tissues.

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Enzyme replacement therapy (ERT) Enzyme replacement therapy has been approved for several of the MPS diseases. The recombinant enzyme is typically given by weekly intravenous infusion. Although ERT has not been attempted in patients with MPS VII, this approach has been shown to be very effective in animal models of this disease. There is reason to hope that ERT will help some of the physical problems, but the bloodbrain barrier may prevent enzyme therapy from directly helping the brain.

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Gene therapy: Gene therapy research conducted in animals with MPS VII has shown positive results. There are plans to begin a clinical gene therapy trial in individuals with MPS VII.

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Life Expectancy:Life expectancy is younger than two to three months of age for children inflicted with an extreme case of MPS VII. Life expectancy for those with milder forms of MPS VII is varied: Some can live until their teenaged years while others can live to adulthood.

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We wish a better future for all patients with MPS and we thank allah for giving us health.

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Thank You…