Mucopolysaccharidoses, which are also known as mucopolysaccharide storage (MPS) diseases, are a group of rare genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes. The lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, undegraded mucopolysaccharides in the cells of the body causes a number of physical symptoms and abnormalities.
Sly syndrome (MPS-VII) is an MPS storage disease caused by a deficiency of the enzyme beta-glucuronidase that leads to an accumulation of dermatan sulfate (DS), heparan sulfate (HS) and chondroitin sulfate (CS) in many tissues and organs of the body including the central nervous system.
The clinical features of Sly syndrome vary from patient to patient, but all have short stature due to growth retardation, changes in bones visible on X-rays and some degree of mental retardation. Survival into adulthood is common with milder cases and osteoarthritis is a common complication.
The symptoms of Sly Syndrome are similar to those of Hurler Syndrome (MPS I) and the other Mucopolysaccharidoses. Symptoms may include mental retardation, short stature with an unusually short trunk, and/or abnormalities of the intestines, corneas of the eyes, and/or the skeletal system. Sly Syndrome is inherited as an autosomal recessive genetic trait.
In some cases, the symptoms of Sly syndrome may be obvious during early infancy. Other cases of this disorder may be diagnosed during late infancy or childhood. The most common feature of Sly syndrome is moderate and nonprogressive mental retardation that is usually evident around the age of 3 years. Developmental delays in speech and language may occur. Children with this disorder may develop an unusual “coarse” facial appearance. Between the ages of 7 months and 8 years, cloudiness (opacity) may occur in the corneas of the eyes. A severe form of Sly syndrome may affect newborns (neonates) and is characterized by multiple bone malformations at birth and the accumulation of excessive fluid in many parts of the body (hydrops fetalis) and neonatal jaundice.
Children with Sly syndrome may have an unusually short trunk and growth retardation, resulting in short stature (short trunk dwarfism). The head may be excessively large (macrocephalic) and the neck may be short. A variety of multiple bone deformities (dysostosis multiplex), which are frequently observed in people with mucopolysaccharidoses, are also common in children with Sly syndrome. These bone deformities may include a prominent breast bone (pectus carinatum), flared ribs, frequent hip dislocations, “frozen” joints (contractures), club foot, and/or an inward curve of the knees and outward bowing of the ankles (genu valgum). In some rare cases, spinal malformations may be present including mild curvature of the spine from side to side (scoliosis) and/or front to back (kyphosis).
Occasionally, other symptoms of Sly syndrome may include a swollen abdomen due to abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) and protrusion of the intestines through an abnormal opening in the muscular wall of the abdomen (inguinal hernia). In some cases, the intestines may also protrude through the abdominal wall in the area of the navel (umbilical hernia). Some affected children may experience profound hearing loss, recurrent upper respiratory and middle ear infections, thickening of the soft tissues of the throat and/or vocal cords, an abnormally enlarged tongue (macroglossia), and/or heart problems (i.e., heart murmur or aortic regurgitation). Excessive hairiness (hirsutism) may be present.
Survival to age 19-20 years has been reported in mild cases. Life expectancy is reduced as a result of frequent upper respiratory tract infections, neurodegenerative complications and abnormalities of the gastrointestinal tract.
Six cases of a mild form of Sly syndrome, beginning during the 2nd decade of life, have been described in the medical literature. In these cases, the symptoms of the disorder appear to be less severe than classical Sly syndrome and may include minor bony changes and very mild facial coarseness. Growth rate and mental abilities are usually normal. Abnormal enlargement of the liver and spleen has not been noticed in this form of Sly syndrome.
Sly syndrome is inherited as an autosomal recessive genetic trait. Symptoms develop due to a deficiency of the enzyme beta-glucuronidase. The gene responsible for this disorder is located on the long arm of chromosome 7 (7q21.11) and has been termed the GUSB gene. A variety of different changes (mutations) in this particular gene (allelic variations) may account for the wide range of symptoms and physical findings as well as the variability in the age of onset.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Sly syndrome is extremely rare, affecting only about one in one million births. Fewer than 100 cases have been reported in the United States. Males and females are affected in equal numbers.
Urinary levels of the mucopolysaccharides dermatan sulfate, heparan sulfate and chondroitin sulfate are increased in affected individuals. The diagnosis of Sly syndrome may be confirmed by a thorough clinical evaluation that includes a detailed patient history and specialized tests that measure the level of beta-glucuronidase activity in skin fibroblasts or blood leukocytes. Prenatal diagnosis is also possible through amniocentesis or chorionic villus sampling for beta-glucuronidase activity.
The treatment of Sly syndrome is symptomatic and supportive. Bone deformities and hernias may require surgical correction. Ocular and cardiovascular abnormalities may also be treated surgically. Patients with MSP storage disorders may be sensitive to anesthesia because of malformations in the airway or cervical spine; therefore, precautions should be taken prior to surgery. Genetic counseling will be helpful for people with Sly syndrome and their families.
Enzyme replacement therapy and bone marrow transplantation are being investigated for the treatment of this disorder. Scientific study of these therapies in animal models raises the hope that they may someday be made available to people with genetic disorders such as Sly syndrome or other Mucopolysaccharidoses. Neither therapy has been attempted yet in humans.
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