About sly syndrome

What is sly syndrome?

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.

What are the symptoms for sly syndrome?

Irritability or restlessness symptom was found in the sly syndrome condition

The most severe cases of MPS VII are characterized by hydrops fetalis, or when excess fluid accumulates in the body before birth. This can result in a stillborn or death shortly after birth. Neonatal jaundice or the yellowing of the skin may occur.

Children with more mild cases of MPS VII begin to show symptoms in early childhood. Children with MPS VII may have an unusually short trunk and growth disability, 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 MPS VII. 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).Rarely, spinal malformations may be present including mild curvature of the spine from side to side (scoliosis) and/or front to back (kyphosis). 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.

Affected individuals may have developmental delays in language and speech and progressive intellectual disability, although intelligence is normal in some people with this condition.

Other symptoms of MPS VII 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 children, 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.

Children may develop carpal tunnel syndrome characterized by numbness, tingling and Weakness in the hands and fingers.

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.

A mild form of MPS VII, beginning during the 2nd decade of life, has been described in the medical literature. In these patients, the symptoms of the disorder appear to be less severe than classical MPS VII 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 MPS VII.

What are the causes for sly syndrome?

MPS VII is caused by changes (mutations) in the GUSB gene that lead to deficiency of the beta-glucuronidase enzyme. A variety of different mutations in this gene may account for the wide range of symptoms and physical findings as well as the variability in the age of onset.

The beta-glucuronidase enzyme is involved in the breakdown of large sugar molecules called glycosaminoglycans or GAGs. The shortage of beta-glucuronidase leads to a buildup of GAGs in the cells, specifically in the lysosomes. Lysosomes digest and recycle molecules; this disorder causes a lysosomal storage disorder. The accumulation of GAGs increases the size of the lysosomes causing the tissues and organs to become enlarged. GAGs are believed to interpret the function of proteins within the lysosomes and disrupt the normal function of cells.

MPS VII is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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 is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

What are the treatments for sly syndrome?

In 2017, Mepsevii (vestronidase alfa-jvbk), an enzyme replacement therapy, was approved to treat pediatric and adult patients with MPS VII. Mepsevii is manufactured by Ultragenyx Pharmaceutical, Inc.

Other treatment of MPS VII is symptomatic and supportive. Bone deformities and hernias may require surgical correction. Ocular and cardiovascular abnormalities may also be treated surgically. Patients with MSP 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 is recommended for people with MPS VII and their families.

Hematopoietic Stem Cell Therapy (HSCT) A Japanese patient underwent successful HSCT at 12 years of age and after 2 years the levels of GUS were stable, with improvement of motor functions (walking, riding, and taking bath alone), recurrent infections and snoring; neurological damage has been kept stable (Yamada et al., 1998). A Mexican female patient with MPS VII with genotype p.P408S/p.P415L underwent HSCT at 11 years of age and was reported to be doing well 2 years after the transplantation (Islam et al., 1996). There were more than 7 patients that underwent HSCT (Islam et al., 1996; Yamada et al., 1998; Montaño et al., 2016). The limited results suggest that HSCT can slow or even prevent further neurological complications, but has little to no effect on the skeletal disease unless it is performed in an early stage.

What are the risk factors for sly syndrome?

There are a few risk factors that can make you more likely to get sly syndrome.

  • One of the main risk factors is age-sly syndrome is most commonly diagnosed in people between ages 45 and 65. It's more common in men than women, but it can happen to anyone of any age and gender.
  • Also, One of the main risk factors for Sly syndrome is genetic. If someone in your family has Sly syndrome, you have a higher chance of developing it yourself.
  • Another risk factor for Sly syndrome is having certain genes that affect how your body works or how it interacts with other things in the environment, like chemicals or viruses.
  • Some people also have conditions that put them at higher risk for Sly syndrome, like kidney disease or diabetes-related to obesity or being overweight.
  • Another factor that increases your risk for the sly syndrome is having a history of other autoimmune diseases like rheumatoid arthritis or multiple sclerosis. If you have one of these conditions, you may be at greater risk for developing sly syndrome as well.
  • Finally, if you're pregnant or have been within the last six months, it might be a good idea to talk with your doctor about whether or not you should get tested for Sly Syndrome.

Fever,Shortness of breath,Coughing up blood (hemoptysis),Chest pain or shortness of breath with exercise or exertion,Loss of appetite and weight loss (cachexia)
Infections (such as tuberculosis),Inflammatory conditions (such as rheumatoid arthritis or Crohn's disease),Blood disorders (such as polycythemia vera or hemophilia)

Is there a cure/medications for sly syndrome?

The sly syndrome is a rare genetic disorder that causes the body to produce too much of a hormone called ACTH.

  • There is no cure for sly syndrome, but there are medications that can help you manage it.
  • The first step in treating Sly syndrome is getting your blood pressure under control with medications such as blood pressure medicine or diuretics (water pills).
  • The next step is to control your cortisol levels by taking glucocorticoids (corticosteroids).
  • If these medications don't work or your symptoms worsen, you may need surgery to remove part of your adrenal gland or have an implant near your pituitary gland that releases hormones into your bloodstream.
  • There are two types of medications that can help reduce the symptoms of sly syndrome: anticonvulsants (which treat seizures) and botulinum toxin injections (which treat muscle spasms).
  • These medications help by regulating the electrical signals in your brain and nervous system.
  • The best treatment for Sly syndrome is a combination of medication and lifestyle changes.
  • Your doctor may prescribe various medications to treat Sly syndrome's symptoms, including oral steroids (Prednisone), anti-inflammatory drugs (NSAIDs), and anticonvulsants.

Fever,Shortness of breath,Coughing up blood (hemoptysis),Chest pain or shortness of breath with exercise or exertion,Loss of appetite and weight loss (cachexia)
Infections (such as tuberculosis),Inflammatory conditions (such as rheumatoid arthritis or Crohn's disease),Blood disorders (such as polycythemia vera or hemophilia)

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