Sly syndrome (Mucopolysaccharidosis type VII, Sly syndrome) - Gen GUSB.
Mucopolysaccharidoses encompasses a group of inherited metabolic diseases caused by the absence or malfunction of certain necessary for processing glycosaminoglycans, found in bone, cartilage, tendons, corneas, skin and connective tissue enzymes. The glycosaminoglycans (formerly called mucopolysaccharides) are also present in the synovial fluid of the joints. People suffering from mucopolysaccharidosis not encode sufficient quantities of one of the eleven enzymes required to transform glycosaminoglycans in protein and simpler molecules, or encode enzymes that do not work properly. Over time, these glycosaminoglycans accumulate in cells, blood and connective tissues. This produces permanent and progressive cellular damage that affect the appearance and physical abilities, organs and body functions of the individual and, in most cases, mental development.
Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome is a progressive disease that affects most tissues and organs. MPS VII severity varies widely among affected individuals.
More severe cases of MPS are characterized by fetal hydrops. Most babies with fetal hydrops are stillborn or die shortly after birth. Others affected, they begin to show signs and symptoms of the disease during early childhood. These signs and symptoms can include microcephaly, hydrocephalus, macroglossia, hepatosplenomegaly, valvular heart abnormalities, umbilical hernia or inguinal hernia. Furthermore, the airway can become narrow in some individuals, resulting in frequent respiratory infections and sleep apnea. Over time, the cornea becomes opaque, which can cause significant loss of vision. Other signs and symptoms may include recurrent ear infections, hearing loss, developmental delay, progressive mental retardation. Likewise, the disease causes various skeletal abnormalities which are most noticeable with age, including short stature, joint deformities that affect mobility, dysostosis multiplex, carpal tunnel syndrome and spinal stenosis in the neck that can compress and damage spinal cord.
The life expectancy of individuals with MPS VII depends on the severity of symptoms. Some affected individuals do not survive childhood, while others may live into adolescence or adulthood. Heart disease and obstruction of the airways are the main causes of death in people with MPS VII.
Type VII mucopolysaccharidosis (MPS VII) is due to mutations in the GUSB gene, located on the long arm of chromosome 7 (7q21.11). This gene encoding the enzyme beta-glucuronidase (?-glucuronidase), involved in the breakdown of glycosaminoglycans (GAG). Glycosaminoglycan molecules consist of carbohydrate that are bonded together to form a long chain. ?-glucuronidase enzyme is involved in the decomposition of the three types of GAG: dermatan sulfate, heparan sulfate and chondroitin sulfate. This enzyme removes a carbohydrate, glucuronic acid when at the end of the GAG chain.
They have identified at least 55 GUSB gene mutations associated with Sly syndrome (MPS VII). Most of these mutations change nucleotides in the gene. All GUSB gene mutations reduce or completely eliminate the function of the ?-glucuronidase, which leads to accumulation of GAGs inside the cells, specifically in the lysosomes. Lysosomes digest and recycle different types of molecules. Due to the accumulation of molecules within lysosomes, this disease is considered an alteration of lysosomal storage. Accumulation of GAG increases the size of lysosomes, so many tissues and organs are enlarged. Furthermore, glycosaminoglycans likely interfere with the functions of other proteins in lysosomes, disrupting various cellular functions.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with Sly syndrome (MPS VII), by complete PCR amplification of exons GUSB gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).