Morquio Syndrome (Mucopolysaccharidosis type IV) - Genes and GLB1 GALNS.
The type IV mucopolysaccharidosis (MPS IV), also known as Morquio syndrome, is a progressive disorder that primarily affects the skeleton. The rate at which symptoms worsen varies among affected individuals. In general, the early signs and symptoms of MPS IV become apparent in infancy. Affected individuals develop various skeletal abnormalities, including short stature, impaired knees, ribs, chest, spine, hips and wrists. Often, those affected have hypermobility or otherwise may have restricted movement in some joints. A characteristic feature of this disorder is the hypoplasia of the odontoid, which helps stabilize the cervical vertebrae. Odontoid hypoplasia can lead to misalignment of the cervical vertebrae, which can compress and damage the spinal cord, which can lead to paralysis or death. Generally, in people with the disease, the cornea becomes cloudy and can cause vision loss. Some people affected with recurrent ear infections and hearing loss. Airway may narrow in some people, leading to frequent respiratory infections and sleep apnea. Other common features of this disease include thin tooth enamel, abnormal heart valves, hepatomegaly and umbilical or inguinal hernia. Unlike other types of mucopolysaccharidosis, MPS IV does not affect intelligence.
The life expectancy of individuals depends on the severity of symptoms. Severely affected individuals can survive only until late childhood or adolescence. People with milder forms of the disease usually live into adulthood, although their life expectancy can be reduced. Compression of the spinal cord and the obstruction of the airways are major causes of death in people with the disease.
This process is due to mutations in the GALNS and GLB1 gene.
The GALNS gene, located on the long arm of chromosome 16 (16q24.3), encoding the enzyme N-acetylgalactosamine 6-sulfatase. This enzyme is found in lysosomes, and is involved in the breakdown of glycosaminoglycans (GAGs) or mucopolysaccharides. Specifically, this enzyme removes GAG sulfates (Keratan sulfate), particularly abundant in cartilage and cornea.
They have identified more than 148 mutations in the GALNS gene causing the disease. When the disease is caused by mutations in the gene GALNS called MPS type IVA (MPS IVA). Most of these mutations change the gene isolated nucleotide. All mutations that cause MPS IV reduce or eliminate the function of the N-acetylgalactosamine 6-sulfatase. The lack of activity of N-acetylgalactosamine 6-sulfatase leads to accumulation of keratan sulfate within lysosomes. The accumulation of this substance causes skeletal abnormalities and corneal opacity. It is believed that an accumulation of GAGs can also cause the characteristics of the disease by interfering with the functions of other proteins within the lysosomes and interrupting the movement of molecules within the cell.
The GLB1 gene, located on the short arm of chromosome 3 (3p21.33), encoding the enzyme beta-galactosidase (?-galactosidase), located in the lysosomes, which helps break down certain molecules, including substances called gangliosides GM1 and keratan sulfate. The ganglioside GM1 is important for the normal functioning of nerve cells in the brain, and keratan sulfate is particularly abundant in cartilage and cornea. The GLB1 gene also encodes the protein elastin binding, which interact at the cell surface with cathepsin A 1 and neuraminidase proteins to form the elastin receptor complex. This complex plays a role in the formation of elastic fibers.
They have identified more than 10 mutations in the gene cause the disease GLB1. When it caused by mutations in the gene GLB1 called MPS type IV B (MPS IVB). Most of these mutations change individual nucleotides in the gene. All mutations disrupt the breakdown of keratan sulfate of ?-galactosidase by. GM1 ganglioside degradation is not affected by these mutations. The lack of ?-galactosidase activity leads to accumulation of keratan sulfate within the lysosomes causing skeletal abnormalities and corneal opacity. It is believed that an accumulation of GAGs can also cause the characteristics of the disease by interfering with the functions of other proteins within the lysosomes and interrupting the movement of molecules within the cell.
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 in IVAMI: in IVAMI perform detection of mutations associated with type IV mucopolysaccharidosis (MPS IV), by complete PCR amplification of the exons of GALNS and GLB1 respectively genes 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).