Mucopolysaccharidosis type IV (MPS IV), also known as Morquio syndrome, is a progressive condition that mainly affects the skeleton. The rate at which symptoms worsen varies among affected individuals.

The first signs and symptoms of MPS IV usually become apparent during early childhood. Affected individuals develop various skeletal abnormalities, including short stature, knock knees, and abnormalities of the ribs, chest, spine, hips, and wrists. People with MPS IV often have joints that are loose and very flexible (hypermobile), but they may also have restricted movement in certain joints. A characteristic feature of this condition is underdevelopment (hypoplasia) of a peg-like bone in the neck called the odontoid process. The odontoid process helps stabilize the spinal bones in the neck (cervical vertebrae). Odontoid hypoplasia can lead to misalignment of the cervical vertebrae, which may compress and damage the spinal cord, resulting in paralysis or death.

In people with MPS IV, the clear covering of the eye (cornea) typically becomes cloudy, which can cause vision loss. Some affected individuals have recurrent ear infections and hearing loss. The airway may become narrow in some people with MPS IV, leading to frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). Other common features of this condition include mildly "coarse" facial features, thin tooth enamel, multiple cavities, heart valve abnormalities, a mildly enlarged liver (hepatomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). Unlike some other types of mucopolysaccharidosis, MPS IV does not affect intelligence.

The life expectancy of individuals with MPS IV depends on the severity of symptoms. Severely affected individuals may survive only until late childhood or adolescence. Those with milder forms of the disorder usually live into adulthood, although their life expectancy may be reduced. Spinal cord compression and airway obstruction are major causes of death in people with MPS IV.

Mutations in the GALNS and GLB1 genes cause MPS IV. These genes provide instructions for producing enzymes involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name. When MPS IV is caused by mutations in the GALNS gene it is called MPS IV type A (MPS IVA), and when it is caused by mutations in the GLB1 gene it is called MPS IV type B (MPS IVB). In general, the two types of MPS IV cannot be distinguished by their signs and symptoms.

Mutations in the GALNS and GLB1 genes reduce or completely eliminate the activity of the enzymes produced from these genes. Without these enzymes, GAGs accumulate within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that break down and recycle different types of molecules. Conditions such as MPS IV that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. In MPS IV, GAGs accumulate to toxic levels in many tissues and organs, particularly in the bones. The accumulation of GAGs causes the bone deformities in this disorder. Researchers believe that the buildup of GAGs may also cause the features of MPS IV by interfering with the functions of other proteins inside lysosomes and disrupting the movement of molecules inside the cell.

Normal Function

The GALNS gene provides instructions for producing an enzyme called N-acetylgalactosamine 6-sulfatase. This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. N-acetylgalactosamine 6-sulfatase is involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs) or mucopolysaccharides. Specifically, this enzyme removes a chemical group known as a sulfate from a GAG called keratan sulfate. Keratan sulfate is particularly abundant in cartilage and the clear covering of the eye (cornea).

Health Conditions Related to Genetic Changes

Mucopolysaccharidosis type IV

More than 148 mutations in the GALNS gene have been found to cause mucopolysaccharidosis type IV (MPS IV). Most of these mutations change single DNA building blocks (nucleotides) in the gene. All of the mutations that cause MPS IV reduce or eliminate the function of N-acetylgalactosamine 6-sulfatase.

The lack of N-acetylgalactosamine 6-sulfatase activity leads to the accumulation of keratan sulfate within lysosomes. Because keratan sulfate is predominantly found in cartilage and the cornea, the buildup of this substance causes skeletal abnormalities and cloudy corneas. Researchers believe that a buildup of GAGs may also cause the features of MPS IV by interfering with the functions of other proteins inside lysosomes and disrupting the movement of molecules inside the cell.

Other Names for This Gene

• chondroitinase
• chondroitinsulfatase
• FLJ17434
• FLJ42844
• FLJ98217
• galactosamine (N-acetyl)-6-sulfate sulfatase
• galactose-6-sulfate sulfatase
• GALNAC6S
• galNAc6S sulfatase
• GALNS_HUMAN
• GAS
• MPS4A
• N-acetylgalactosamine-6-sulfatase
• N-acetylgalactosamine-6-sulfatase precursor
• N-acetylgalactosamine-6-sulfate sulfatase

Genomic Location

Normal Function

The GLB1 gene provides instructions for producing two different proteins. The primary protein produced from the GLB1 gene is an enzyme called beta-galactosidase (β-galactosidase). This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. β-galactosidase helps break down certain substances, including GM1 ganglioside and keratan sulfate. GM1 ganglioside is important for normal functioning of nerve cells (neurons) in the brain. Keratan sulfate is particularly abundant in cartilage and the clear covering of the eye (cornea). Keratan sulfate belongs to a group of large sugar molecules called glycosaminoglycans or mucopolysaccharides.

The GLB1 gene also provides instructions for making the elastin-binding protein. This protein is smaller than β-galactosidase and is found on the surface of cells rather than in lysosomes. Elastin-binding protein interacts with other proteins called cathepsin A and neuraminidase 1. This group of proteins forms the elastin receptor complex. This complex plays a role in building elastic fibers, which are a component of the connective tissue that forms the body's supportive framework.

Health Conditions Related to Genetic Changes

GM1 gangliosidosis

Many variants (also called mutations) in the GLB1 gene have been found to cause GM1 gangliosidosis. The signs and symptoms of this condition primarily result from the loss of neurons in the brain and spinal cord over time. Most variants change single DNA building blocks (nucleotides) in the GLB1 gene. These variants often affect the production of both β-galactosidase and elastin-binding protein.

The GLB1 gene variants that cause GM1 gangliosidosis produce versions of β-galactosidase that are not as effective at breaking down GM1 ganglioside and keratan sulfate as the normal version of the enzyme. As a result, these substances build up to toxic levels in many tissues and organs. In the brain, damage caused by the buildup of GM1 ganglioside leads to the loss of neurons, which causes intellectual disability, movement problems, and many of the signs and symptoms of GM1 gangliosidosis.

It is not clear how changes in the elastin-binding protein affect the development of GM1 gangliosidosis. The altered protein may cause the weakened heart muscle (cardiomyopathy) found in some people with GM1 gangliosidosis.

Mucopolysaccharidosis type IV

Variants in the GLB1 gene have been found to cause mucopolysaccharidosis type IV (MPS IV). This is a progressive condition that mainly affects the skeleton. Most of the variants that cause MPS IV change single nucleotides in the GLB1 gene. All of the variants that cause MPS IV disrupt the breakdown of keratan sulfate by β-galactosidase. The breakdown of GM1 ganglioside is not affected by these variants.

Because keratan sulfate is predominantly found in cartilage and the cornea, the buildup of this substance causes skeletal abnormalities and cloudy corneas. Researchers believe that a buildup of glycosaminoglycans may also cause the features of MPS IV by interfering with the functions of other proteins inside lysosomes and disrupting the movement of molecules inside the cell.

Other Names for This Gene

• BGAL_HUMAN
• EBP
• elastin receptor 1, 67kDa
• ELNR1

Genomic Location

• 25% (1 in 4) chance to be affected
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not be a carrier

• Coarse facial features
• Hypermobile joints
• Corneal clouding and vision loss
• Heart valve abnormalities
• Respiratory complications, including airway obstruction, sleep apnea and restrictive lung disease
• Widely-spaced, discolored teeth with thin enamel
• Mild to moderate hearing loss
• Mild hepatomegaly

• X-rays
• Specialized urine and blood tests
• Eye exam
• Skin fibroblast culture
• Genetic testing to identify mutations in the GALNS or GLB1 genes

Currently, there is no cure for these disorders. Medical care is directed at treating systemic conditions and improving the person's quality of life. Changes to the diet will not prevent disease progression.

Surgery can help drain excessive cerebrospinal fluid from the brain and free nerves and nerve roots compressed by skeletal and other abnormalities. Corneal transplants may improve vision among individuals with significant corneal clouding. Removing the tonsils and adenoids may improve breathing among individuals with obstructive airway disorders and sleep apnea. Some people may require surgical insertion of an endotracheal tube to aid breathing.

Enzyme replacement therapy is currently in use for MPS I, MPS II, MPS IVA, MPS VI, and MPS VII, and is being tested in other MPS disorders. It does not cure the neurological manifestations of the disease but has proven useful in reducing non-neurological symptoms and pain.

Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have had limited success in treating the mucopolysaccharidoses. Abnormal physical characteristics, except for those affecting the skeleton and eyes, may be improved, but neurologic outcomes have varied. BMT and UCBT are high-risk procedures and are usually performed only after family members receive extensive evaluation and counseling.

Physical therapy and daily exercise may delay joint problems and improve movement.