Mucopolysaccharidosis type IVA

Other Names: MPS IVA; MPS 4A; Morquio A disease; Galactosamine-6-sulfatase deficiency; GALNS deficiency; Morquio disease type A; MPS4A; MPSIVA; Mucopolysaccharidosis type 4A; N-acetylgalactosamine-6-sulfate sulfatase deficiency; Morquio syndrome A

Mucopolysaccharidosis type IVA (MPS IVA, also called Morquio syndrome, type A) is a metabolic condition that primarily affects the skeleton. The severity, age of onset, and associated symptoms vary significantly from person to person and range from a severe and rapidly progressive, early-onset form to a slowly progressive, later-onset form. The severe form is usually diagnosed between ages 1 and 3, while the milder form may not become evident until late childhood or adolescence.

Corneal clouding in a 30-year-old male with MPS VI. Morquio syndrome and other MPS disorders may also present with corneal clouding

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

he 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.

Diagnosis

Mucopolysaccharidosis IVA (MPS IVA) should be suspected in an individual with the following findings on medical history, physical examination, skeletal radiographs, and ophthalmologic examination; and suggestive laboratory findings [Wood et al 2013].

Medical history

• No distinctive clinical findings at birth
• History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS disorders)
• History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique to MPS IVA among all MPS disorders)
• Respiratory compromise (sleep apnea, endurance limitations, snoring)
• Cardiac valve abnormalities
• Dental abnormalities

Physical examination. In severe MPS IVA the following findings are usually observed between ages one and three years; in slowly progressive MPS IVA the following findings may not become evident until as late as the second decade of life:

• Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
• Ulnar deviation of the wrists
• Pectus carinatum and flaring of the lower rib cage
• Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
• Genu valgum (knock-knee)
• Hypermobile joints
• Waddling gait with frequent falls

Suggestive laboratory findings Qualitative urine glycosaminoglycan (GAG) analysis, which uses thin layer chromatography or electrophoresis to identify specific types of GAG , demonstrates keratan sulfate and chondroitin 6-sulfate. Quantitative urine GAG analysis, which measures the total amount of GAG, demonstrates: Elevated keratan sulfate (KS), indicating deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in MPS IVB); Note: Urine KS levels in younger individuals (≤18 years) is higher than in older individuals due to the decrease in cartilage formation in older persons . Elevated chondroitin 6-sulfate (C6S), indicating deficiency of the enzyme N-acetylglactosamine 6-sulfatase (MPS IVA).

Urine keratan sulfate analysis is more sensitive than standard dye-based total GAG quantitative analysis and may be used to replace urine total GAGs in the future. Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when GAG analysis is normal.

Treatment

The treatment for Morquio syndrome consists of prenatal identification and of enzyme replacement therapy. On 12 February 2014, the US Food and Drug Administration approved the drug elosulfase alfa (Vimizim) for treating Type A. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• elosulfase alfa (Brand name: Vimizim) Patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome)