NORD gratefully acknowledges Roland Rebuyon, NORD Editorial Intern from the University of Notre Dame, and Debra S. Regier, MD PhD, Director, Genetic and Genomic Education,Division of Genetics and Metabolism, Children's National Health System, for assistance in the preparation of this report.
Mucopolysaccharidosis IV (MPS IV) is a mucopolysaccharide storage disease that exists in two forms (MPS IVA and MPS IVB). These are autosomal recessive genetic conditions that comprise a continuum consisting of a severe form with rapid progression and another slowly progressing form. The severe form becomes apparent between the ages of one and three and typically presents with knock-knees and breastbone prominence. The slowly progressing form, which may not become apparent until adolescence, presents with hip pain and stiffness.
Although they are subtypes of the same disease, it is important to distinguish MPS IVA from MPS IVB for the purposes of effective treatment and disease management. MPS IVA can only be distinguished from MPS IVB by molecular genetic or biochemical testing because of the similarities in the symptoms they present. MPS IV occurs because of a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase (GALNS) and MPS IVB occurs due to a deficiency of beta-galactosidase.
A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with MPS IV have normal intelligence. The clinical features of MPS IVB are usually fewer and milder than those associated with MPS IVA. Enzyme replacement therapy is available to treat MPS IVA.
The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis.
Symptoms of MPS IV may include growth retardation; a prominent lower face; abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis) or concern for a spine abnormality; an abnormally short neck; knees that are abnormally close together (knock knees or genu valgum); flat feet; abnormal development of the growing ends of the long bones (epiphyses); hip dislocation and arthritis and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or additional abnormalities may also occur.
Affected children have a characteristic facial appearance that may include an enlarged head, broad mouth, prominent cheekbones, an unusually small nose, widely spaced and thinly enameled teeth, and widely separated eyes with subtle corneal clouding. The liver and spleen may be mildly enlarged. Children with MPS IV show marked growth retardation with short trunks and normal limbs from early in life. The elbows, wrists, hips, knees and other large joints are abnormally flexible, causing overall instability. Affected individuals exhibit a waddling gait with frequent falls. Early development and intelligence are typically normal, unlike other MPS storage disorders. High frequency hearing impairment is common.
Skeletal X-rays typically show marked flattening of the vertebra. The long bones of the arms and legs are characteristically shorter and thicker than normal. The skull is large for the rest of the body. The connection between the first and second vertebrae in the neck is poorly developed and this abnormality can be life threatening. A trivial injury may cause the two vertebrae to slip on each other and compress the spinal cord. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can be lifesaving but life expectancy is decreased somewhat despite surgery. The deformity of the chest causes a strain on the heart and lungs, which may eventually cause respiratory failure.
MPS IVA is an autosomal recessive genetic disorder caused by deficiency of the GALNS enzyme due to mutations in the GALNS gene.
MPS IVB is an autosomal recessive genetic disorder caused by deficiency of the beta-galactosidase enzyme due to mutations in the GLB1 gene.
Both lead to an accumulation of keratan sulfate (KS) in the cells and tissues of the body. The accumulation of KS in the cornea and bone leads to reduced vision and skeletal deformities, respectively. The two types never occur together in the same family.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
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 receives 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 defective 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. 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.
MPS IV affects males and females equally often. Estimates of prevalence range from 1/40,000 to 1/200,000 births. MPS IVA (95% of individuals affected by MPS IV) occurs more often than MPS IVB (5% of affected individuals).
As a group, lysosomal storage diseases (of which the MPS are a subgroup) are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world.
MPS IV diagnosis is suggested by the findings of medical history, physical examinations, skeletal X-rays, and urine glycosaminoglycans (GAG) analysis. Excessive amounts of keratan sulfate will usually be present in the urine.
Diagnosis of MPS IVA is confirmed by low GALNS enzyme activity in cultured blood or skin cells and/or molecular genetic testing to identify GALNS gene mutations.
MPS IVB diagnosis is confirmed by the finding of a beta-galactosidase deficiency in blood or skin cells and/or molecular genetic testing to identify GLB1 gene mutations.
In 2014, the FDA approved a recombinant human GALNS enzyme replacement therapy (elosulfase alfa, or Vimizim) for the treatment of MPS IVA:
Weekly infusions of the drug are now available for MPS IVA patients through BioMarin Pharmaceutical Inc.:
Other treatment of MPS IV is symptomatic and supportive. Surgery to decompress and fuse the bones of the upper neck to the base of the skull can prevent destabilization of the cervical vertebrae and potential damage to the spinal cord.
Management of affected individuals with MPS IV is best undertaken by multiple specialists, including: a physical therapist for physical rehabilitation, a psychiatrist for psychological support, educational professionals for learning optimization, and home care professionals for affected individuals with medical equipment dependence.
Surgeons may also play a crucial role in treating affected individuals. The placement of a bioprosthetic or prosthetic valve may be required for affected induvial with ventricular hypertrophy (overgrowth). Enlarged tonsils and adenoids may need to be removed in order to relieve upper-airway obstruction and sleep apnea. Additionally, ventilation tubes and hearing aids may be needed for individuals with hearing loss. Penetrating keratoplasty (corneal replacement) may be needed to treat corneal opacification (scarring or clouding of the cornea), which causes impaired vision.
Since children with MPS IVA are of normal intelligence, they usually attend regular classes, but they made need to sit close to the front of the classroom if they have difficulties hearing or seeing. They may also need to use a wheelchair around school grounds.
Genetic counseling is recommended for affected individuals and their families.
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