Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. GAGs (formerly called mucopolysaccharides) are also found in the fluids that lubricate joints.
Individuals with mucopolysaccharidosis either do not produce enough of one of the eleven enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly. Over time, these GAGs collect in the cells, blood and connective tissues. The result is permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning.
The mucopolysaccharidoses are part of the lysosomal storage disease family, a group of genetic disorders that result when the lysosome organelle in animal cells malfunctions. The lysosome can be thought of as the cell's recycling center because it processes unwanted material into other substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival. Lysosomal disorders like mucopolysaccharidosis are triggered when a particular enzyme exists in too small an amount or is missing altogether.
Signs and symptoms
The mucopolysaccharidoses share many clinical features but have varying degrees of severity. These features may not be apparent at birth but progress as storage of GAGs affects bone, skeletal structure, connective tissues, and organs. Neurological complications may include damage to neurons (which send and receive signals throughout the body) as well as pain and impaired motor function. This results from compression of nerves or nerve roots in the spinal cord or in the peripheral nervous system, the part of the nervous system that connects the brain and spinal cord to sensory organs such as the eyes and to other organs, muscles, and tissues throughout the body.
Depending on the mucopolysaccharidosis subtype, affected individuals may have normal intellect or have cognitive impairments, may experience developmental delay, or may have severe behavioral problems. Many individuals have hearing loss, either conductive (in which pressure behind the eardrum causes fluid from the lining of the middle ear to build up and eventually congeal), neurosensory (in which tiny hair cells in the inner ear are damaged), or both. Communicating hydrocephalus—in which the normal reabsorption of cerebrospinal fluid is blocked and causes increased pressure inside the head—is common in some of the mucopolysaccharidoses. Surgically inserting a shunt into the brain can drain fluid. The eye's cornea often becomes cloudy from intracellular storage, and glaucoma and degeneration of the retina also may affect the patient's vision.
Physical symptoms generally include coarse or rough facial features (including a flat nasal bridge, thick lips, and enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism), dysplasia (abnormal bone size and/or shape) and other skeletal irregularities, thickened skin, enlarged organs such as liver (hepatomegaly) or spleen (splenomegaly), hernias, and excessive body hair growth. Short and often claw-like hands, progressive joint stiffness, and carpal tunnel syndrome can restrict hand mobility and function. Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea. Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.
Another lysosomal storage disease often confused with the mucopolysaccharidoses is mucolipidosis. In this disorder, excessive amounts of fatty materials known as lipids (another principal component of living cells) are stored, in addition to sugars. Persons with mucolipidosis may share some of the clinical features associated with the mucopolysaccharidoses (certain facial features, bony structure abnormalities, and damage to the brain), and increased amounts of the enzymes needed to break down the lipids are found in the blood.
Genetics
It is estimated that 1 in 25,000 babies born in the United States will have some form of the mucopolysaccharidoses. Approximately 1 in 100,000 newborns will experience severe mucopolysaccharidosis type I, while approximately 1 in 500,000 newborns will experience attenuated mucopolysaccharidosis type I. Most mucopolysaccharidoses are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children.
Diagnosis Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder. Genetic counseling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.
Types Seven distinct clinical types and numerous subtypes of the mucopolysaccharidoses have been identified. Although each mucopolysaccharidosis (MPS) differs clinically, most patients generally experience a period of normal development followed by a decline in physical and/or mental function. (Note: MPS-V and MPS-VIII are no longer in use as designations for any disease.)
Overview table + Main mucopolysaccharidoses Type Common nameOther names OMIM Gene Locus Deficient enzyme Accumulated products Symptoms Incidence MPS IH Hurler syndrome IDUA 4p16.3 α-L-iduronidase Heparan sulfateDermatan sulfate Intellectual disability, micrognathia, coarse facial features, macroglossia, retinal degeneration, corneal clouding, cardiomyopathy, hepatosplenomegaly 1:100,000eMedicine Specialties > Mucopolysaccharidosis Type I Author: Maryam Banikazemi. Updated: Apr 14, 2009 MPS IH/S Hurler–Scheie syndrome MPS IS Scheie syndromeFormerly: Mucopolysaccharidosis type V MPS II Hunter syndrome IDS Xq28 Iduronate sulfatase Heparan sulfateDermatan sulfate Intellectual disability (similar, but milder, symptoms to MPS I). This type exceptionally has X-linked recessive inheritance 1:100,000-1:150,000 males MPS IIIA Sanfilippo syndrome ASulfamidase deficiency SGSH 17q25.3 Heparan sulfamidase Heparan sulfate Developmental delay, severe hyperactivity, spasticity, motor dysfunction, death by the second decade 1:280,000 – 1:50,000 MPS IIIB Sanfilippo syndrome BNAGLU deficiency NAGLU 17q21.2 N-acetylglucosaminidase MPS IIIC Sanfilippo syndrome C HGSNAT 8p11.21 Heparan-α-glucosaminide N-acetyltransferase MPS IIID Sanfilippo syndrome D GNS 12q14.3 N-acetylglucosamine 6-sulfatase MPS IVA Morquio syndrome A GALNS 16q24.3 Galactose-6-sulfate sulfatase Keratan sulfateChondroitin 6-sulfate Severe skeletal dysplasia, short stature, motor dysfunction 1 in 75,000 MPS IVB Morquio syndrome B GLB1 3p22.3 β-galactosidase Keratan sulfate MPS V See MPS IS (Scheie syndrome) above MPS VI Maroteaux–Lamy syndromeARSB deficiency ARSB 5q14.1 N-acetylgalactosamine-4-sulfatase Dermatan sulfate Severe skeletal dysplasia, short stature, motor dysfunction, kyphosis, heart defects MPS VII Sly syndromeGUSB deficiency GUSB 7q11.21 β-glucuronidase Heparan sulfateDermatan sulfateChondroitin 4,6-sulfate Hepatomegaly, skeletal dysplasia, short stature, corneal clouding, developmental delay <1:250,000 MPS IX Natowicz syndromeHyaluronidase deficiency HYAL1 3p21.31 Hyaluronidase Hyaluronic acid Nodular soft-tissue masses around joints, episodes of painful swelling of the masses, short-term pain, mild facial changes, short stature, normal joint movement, normal intelligence
MPS I MPS I is divided into three subtypes based on severity of symptoms. All three types result from an absence of, or insufficient levels of, the enzyme alpha-L-iduronidase. Children born to an MPS I parent carry the defective gene. MPS I H (also called Hurler syndrome or α-L-iduronidase deficiency), is the most severe of the MPS I subtypes. Developmental delay is evident by the end of the first year, and patients usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Language may be limited due to hearing loss and an enlarged tongue. In time, the clear layers of the cornea become clouded and retinas may begin to degenerate. Carpal tunnel syndrome (or similar compression of nerves elsewhere in the body) and restricted joint movement are common.
Affected children may be quite large at birth and appear normal but may have inguinal (in the groin) or umbilical (where the umbilical cord passes through the abdomen) hernias. Growth in height may be faster than normal but begins to slow before the end of the first year and often ends around age 3. Many children develop a short body trunk and a maximum stature of less than 4 feet. Distinct facial features (including flat face, depressed nasal bridge, and bulging forehead) become more evident in the second year. By age 2, the ribs have widened and are oar-shaped. The liver, spleen, and heart are often enlarged. Children may experience noisy breathing and recurring upper respiratory tract and ear infections. Feeding may be difficult for some children, and many experience periodic bowel problems. Children with Hurler syndrome often die before age 10 from obstructive airway disease, respiratory infections, and cardiac complications. MPS I S, Scheie syndrome, is the mildest form of MPS I. Symptoms generally begin to appear after age 5, with diagnosis most commonly made after age 10. Children with Scheie syndrome have normal intelligence or may have mild learning disabilities; some may have psychiatric problems. Glaucoma, retinal degeneration, and clouded corneas may significantly impair vision. Other problems include carpal tunnel syndrome or other nerve compression, stiff joints, claw hands and deformed feet, a short neck, and aortic valve disease. Some affected individuals also have obstructive airway disease and sleep apnea. Persons with Scheie syndrome can live into adulthood. MPS I H-S, Hurler–Scheie syndrome, is less severe than Hurler syndrome alone. Symptoms generally begin between ages 3 and 8. Children may have moderate intellectual disability and learning difficulties. Skeletal and systemic irregularities include short stature, marked smallness in the jaws, progressive joint stiffness, compressed spinal cord, clouded corneas, hearing loss, heart disease, coarse facial features, and umbilical hernia. Respiratory problems, sleep apnea, and heart disease may develop in adolescence. Some persons with MPS I H-S need continuous positive airway pressure during sleep to ease breathing. Life expectancy is generally into the late teens or early twenties.
Although no studies have been done to determine the frequency of MPS I in the United States, studies in British Columbia estimate that 1 in 100,000 babies born has Hurler syndrome. The estimate for Scheie syndrome is one in 500,000 births and for Hurler-Scheie syndrome it is one in 115,000 births.
MPS II