Mucopolysaccharidosis
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Mucopolysaccharidosis | |
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A 16-year-old male with rapidly progressing MPS-VI, showing characteristic facial features and skeletal abnormalities | |
Specialty | Endocrinology |
Mucopolysaccharidoses are a group of
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
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 (
Another lysosomal storage disease often confused with the mucopolysaccharidoses is
Genetics
It is estimated that 1 in 25,000 babies born in the United States will have some form of the mucopolysaccharidoses.
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
Type[3] | Common name Other names |
OMIM
|
Gene | Locus | Deficient enzyme | Accumulated products | Symptoms | Incidence |
---|---|---|---|---|---|---|---|---|
MPS IH | Hurler syndrome | 607014 | IDUA
|
4p16.3 | α-L-iduronidase
|
Heparan sulfate Dermatan sulfate |
micrognathia, coarse facial features, macroglossia, retinal degeneration, corneal clouding, cardiomyopathy, hepatosplenomegaly
|
1:100,000[4] |
MPS IH/S | Hurler–Scheie syndrome | 607015 | ||||||
MPS IS | Scheie syndrome Formerly: Mucopolysaccharidosis type V |
607016 | ||||||
MPS II | Hunter syndrome | 309900 | IDS
|
Xq28 | Iduronate sulfatase
|
Heparan sulfate Dermatan sulfate |
X-linked recessive inheritance
|
1:100,000-1:150,000 males[1] |
MPS IIIA | Sanfilippo syndrome A Sulfamidase deficiency |
252900 | SGSH | 17q25.3 | Heparan sulfamidase
|
Heparan sulfate | motor dysfunction , death by the second decade
|
1:280,000[5] – 1:50,000[6] |
MPS IIIB | Sanfilippo syndrome B NAGLU deficiency |
252920 | NAGLU | 17q21.2 | N-acetylglucosaminidase
| |||
MPS IIIC | Sanfilippo syndrome C | 252930 | HGSNAT | 8p11.21 | Heparan-α-glucosaminide N-acetyltransferase
| |||
MPS IIID | Sanfilippo syndrome D | 252940 | GNS
|
12q14.3 | N-acetylglucosamine 6-sulfatase
| |||
MPS IVA | Morquio syndrome A | 253000 | GALNS
|
16q24.3 | Galactose-6-sulfate sulfatase
|
Chondroitin 6-sulfate
|
Severe skeletal dysplasia , short stature, motor dysfunction
|
1 in 75,000[5] |
MPS IVB | Morquio syndrome B | 253010 | GLB1 | 3p22.3 | β-galactosidase
|
Keratan sulfate | ||
MPS V | See MPS IS (Scheie syndrome) above | |||||||
MPS VI | Maroteaux–Lamy syndrome ARSB deficiency |
253200 | ARSB
|
5q14.1 | N-acetylgalactosamine-4-sulfatase | Dermatan sulfate | Severe skeletal dysplasia, short stature, motor dysfunction, kyphosis , heart defects
|
|
MPS VII | Sly syndrome GUSB deficiency |
253220 | GUSB
|
7q11.21 | β-glucuronidase
|
Chondroitin 4,6-sulfate
|
Hepatomegaly, skeletal dysplasia, short stature, corneal clouding, developmental delay | <1:250,000[1] |
MPS IX | Natowicz syndrome Hyaluronidase deficiency |
601492 | 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 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
MPS II,
MPS III
MPS III,
Thickened skin and mild changes in facial features, bone, and skeletal structures become noticeable with age. Growth in height usually stops by age 10. Other problems may include narrowing of the airway passage in the throat and enlargement of the
There are four distinct types of Sanfilippo syndrome, each caused by alteration of a different enzyme needed to completely break down the heparan sulfate sugar chain. Little clinical difference exists between these four types but symptoms appear most severe and seem to progress more quickly in children with type A. The average duration of Sanfilippo syndrome is 8 to 10 years following onset of symptoms. Most persons with MPS III live into their teenage years, and some live longer.
- Sanfilippo A is the most severe of the MPS III disorders and is caused by the missing or altered enzyme heparan N-sulfatase. Children with Sanfilippo A have the shortest survival rate among those with the MPS III disorders.
- Sanfilippo B is caused by the missing or deficient enzyme alpha-N-acetylglucosaminidase.
- Sanfilippo C results from the missing or altered enzyme acetyl-CoAlpha-glucosaminide acetyltransferase.
- Sanfilippo D is caused by the missing or deficient enzyme N-acetylglucosamine 6-sulfatase.
The incidence of Sanfilippo syndrome (for all four types combined) is about one in 70,000 births.
MPS IV
MPS IV, Morquio syndrome, is estimated to occur in 1 in 700,000 births. Its two subtypes result from the missing or deficient enzymes N-acetylgalactosamine-6-sulfatase (GALNS) (Type A) or beta-galactosidase (Type B) needed to break down the keratan sulfate sugar chain. Clinical features are similar in both types but appear milder in Morquio Type B. Onset is between ages 1 and 3. Neurological complications include spinal nerve and nerve root compression resulting from extreme, progressive skeletal changes, particularly in the ribs and chest; conductive and/or neurosensitive loss of hearing and clouded corneas. Intelligence is normal unless hydrocephalus develops and is not treated.
Physical growth slows generally around the age of 18 months, and stops completely by the age of 8. Skeletal abnormalities include a bell-shaped chest, a flattening or curvature of the spine, shortened long bones, and dysplasia of the hips, knees, ankles, and wrists. The bones that stabilize the connection between the head and neck can be malformed (odontoid hypoplasia); in these cases, a surgical procedure called spinal cervical bone fusion can be lifesaving. Restricted breathing, joint stiffness, and heart disease are also common. Children with the more severe form of Morquio syndrome may not live beyond their twenties or thirties.
MPS VI
Children with MPS VI, Maroteaux–Lamy syndrome, usually have normal intellectual development but share many of the physical symptoms found in Hurler syndrome. Caused by the deficient enzyme N-acetylgalactosamine 4-sulfatase, Maroteaux-Lamy syndrome has a variable spectrum of severe symptoms. Neurological complications include clouded corneas, deafness, thickening of the dura (the membrane that surrounds and protects the brain and spinal cord), and pain caused by compressed or traumatized nerves and nerve roots.
Growth is normal at first but stops suddenly around age 8. By age 10 children have developed a shortened trunk, crouched stance, and restricted joint movement. In more severe cases, children also develop a protruding abdomen and forward-curving spine. Skeletal changes (particularly in the pelvic region) are progressive and limit movement. Many children also have umbilical or inguinal hernias. Nearly all children have some form of heart disease.
An enzyme replacement therapy was tested on patients with MPS VI and was successful in that it improved growth and joint movement. An experiment was then carried out to see whether an injection of the missing enzyme into the hips would help the range of motion and pain.
MPS VII
MPS VII, Sly syndrome, one of the least common forms of the mucopolysaccharidoses, is estimated to occur in fewer than one in 250,000 births. The disorder is caused by deficiency of the enzyme beta-glucuronidase. In its rarest form, Sly syndrome causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body. Survival is usually a few months or less. Most children with Sly syndrome are less severely affected. Neurological symptoms may include mild to moderate intellectual disability by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision. Other symptoms include short stature, some skeletal irregularities, joint stiffness and restricted movement, and umbilical and/or inguinal hernias. Some patients may have repeated bouts of pneumonia during their first years of life. Most children with Sly syndrome live into the teenage or young adult years.
MPS IX
As of 2001, only one case of
Treatment
Currently there is no cure for these disorders. Medical care is directed at treating systemic conditions and improving the person's quality of life. Physical therapy and daily exercise may delay joint problems and improve the ability to move.
Changes to the diet will not prevent disease progression, but limiting milk, sugar, and dairy products has helped some individuals experiencing excessive mucus.
Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea. Sleep studies can assess airway status and the possible need for nighttime oxygen. Some patients may require surgical insertion of an endotrachial tube to aid breathing. Surgery can also correct hernias, 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 patients with significant corneal clouding.
See also
- Alder–Reilly anomaly — a morphologic abnormality of white blood cells associated with mucopolysaccharidosis
- Lysosomal storage disease
References
- ^ a b c "Mucopolysaccharidoses Face Sheet". National Institute of Neurological Disorders and Stroke. 15 Nov 2017. Archived from the original on 18 August 2016. Retrieved 11 May 2018.
- ^ "Mucopolysaccharidosis type I: MedlinePlus Genetics". medlineplus.gov. Retrieved 30 January 2023.
- ISBN 978-0-7817-8624-9.
- ^ eMedicine Specialties > Mucopolysaccharidosis Type I Author: Maryam Banikazemi. Updated: Apr 14, 2009
- ^ S2CID 23099247.
- PMID 10480370.
- ^ "Aldurazyme (laronidase) for MPS I and approved in April 2003". BioMarin. Retrieved 12 June 2015.
- ^ "Naglazyme". Drugs@FDA: FDA-Approved Drugs.
- ^ "MEPSEVIITM (vestronidase alfa-vjbk)" (PDF). Highlights of Prescribing Information. U.S. Food and Drug Administration.