Mucopolysaccharidosis

# Overview
The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. Glycosaminoglycans (formerly called mucopolysaccharides) are also found in the fluid that lubricates our joints.
The mucopolysaccharidoses are classified as lysosomal storage diseases. These are conditions in which large numbers of molecules that are normally broken down or degraded into smaller pieces by intracellular units called lysosomes accumulate in harmful amounts in the body's cells and tissues, particularly in the lysosomes.

# Classification Scheme
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

## 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.
Hurler syndrome (MPS I H or -L-iduronidase deficiency):   It 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.
- 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.
- Large at birth
- May have inguinal  or umbilical 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, or cardiac complications.
Scheie syndrome (MPS I S): It  is the mildest form of MPS I.
- Symptoms generally begin to appear after age 5, with diagnosis most commonly made after age 10.
- Normal intelligence or may have mild learning disabilities; some may have psychiatric problems.
- Glaucoma, retinal degeneration, and clouded corneas may significantly impair vision.
- 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.
Hurler-Scheie syndrome (MPS I H-S):   It is less severe than Hurler syndrome alone.
- Symptoms generally begin between ages 3 and 8.
- Moderate mental retardation 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
- 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
Hunter syndrome  (MPS II or iduronate sulfatase deficiency) is caused by lack of the enzyme iduronate sulfatase. Hunter syndrome has two clinical subtypes and (since it shows X-linked recessive inheritance) is the only one of the mucopolysaccharidoses in which the mother alone can pass the defective gene to a son. The incidence of Hunter syndrome is estimated to be 1 in 100,000 to 150,000 male births.
MPS II A:  It more severe form of Hunter syndrome, share many of the same clinical features associated with Hurler syndrome (MPS I H) but with milder symptoms. Onset of the disease is usually between ages 2 and 4.
- Developmental decline is usually noticed between the ages of 18 and 36 months, followed by progressive loss of skills.
- Coarse facial features
- Skeletal irregularities
- Obstructive airway and respiratory complications
- Short stature
- Joint stiffness
- Retinal degeneration (but no corneal clouding)
- Communicating hydrocephalus
- Chronic diarrhea
- Enlarged liver
- Enlarged spleen
- Progressive hearing loss
- Whitish skin lesions may be found on the upper arms, back, and upper legs. Death from upper airway disease or cardiovascular failure usually occurs by age 15.
MPS II B : They are less obvious and progress at a much slower rate. Diagnosis is often made in the second decade of life.
- Intellect and social development are not affected.
- Skeletal problems may be less severe, but carpal tunnel syndrome and joint stiffness can restrict movement and height is somewhat less than normal.
- Hearing loss
- Poor peripheral vision
- Diarrhea
- Sleep apnea
- Although respiratory and cardiac complications can contribute to premature death. Persons with MPS II B may live into their 50s or beyond.

## MPS III
Sanfilippo syndrome (MPS III) is marked by severe neurological symptoms.
- Progressive dementia
- Aggressive behavior
- Hyperactivity
- Seizures
- Some deafness
- Loss of vision
- An inability to sleep for more than a few hours at a time.
- Thickened skin
- Mild changes in facial features, bone, and skeletal structures become noticeable with age
- Growth in height usually stops by age 10
- Narrowing of the airway passage in the throat and enlargement of the tonsils and adenoids, making it difficult to eat or swallow.
- Recurring respiratory infections are common.
This disorder tends to have three main stages.
- First stage:  Early mental and motor skill development may be somewhat delayed. Affected children show a marked decline in learning between ages 2 and 6, followed by eventual loss of language skills and loss of some or all hearing. Some children may never learn to speak.
- Second stage:  Aggressive behavior, hyperactivity, profound dementia, and irregular sleep may make children difficult to manage, particularly those who retain normal physical strength.
- Third stage: Children become increasingly unsteady on their feet and most are unable to walk by age 10.
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
Morquio syndrome (MPS IV) is estimated to occur in 1 in 700,000 births. Its two subtypes result from the missing or deficient enzymes N-acetylgalactosamine 6-sulfatase (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
- Particularly in the ribs and chest
- Conductive and/or neurosensitive loss of hearing (see "What are the signs and symptoms?");
- Clouded corneas
- Intelligence is normal unless hydrocephalus develops and is not treated.
- Physical growth slows and often stops between the ages of 4-8.
- 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
Maroteaux-Lamy syndrome (MPS VI) 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.
- Clouded corneas
- Deafness
- Thickening of the dura (the membrane that surrounds and protects the brain and spinal cord)
- 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, usually involving valve dysfunction.

## MPS VII
Sly syndrome (MPS VII) is 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.
- Hydrops fetalis
- Mild to moderate mental retardation by age 3
- Communicating hydrocephalus
- Nerve entrapment
- Corneal clouding
- Some loss of peripheral and night vision
- Short stature
- Some skeletal irregularities
- Joint stiffness and restricted movement
- Umbilical and/or inguinal hernias
- 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.
- Survival is usually a few months or less. Most children with Sly syndrome are less severely affected.

## MPS IX
As of 2001, only one case of MPS IX (Online Mendelian Inheritance in Man (OMIM) 601492) had been reported. The disorder results from hyaluronidase deficiency. Symptoms included nodular soft-tissue masses located around joints, with episodes of painful swelling of the masses and pain that ended spontaneously within 3 days. Pelvic radiography showed multiple soft-tissue masses and some bone erosion. Other traits included mild facial changes, acquired short stature as seen in other MPS disorders, and normal joint movement and intelligence.

# Pathophysiology
People with a mucopolysaccharidosis either do not produce enough of one of the 11 enzymes required to break down these sugar chains into proteins and simpler molecules, or they produce enzymes that do not work properly. Over time, these glycosaminoglycans collect in the cells, blood and connective tissues. The result is permanent, progressive cellular damage that affects the individual's appearance, physical abilities, organ and system functioning, and, in most cases, mental development.

## Genetics
It is an autosomal recessive disorder, 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.  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.

# Causes

# Differentiating Mucopolysaccharidosis from other Disorders
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.

# Epidemiology and Demographics
It is estimated that 1 in 25,000 babies born in the United States will have some form of the mucopolysaccharidoses.

# Natural History, Complications and Prognosis
Prognosis depends on the type of mucopolysaccharidosis. Prognosis is usually poor if the disease has an early onset and is severe.

# Diagnosis

## Diagnostic Criteria

## History 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 glycosaminoglycans affects bone, skeletal structure, connective tissues, and organs. Depending on the mucopolysaccharidoses subtype, affected individuals may have
- Normal intellect or may be profoundly retarded
- May experience developmental delay or may have severe behavioral problems
- Conductive hearing loss (in which pressure behind the ear drum causes fluid from the lining of the middle ear to build up and eventually congeal), neurosensitive (in which tiny hair cells in the inner ear are damaged), or both.
- Communicating hydrocephalus  is common in some of the mucopolysaccharidoses.
- Cornea become cloudy from intracellular storage
- Glaucoma and degeneration of the retina also may affect the patient's vision.
- Recurring respiratory infections are common
- Obstructive airway disease and obstructive sleep apnea
- Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.
- 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.

## Physical Examination

### Appearance
- Short stature with disproportionately short trunk (dwarfism)

### Skin
- Thickened skin
- Excessive body hair growth

### HEENT
- Coarse or rough facial features (including a flat nasal bridge, thick lips, and enlarged mouth and tongue)

### Abdomen
- Enlarged organs such as liver or spleen
- Hernias

### Extremities
- Dysplasia (abnormal bone size and/or shape) and other skeletal irregularities
- Short and often claw-like hands,
- Progressive joint stiffness, and carpal tunnel syndrome can restrict hand mobility and function.

## Laboratory Findings
- 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.
- Amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder.

## Imaging Findings

## Other Diagnostic Studies

# Treatment

## Medical Therapy
- 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.
- Enzyme replacement therapies are currently in use or are being tested. Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain. Currently BioMarin Pharmaceutical produces enzyme replacement therapies for MPS type I and VI.  In July 2006, the United States Food and Drug Administration approved a synthetic version of I2S produced by Shire Pharmaceuticals Group, called Elaprase, as a treatment for MPS type II (Hunter syndrome).

## Surgery
- Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea.
- Some patients may require surgical insertion of an endotracheal 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.
- 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.

## Prevention