Seven distinct clinical types and numerous subtypes of mucopolysaccharidoses have been identified. Although each mucopolysaccharidosis (MPS) differs clinically, most individuals experience a period of normal development followed by a decline in physical and/or mental function.
MPS I has historically been divided into three broad groups based on severity of symptoms in decreasing order—Hurler, Hurler-Scheie, and Scheie. (Scheie syndrome was previously known as MPS V before being included in MPS I.)
MPS I may be viewed as a continuous spectrum of disease, with the most severely affected individuals on one end, the less severely affected on the other end, and a wide range of different severities in between. All individuals with MPS I have an absence of, or insufficient levels of, the enzyme alpha-L-iduronidase, which is needed to break down glyclosaminoglycans.
In the most severe form of MPS I (Hurler syndrome), developmental delay is evident by the end of the first year. Children 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. Physical symptoms include a slowing in growth before the end of the first year, short stature, multiple skeletal abnormalities, hernias, distinct facial features, and enlarged organs. Feeding may be difficult for some children. Children with severe MPS I often die before age 10 due to obstructive airway disease, respiratory infections, or cardiac complications.
- Children with MPS l often show no symptoms at birth but they develop complications after the first year of life. Neurological symptoms may include hydrocephalus (the excess build-up of cerebrospinal fluid in the brain), an enlarged head, and clouded corneas as the child ages. Other common neurological complications may include impaired vision and vision loss, carpal tunnel syndrome or other nerve compression, and restricted joint movement.
- Children with less severe forms of MPS l may have average intelligence or mild to moderate mental impairment or learning difficulties. Some children may have psychiatric problems. Respiratory problems, sleep apnea, and heart disease may develop in adolescence. Individuals with the least severe form of MPS can live into adulthood, while other individuals in this spectrum may live into their late teens or early 20s.
MPS II (also known as Hunter syndrome) is caused by lack of the enzyme iduronate sulfatase (which breaks down the glycosaminoglycans heparin sulfate and dermatan sulfate inside cells). Although it was once divided into two groups based on the severity of symptoms, MPS II is also considered a continuous spectrum of disease.
MPS II is the only mucopolysaccharidosis disorder in which the mother alone can pass the defective gene to a son (called X-linked recessive). The disease is almost exclusively found in young males, although cases of affected females have been reported.
- Children with the more severe form of MPS II share many of the neurological and physical features associated with severe MPS I 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. Other neurological symptoms may include increased intracranial pressure, joint stiffness, retinal degeneration, and 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.
- Children with a less severe form of MPS II are often diagnosed in the second decade of life. Intellect and social development are not affected. Physical characteristics in these children are less obvious and progress at a much slower rate, and skeletal problems may be less severe. Individuals with less severe MPS II may live into their 50s or beyond, although respiratory and cardiac complications can contribute to premature death.
MPS III (also known as Sanfilippo syndrome) is marked by severe neurological symptoms that include progressive dementia, aggressive behavior, hyperactivity, seizures, some deafness and vision loss, and an inability to sleep for more than a few hours at a time.
- MPS III affects children differently and progresses faster in some children than in others. 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. These children tend to lose learned words first followed by loss of motor function. Some children may never learn to speak. As the disease progresses, children become increasingly unsteady on their feet and most are unable to walk by age 10.
Life expectancy in MPS III is extremely varied. Most individuals with MPS III live into their teenage years, and some live into their 20s or 30s.
There are four distinct types of MPS III, each caused by alteration of a different enzyme needed to completely break down the heparan sulfate sugar chain. Few clinical differences exist between these four types but symptoms appear most severe and seem to progress more quickly in children with type A.
- MPS IIIA is caused by the missing or altered enzyme heparan N-sulfatase
- MPS IIIB is caused by the missing or deficient enzyme alpha-N-acetylglucosaminidase
- MPS IIIC results from the missing or altered enzyme acetyl-CoA:alpha-glucosaminide acetyltransferase
- MPS IIID is caused by the missing or deficient enzyme N-acetylglucosamine-6-sulfate
MPS IV (also known as Morquio syndrome) has two subtypes that 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 MPS IVB. Onset is between ages 1 and 3. Neurological complications include spinal nerve and nerve root compression resulting from extreme, progressive skeletal changes, as well as hearing loss and clouded corneas. Intelligence is normal unless hydrocephalus develops and is not treated.
Physical growth slows and often stops around age 8. Among the many skeletal abnormalities seen in individuals with Morquio syndrome, the bones that stabilize the connection between the head and neck can be malformed (odontoid hypoplasia), and a surgical procedure called spinal cervical bone fusion can be lifesaving. Other skeletal changes include a protruded sternum, a spine that is curved side to side and back to front, and knock-knee deformity (where the knees angle in and touch each other). Restricted breathing, joint stiffness, and heart disease are also common. Children with the more severe form of MPS IV may not live beyond their 20s or 30s.
MPS VI (also known as Maroteaux-Lamy syndrome) is caused by the deficient enzyme N-acetylgalactosamine 4-sulfatase. MPS VI has a variable range of severe symptoms. While children usually have average intellectual development, they share many of the physical symptoms found in severe MPS I. In addition to many of the neurological complications seen in other MPS disorders, individuals with MPS VI have a thickening of the dura (the membrane that surrounds and protects the brain and spinal cord) and may become deaf. Eye problems include clouding of the cornea, glaucoma (a group of disorders that damage the optic nerve), swelling of the optic nerve or disc, and a degeneration of the optic nerve.
Growth is normal at first but stops suddenly around age 8. Skeletal changes are progressive, and this limits movement. Nearly all children have some form of heart disease, usually involving valve dysfunction.
MPS VII (also known as Sly syndrome) is one of the least common forms of the mucopolysaccharidoses. The disorder is caused by deficiency of the enzyme beta-glucuronidase. In its rarest form, MPS VII causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body. Survival in these cases is usually a few months or less. Most children with MPS VII are less severely affected. Neurological symptoms may include mild to moderate intellectual disability by age 3, hydrocephalus, nerve entrapment, some loss of vision, joint stiffness, and restricted movements. In addition to skeletal problems, some individuals may have repeated bouts of pneumonia during their first years of life. Most children with MPS VII live into their teens or young adult years.
MPS IX disorder results from hyaluronidase deficiency. It is extremely rare. Joint movement and intelligence are not affected. Symptoms include nodular soft-tissue masses located around joints, with episodes of painful swelling of the tissue masses and pain that ends spontaneously within three days. Other traits include mild facial changes, short stature, multiple soft-tissue masses, and some bone erosion seen on pelvic radiography.