Mucopolysaccharidosis (MPS) is a general term for many different related
inherited disorders that are caused by the accumulation of
mucopolysaccharides in body tissues. This accumulation interferes with the
Mucopolysaccharides are long chains of sugar molecules that are essential
for building the bones, cartilage, skin, tendons, and other tissues in the
body. Another name for mucopolysaccharides is glycosaminoglycans (GAGs).
Normally, the human body continuously breaks down and rebuilds cells that
contain GAGs. There are many different types of GAGs, and different GAGs
are unable to be broken down in each of the MPS conditions. Several
enzymes are involved in breaking down each GAG, and a deficiency or
absence of any of the essential enzymes can cause the GAG not to be broken
down completely. This condition results in the accumulation of GAGs in the
tissues and organs in the body. The accumulating GAGs are stored in
cellular structures called lysosomes, and these disorders are known as
lysosomal storage diseases. When too many GAGs accumulate, organs and
tissues become damaged or do not function properly.
Before specific deficient enzymes were identified, MPS disorders were
diagnosed by the signs and symptoms seen in an individual. The discovery
of individual enzyme deficits resulted in a reclassification of some of
the MPS disorders. Types of MPS disorders are MPS I, MPS II, MPS III, MPS
IV, MPS VI, MPS VII, and MPS IX. However, these conditions are also
referred to by their original names, which are Hurler, Hurler-Scheie,
Scheie (all MPS I), Hunter (MPS II), Sanfilippo (all MPS III), Morquio
(all MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase
deficiency (MPS IX).
MPS disorders are rare, and the frequency with which they occur varies
depending on the type of the disorder. For all MPS types combined, the
disorder occurs in only about one of every 25,000 people. Except for MPS
II, individuals of both genders are affected equally. Because of its
inheritance pattern, MPS II is found only in males. All MPS disorders are
present at birth, although symptoms appear at different times, depending
on the type of disorder. There appears to be no race or ethnic component
in the distribution of MPS disorders.
Causes and symptoms
All MPS disorder except MPS II are inherited in an autosomal recessive
manner. An individual with an autosomal recessive disorder inherits one
non-working genes from each parent. The parents are called carriers of the
disorder. If the parent has one good copy of the gene and one defective
copy, the parent will not have MPS and may be unaware that he or she has a
defective gene. MPS only occurs when both of an individual's genes
that produce the same enzyme contain a mutation or defect, causing them
not to function properly. As a result, either no enzyme is produced, or
the amount produced is inadequate. When two people are carriers for an
autosomal recessive disorder, they have a 25 percent chance with each
pregnancy to have a child with the disorder. Some individuals who have MPS
are able to have children. Children of MPS parents are all carriers of the
disorder, because they inherit one bad copy of the gene from the affected
parent. However, these children are not at risk to develop the disorder
unless the other parent is a carrier or affected with the same autosomal
Unlike the other MPS conditions, MPS II is inherited in an X-linked
recessive manner, which means that the gene causing the condition is
located on the X chromosome, one of the two sex chromosomes. A male child
inherits an X chromosome from his mother and a Y chromosome from his
father. He will have the disorder if the X chromosome inherited from his
mother carries the defective gene, since he has only one (nonfunctioning)
copy of the gene. Females inherit one X chromosome from their mother and a
second X chromosome from their father. Because they have two X
chromosomes, they are carriers of the disorder if one of their X
chromosomes has the gene that causes the condition, while the other X
chromosome does not.
Although MPS are all inherited disorders, each type is caused by a
deficiency of one particular enzyme involved in breaking down GAGs. The
accumulation of the GAGs in the tissues and organs in the body causes the
symptoms characteristic of the MPS disorders. Symptoms and their time of
onset vary widely depending on which form of the disorder the individual
MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase. Three
conditions, Hurler, Hurler-Scheie, and Scheie syndromes, are caused by a
deficiency of this enzyme. Initially, these three conditions were believed
to be separate, because each was associated with different physical
symptoms and prognoses. However, once the underlying cause of these
conditions was identified, it was realized that these three conditions are
variants of the same disorder.
About one child in 100,000 is born with Hurler syndrome. This tends to be
the most severe form of MPS I. Symptoms of Hurler syndrome are often
evident within the first year or two after birth. Often these infants
initially grow faster than expected, but then reach a point where they
begin to lose the skills that they have learned. Their growth slows and
typically stops by age three.
Facial features begin to coarsen. These children develop a short nose,
flatter face, thicker skin, and a protruding tongue. Their heads become
larger, and they develop more hair on their bodies, with the hair becoming
coarser. Their bones are also affected, and they usually develop joint
contractures (stiff joints), kyphosis (a specific type of curve to the
spine), and broad hands with short fingers. Many of these children have
breathing difficulties, and respiratory infections are common. Other
common problems include heart valve dysfunction, thickening of the heart
muscle (cardiomyopathy), enlarged spleen and liver, clouding of the
cornea, hearing loss, and carpal tunnel syndrome. These children typically
do not live past age 12.
Hurler-Scheie syndrome an intermediate form of MPS I, meaning that the
symptoms are not as severe as those in individuals who have MPS I H but
not as mild as those in MPS I S. Approximately one baby in 115,000 is born
with Hurler-Scheie syndrome. These individuals tend to be shorter than
expected. They can have normal
; however, some individuals with MPS I H/S experience learning
difficulties. These individuals may develop some of the same physical
features as those with Hurler syndrome, but usually they are not as
severe. The prognosis for children with MPS I H/S is variable with some
individuals dying during childhood, while others live to adulthood.
Scheie syndrome is the mild form of MPS I. About one baby in 500,000 is
born with Scheie syndrome. Individuals with MPS I S usually have normal
intelligence, although there have been some reports of individuals with
MPS I S developing psychiatric problems. Common physical problems include
corneal clouding, heart abnormalities, and orthopedic difficulties
involving their hands and back. Individuals with MPS I S do not develop
the facial features seen with MPS I H and usually these individuals have a
normal life span.
Hunter syndrome is caused by a deficiency of the enzyme
iduronate-2-sulphatase. All individuals with Hunter syndrome are male,
because the gene that causes the condition is located on their single X
chromosome. Like many MPS conditions, Hunter syndrome is divided into two
forms, mild and severe. About one in 110,000 males are born with Hunter
syndrome, with the severe form being three times more common than the mild
The severe form of MPS II is associated with progressive
and physical disability, with most individuals dying before age 15. In
the milder form, most of these individuals live to adulthood and have
normal intelligence or only mild mental impairments. Males with the mild
form of Hunter syndrome develop physical differences similar to the males
with the severe form, but not as quickly. Males with mild Hunter syndrome
can have a normal life span and some have had children. Most males with
Hunter syndrome develop joint stiffness, chronic
, enlarged liver and spleen, heart valve problems, hearing loss, and
kyphosis. They also tend to be shorter than expected. These symptoms
progress at different rates depending on whether the individual has the
mild or severe form of MPS II.
MPS III, like the other MPS conditions, was initially diagnosed by the
individual having certain physical signs and symptoms. It was later
discovered that the physical symptoms associated with Sanfilippo syndrome
could be caused by a deficiency in one of four enzymes. MPS III is in the
early 2000s subdivided into four groups, labeled A through D, based on the
specific enzyme that is deficient. All four of these enzymes are involved
in breaking down the same GAG, heparan sulfate. Heparan sulfate is mainly
found in the central nervous system and accumulates in the brain when it
cannot be broken down because one of those four enzymes is deficient or
MPS III is a variable condition, with symptoms beginning to appear between
two and six years of age. Because of the accumulation of heparan sulfate
in the central nervous system (CNS), the CNS is severely affected. In MPS
III, signs that the CNS is degenerating usually become evident between six
and ten years of age. Many children with MPS III develop seizures,
sleeplessness, thicker skin, joint contractures, enlarged tongues,
cardiomyopathy, behavior problems, and mental retardation. The life
expectancy in MPS III is also variable. On average, individuals with MPS
III live until they are teenagers, with some living longer and others not
MPS IIIA (Sanfilippo syndrome type A) is caused by a deficiency of the
enzyme heparan N-sulfatase. Type IIIA is the most severe of the four types
of MPS III. Symptoms appear and death occurs at an earlier age than in
other subtypes. A study in British Columbia estimated that one in every
325,000 babies is born with MPS IIIA. MPS IIIA is the most common of the
four types in Northwestern Europe. The gene that causes MPS IIIA is
located on the long arm of chromosome 17.
MPS IIIB( Sanfilippo syndrome type B) is due to a deficiency in
N-acetyl-alpha-D-glucosaminidase (NAG). This type of MPS III is not as
severe as type IIIA, and the characteristic signs and symptoms vary. Type
IIIB is the most common of the type III disorders in southeastern Europe.
The gene associated with MPS IIIB is also located on the long arm of
MPS IIIC (Sanfilippo syndrome type C) is caused by a deficiency in the
enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase. This is a rare
form of MPS III. The gene involved in MPS IIIC is believed to be located
on chromosome 14.
MPS IIID (Sanfilippo syndrome type D) is caused by a deficiency in the
enzyme N-acetylglucosamine-6-sulfatase. This form of MPS III is also rare.
The gene involved in MPS IIID is located on the long arm of chromosome 12.
MPS IV A is the severe form of the disorder and is caused by a deficiency
in the enzyme galactosamine-6-sulphatase. The gene involved with MPS IV A
is located on the long arm of chromosome 16. The major organs affected by
MPS IV are the cornea and the cartilage, particularly the cartilage of the
neck. Bowel and bladder function also can be impaired. Respiratory
apnea are common. Individuals with MPS IV appear healthy at birth but
show skeletal deformities and growth retardation by age three. Death often
occurs early in individuals with the severe form of this disorder.
MPS IV B (Morquio syndrome type B) is the milder form of the disorder. The
enzyme, beta-galactosidase, is deficient in MPS IV B. The gene that
produces beta-galactosidase is located on the short arm of chromosome 3.
Individuals with the MPS IV B can have normal lifespans (into their 70s).
MPS VI, which is another rare form of MPS, is caused by a deficiency of
the enzyme N-acetylglucosamine-4-sulphatase. This condition is also
variable; individuals may have a mild or severe form of the disorder.
Typically, the nervous system or intelligence of an individual with MPS VI
is not affected. Individuals with a more severe form of MPS VI can have
airway obstruction, develop
(accumulation of fluid in the brain), and exhibit bone changes.
Individuals with a severe form of MPS VI are more likely to die while in
their teens. With a milder form of the disorder, individuals tend to be
shorter than expected for their age, develop corneal clouding, and live
longer. The gene involved in MPS VI is believed to be located on the long
arm of chromosome 5.
MPS VII is an extremely rare form of MPS and is caused by a deficiency of
the enzyme beta-glucuronidase. It is also highly variable, but symptoms
are generally similar to those seen in individuals with Hurler syndrome.
The gene that causes MPS VII is located on the long arm of chromosome 7.
MPS IX, a condition first described in 1996, is caused by a deficiency of
the enzyme hyaluronidase. In the few individuals described with this
condition, the symptoms are variable. Some individuals develop soft tissue
masses (growths) under the skin. Also, these individuals are shorter than
expected for their age. The gene involved in MPS IX is believed to be
located on the short arm of chromosome 3.
Parents should inform the doctor immediately if MPS runs in their
, so that early testing can be done on their children. In addition, any
time they have questions about their child's growth and
development, they should talk to their pediatrician.
While a diagnosis for each type of MPS can be made based on the physical
signs described above, several of the conditions have similar features.
Therefore, enzyme analysis is used to determine the specific MPS disorder.
Enzyme analysis often cannot accurately determine if an individual is a
carrier for an MPS disorder, because the enzyme levels in individuals who
are not carriers overlaps the enzyme levels seen in those individuals who
are carrier for MPS. With many of the MPS conditions, several mutations
have been found in each gene involved that can cause symptoms of each
condition. If the specific mutation is known in a family, DNA analysis may
Once a couple has had a child with MPS, prenatal testing is available to
them to help determine if another fetus is affected with the same MPS as
their previous other child. This can be accomplished using procedures such
or chorionic villus sampling (CVS), after which parents can explore their
options relating to the pregnancy.
As of 2004 there was no cure for MPS, although several types of
experimental therapies are being investigated in the early 2000s.
Typically, treatment involves trying to relieve the symptoms and improve
quality of life. For MPS I and VI, bone marrow transplantation has been
attempted as a treatment option. For those types of MPS, bone marrow
transplantation has sometimes helped slow down the progression or reverse
some of symptoms of the disorder in some children. The benefits of bone
marrow transplantation are more likely to be noticed when performed on
children less than two years of age. However, bone marrow transplantation
is not thought to be helpful in other MPS disorders. Availability of
donors is limited, and as a result, very few bone marrow transplantations
are done for MPS. There are risks as well as benefits with this procedure,
and mortality resulting from the procedure is high.
Another experimental treatment for MPS I involves extended treatment with
recombinant human alpha-L-iduronidase. Some individuals treated with this
technique show an improvement in some symptoms. Additionally, there is
ongoing research involving gene replacement therapy (the insertion of
normal copies of a gene into the cells of patients whose gene copies are
defective), although this was as of 2004 still highly experimental.
The course of this disorder varies with the specific type of MPS the
individual has. MPS I H is often fatal in childhood, with individuals
rarely living past age 12. Individuals with MPS I H/S may die in childhood
or live to adulthood. Individuals with MPS I H have health problems but
usually have a normal lifespan. Individuals with mild MPS II live
relatively normal lives, while individuals with the severe form of the
disorder usually die in their teens. The life expectancy in MPS III and
MPS IV is also variable, depending on the severity of the disorder.
Individuals with MPS VI often have shorter than average life spans. As of
2004 MPS IX had been diagnosed so recently that little information is
No specific measures can prevent the gene mutations that cause MPS. For
some of the MPS diseases, biochemical tests may be able to identify
healthy individuals who are carriers of the defective gene, allowing them
to make informed reproductive decisions. Prenatal testing can also
diagnose MPS in the fetus, but this testing is normally done only when
there is some reason to expect to find the disorder (e.g. family history
of the disease).
—A disease of the heart muscle.
—A protein that catalyzes a biochemical reaction without changing
its own structure or function.
—Stiffness of the joints that prevents full extension.
—An extreme, abnormal outward curvature of the spine, with a hump
at the upper back.
—A membrane-enclosed compartment in cells, containing many
hydrolytic enzymes, where large molecules and cellular components are
—A complex molecule made of smaller sugar molecules strung
together to form a chain. It is found in mucous secretions and
—A type of gene that is not expressed as a trait unless inherited
by both parents.
—A gene carried on the X chromosome, one of the two sex
Kakkis, E. D., et al. "Enzyme-Replacement Therapy in
The New England Journal of Medicine
344 (2001): 182–8.
National MPS Society.
PO Box 736, Bangor, ME 04402–0736. Web site:
National Organization for Rare Disorders Inc.
55 Kenosia Ave, PO Box 1968, Danbury, CT 06813–1968. Web site:
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