This casebook is published and has been read 560 times.Notes
What are the mucopolysaccharidoses?
The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or
malfunctioning of certain 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.
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.
Who is at risk?
It is estimated that one in every 25,000 babies born in the United States will have some form of
the mucopolysaccharidoses. 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.
In general, the following factors may increase the chance of getting or passing on a genetic
A family history of a genetic disease.
Parents who are closely related or part of a distinct ethnic or geographic circle.
Parents who do not show disease symptoms but carry a disease gene.
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.
What are the 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 glycosaminoglycans
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 mucopolysaccharidoses subtype, affected individuals may have normal intellect
or may be profoundly retarded, may experience developmental delay, or may have severe behavioral
problems. Many individuals have hearing loss, either conductive (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 ¾ in which the normal circulation of cerebrospinal fluid becomes blocked over time
and causes increased pressure inside the head ¾ 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 degeneration of the retina and glaucoma 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 or spleen, 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.
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, usually involving valve
How are the mucopolysaccharidoses diagnosed?
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.
How are the mucopolysaccharidoses treated?
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.
In 2006, the FDA approved the drug idursulfase (Elaprase) for the treatment of MPS II (Hunter
syndrome), the first treatment ever shown to have beneficial effects for people with this
condition. A double-blind, placebo-controlled clinical trial in approximately 100 patients with
MPS II showed that the drug improved the patients’ ability to walk. Because idursulfase has a
number of potentially serious side effects, patients should be monitored carefully when
receiving this drug.
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
Enzyme replacement therapies are currently in use or are being tested. Enzyme replacement
therapy has proven useful in reducing non-neurological symptoms and pain.
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.
What research is being done?
Research funded by the National Institute of Neurological Disorders and Stroke (NINDS) has shown
that viral-delivered gene therapy in animal models of the mucopolysaccharidoses can stop the
buildup of storage materials in brain cells and improve learning and memory. Researchers are
planning additional studies to understand how gene therapy prompts recovery of mental function
in these animal models. It may be years before such treatment is available to humans.
Scientists are working to identify the genes associated with the mucopolysaccharidoses and plan
to test new therapies in animal models and in humans. Animal models are also being used to
investigate therapies that replace the missing or insufficient enzymes needed to break down the
Gene therapy trials in humans are studying the effects of enzyme replacement on enlarged organs
(such as the liver or spleen) and on cardiac and pulmonary dysfunction. Additional trials will
determine the extent and immediate cause(s) of hearing loss and inner ear dysfunction common to
many storage diseases, and will identify possible methods to correct structural and functional
problems contributing to hearing and balance disturbance.