What are mucopolysaccharidoses?
Mucopolysaccharidoses (MPS) are a group of rare inherited metabolic diseases. There are many different types of MPS which present a variety of physical and neurological symptoms.
Glycosaminoglycans, also known as mucopolysaccharides, are long chains of sugars (carbohydrates) in our cells. They help build bone, cartilage, tendons, corneas (the transparent part of the eye that covers the retina), skin, and connective tissue. Glycosaminoglycans are also found in the fluid that lubricates the joints.
Glycosaminoglycans are recycled and broken down within the cell by one of 11 special enzymes. MPS occurs when the enzymes needed to breakdown glycosaminoglycans are missing or don’t work properly. People with a mucopolysaccharidosis disorder either do not produce enough of the enzymes or they produce enzymes that do not work properly. This results in inability to breakdown glycosaminoglycans, which is necessary for the body to function properly. Over time, these glycosaminoglycans build up in a person’s blood, brain and spinal cord, and connective tissues. This build up causes permanent, progressive cellular damage that affects the person’s appearance, physical abilities, organ and system functioning, and, in most cases, cognitive development. Symptoms depend on the type of mucopolysaccharidosis.
The mucopolysaccharidoses are classified within a larger group of disorders called lysosomal storage disorders. The main function of lysosomes is to break down and recycle waste materials. In lysosomal storage disorders, enzymes that normally break down or degrade complex molecules into smaller pieces are missing or not functioning properly. As a result, there is a build-up of these molecules in the body's cells and tissues.
Signs and symptoms of MPS
Many symptoms are shared among the different types of MPS. However, there is a wide range of symptom severity. Some of these symptoms may be apparent at birth, while others become more pronounced over time as the storage of glycosaminoglycans affects the person’s bones, skeletal structure, connective tissues, and organs. The age of onset varies widely but typically occurs during childhood.
Physical symptoms generally include:
- Coarse facial features (including a flat nasal bridge, thick lips, and enlarged lips and tongue)
- Short stature with disproportionately short trunk/torso (dwarfism)
- Abnormal bone size and/or shape (dysplasia) and other skeletal irregularities
- Thickened skin
- Enlarged organs such as liver or spleen
- Hernias
- Carpal tunnel syndrome restricting hand mobility and function
- Recurring respiratory infections, obstructive airway disease and obstructive sleep apnea
- Heart disease, often involving enlarged or diseased heart valves.
Brain and nervous system symptoms in MPS include damage to neurons (or neurodegeneration), pain, and movement problems. Affected people may have average intellect or may have profound intellectual disabilities, may experience developmental delays, or may have severe behavioral problems. Many people have problems with:
- Hyperactivity
- Depression
- Speech
- Hearing
- Vision
Hydrocephalus is a buildup of fluid in the brain that that can cause increased pressure on the brain, damaging brain tissues and causing a range of issues, including headaches and developmental delay. It is common in some of the mucopolysaccharidoses. Additionally, accumulation of glycosaminoglycans in the eye can lead to impaired vision by damage to the cornea, and retina, as well as increasing pressure in the eye (glaucoma).
People with the least severe form of MPS can live into adulthood, while other individuals in this spectrum may live into their late teens, 20s, or early 30s.
Types of mucopolysaccharidoses
There are seven distinct clinical types and numerous subtypes of mucopolysaccharidoses (MPS). Although each MPS is different, most people with MPS experience a period of normal development followed by a decline in physical and/or mental function. Some MPS types may be fatal in the first few months of life.
MPS I
MPS I has historically been divided into three sub-groups known as Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. These syndromes are categorized by the severity of symptoms across a continuous spectrum. People with more severe symptoms (Hurler syndrome) lay on one end of the spectrum, and those with more mild symptoms (Scheie syndrome) on the other end. People with MPS I symptoms that fall into the middle range are considered to have Hurler-Scheie syndrome.
Hurler syndrome has the most severe symptoms and Scheie syndrome the least. Scheie syndrome was previously classified as MPS V before being included in the MPS I designation.
People with MPS I are either missing or deficient in the enzyme alpha-L-iduronidase, which is needed to break down the glycosaminoglycans dermatan sulphate and heparan sulphate.
In the most severe form of MPS I (Hurler syndrome), developmental delay is evident by the end of the first year of life. Children usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Verbal language may be limited due to hearing loss. Physical symptoms include 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 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.
MPS II
MPS II (also known as Hunter syndrome) is caused by a lack of the enzyme iduronate-2-sulfatase.
MPS II is the only mucopolysaccharidosis disorder in which inheriting a single defective gene from the mother can result in mucopolysaccharidosis in a son (called X-linked recessive inheritance). The disease is almost exclusively found in boys, although cases of affected girls have been reported.
Children with more severe forms 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 evident between the ages of 18 and 36 months, followed by progressive loss of skills. Other symptoms may include increased pressure in the skull (hydrocephalus), joint stiffness, visual impairment, and progressive hearing loss. People with MPS II may have pebble-like skin texture with white or skin-colored nodules 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. People with less severe MPS II may live into their 50s or beyond, although respiratory and cardiac complications can contribute to premature death.
MPS III
MPS III (also known as Sanfilippo syndrome) is has four distinct types (A, B, C and D), which are each caused by changes in a specific enzyme needed to break down heparan sulfate (a type of glycosaminoglycans). Few clinical differences exist between these four types, but symptoms appear most severe and seem to progress most quickly in children with type A.
MPS III is characterized by changes in behavior (aggression, hyperactivity), sleep disorders, progressive cognitive changes (including loss of memory and intellectual disability), hearing loss and vision impairment. MPS III affects each child differently and progresses faster in some children than in others. Children with MPS III may also experience seizures and difficulty walking and can have varying degrees of delay in early cognitive and motor skill development.
Children with MPS III 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, then experience movement problems. 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.
MPS IV
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 mucopolysaccharides chondroitin-6-sulfate and keratan sulfate.
Clinical features are similar in both types but appear milder in Type B. Symptoms include skeletal dysplasia (impaired growth of bone and cartilage), hearing loss, and vision problems (due to clouding of the cornea). The bones that stabilize the connection between the head and neck can be malformed (called odontoid hypoplasia), and a surgical procedure called spinal cervical bone fusion can be lifesaving. Other skeletal changes include a protruded sternum, a curved spine, and knock-knees (where the knees angle in and touch each other). People with MPS IV experience nerve compression resulting from extreme, progressive skeletal changes. Restricted breathing and heart disease are also common. Intelligence is typically not affected in MPS IV.
Onset of MPS IV typically begins between ages 1 and 3. Physical growth slows and often stops around age 8 in children with MPS IV. Children with the more severe form of MPS IV (Type A) may not live beyond their 20s or 30s.
MPS VI
MPS VI (also known as Maroteaux-Lamy syndrome) is caused by the deficient enzyme N-acetylgalactosamine 4-sulfatase. MPS VI has a wide range of symptoms. Some individuals experience a few mild symptoms, while others develop more severe symptoms. People with MPS VI share many of the physical symptoms found in severe MPS I. They have a thickening of the dura (the membrane that surrounds and protects the brain and spinal cord) and may experience problems with hearing and vision, as well as enlarged liver and/or spleen, heart disease, and breathing symptoms. Intellectual development is typically unaffected in MPS VI.
People with MPS VI experience normal growth at first but growth stops suddenly around age 8. Skeletal changes get worse over time and limit mobility. People with MPS VI begin to show symptoms during early childhood. Life expectancy depends on disease severity and is typically around 20-30 years of age.
MPS VII
MPS VII (also known as Sly syndrome) is one of the least common mucopolysaccharidoses. It is caused by a deficiency of the enzyme beta-D-glucuronidase, which leads to a buildup of three glycosaminoglycans: dermatan sulfate, heparan sulfate, and chondroitin sulfate.
Children with MPS VII may have mild to moderate intellectual disability, hydrocephalus, heart disease, vision loss due to corneal clouding, and carpal tunnel syndrome. Skeletal problems, including joint stiffness that may restrict movements and short stature, are often present. In addition to skeletal problems, some children 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. However, in rare cases, newborns with MPS VII may experience abnormal accumulations of fluid within the body (hydrops fetalis). Survival in these cases is usually a few months or less.
MPS IX
MPS IX (also known as Natowicz syndrome) is extremely rare and results from a deficiency of the enzyme hyaluronidase. Joint movement and intellect are not affected. Symptoms include soft-tissue masses (nodes) located around joints with episodes of painful swelling of nodes and pain. Other symptoms include mild facial changes, short stature, frequent ear infections, and some bone erosion (which can be seen on scans of the pelvis).
Who is more likely to get mucopolysaccharidoses?
Approximately one in every 25,000 babies born in the U.S. will have some form of MPS. These are autosomal recessive disorders, meaning that only children inheriting the defective gene from both parents are affected. When each parent has one copy of the defective gene, each pregnancy carries 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 MPS may carry one copy of the defective gene and could pass it on to their own children. The one exception is MPS II, or Hunter syndrome, which is an X-linked recessive disorder in which the unaffected mother passes along the defective gene to a son.
In general, the following factors may increase the chance of having or passing on a genetic disorder:
- A family history of a genetic disorder
- Parents who are closely related or part of a distinct ethnic or geographically clustered community
- Parents who do not show disease symptoms but carry a gene associated with the disorder
How are the mucopolysaccharidoses diagnosed and treated?
Diagnosing MPS
Early diagnosis of MPS is critical and can help prevent some symptoms of the disease. Clinical examination and specialized tests to detect excess mucopolysaccharides (chains of sugars) in the urine are the first steps in diagnosing MPS. Enzyme assays (testing a variety of cells or blood for enzyme deficiency) provide definitive diagnosis.
The Recommended Uniform Screening Panel, a list of disorders that the U.S. Department of Health and Human Services (HHS) recommends for states to screen for, includes MPS I. States can elect whether to screen for MPS I as part of their universal newborn screening programs. If a child’s newborn screening for MPS I is positive, doctors should use an enzyme test to definitively diagnose the disorder.
Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify whether a fetus has the disorder.
Genetic counseling can help parents with a family history of MPS determine if they are carriers of the gene that causes the disorders. Genetic testing is voluntary. Because testing has benefits as well as limitations and risks, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the test and results.
Treating MPS
Currently, there is no cure for these disorders. Medical care is directed at treating symptoms and improving the person's quality of life.
Enzyme replacement therapy (ERT) is is a long-term therapy that introduces missing enzymes into the body via an intravenous infusion. ERT is currently in use for MPS I, MPS II, MPS IVA, MPS VI, and MPS VII, and is being tested in other MPS disorders. It does not cure the disorder but can help reduce non-neurological symptoms and pain. ERT does not help with vision and other nervous system symptoms because it does not allow for the enzymes to cross the blood-brain barrier.
Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have had limited success in treating the mucopolysaccharidoses. If done, these treatments should be performed early in life, preferably before symptoms develop. Abnormal physical characteristics, except for those affecting the skeleton and eyes, may be improved, but neurologic outcomes have varied. These are high-risk procedures and are usually performed only after family members receive extensive evaluation and counseling.
Surgery or shunts can help drain excessive cerebrospinal fluid from the brain in order to free nerves and nerve roots compressed by skeletal and other abnormalities. Corneal transplants may improve vision among people with significant corneal clouding. Removing the tonsils and adenoids may improve breathing among people with obstructive airway disorders and sleep apnea. Some people may require surgical insertion of an endotracheal tube to aid breathing. Changes to the person’s diet will not prevent disease progression. Physical therapy and daily exercise may delay joint problems and improve movement.
What are the latest updates on mucopolysaccharidoses?
NINDS, a component of NIH, the leading supporter of biomedical research in the world, is the primary federal funding agency on mucopolysaccharidoses and other neurological disorders. The NIH’s Eunice Kennedy Shriver National Institute for Child Health and Human Development, along with other components of NIH, also funds research into the mucopolysaccharidoses. NINDS conducts research on MPS and other inherited metabolic disorders that affect the brain and nervous system and funds research at major institutions and universities. Much of what we know about the biochemistry of the mucopolysaccharidoses was discovered at NIH by Dr. Elizabeth Neufeld.
NINDS, along with other NIH institutes, supports the Lysosomal Disease Network, a network of centers that seeks to address some of the major challenges in the diagnosis, management, and therapy of diseases, including the mucopolysaccharidoses. Centers are conducting longitudinal studies of the natural history and/or treatment of these disorders. Additional studies will emphasize quantitative analysis of the central nervous system structure and function, as well as develop biomarkers (signs that can indicate the diagnosis or progression of a disease) for these disorders.
Research funded by NINDS has shown that viral-delivered gene therapy in animal models of the mucopolysaccharidoses can stop the buildup of glycosaminoglycans in brain cells and improve learning and memory. No gene therapy for MPS disorders has been approved for clinical use at this time but several studies are actively recruiting participants. Researchers are planning additional studies to understand how gene therapy prompts recovery of mental function in the animal models.
Scientists are working to understand the genes associated with the mucopolysaccharidoses and plan to test new therapies in animal models and humans. Animal models are also being used to investigate therapies that replace the missing or insufficient enzymes needed to break down the sugar chains. Studies are investigating enzyme replacement therapy to reverse or halt neurologic decline in the mucopolysaccharidoses.
Scientists know that Hurler disease is caused by a nonsense mutation (a point in a mutation of DNA that results in an incomplete and usually malfunctioning protein). NINDS-funded scientists are testing two drugs in an animal model to see if the drugs can suppress the nonsense mutations and restore enough functional protein to reduce disease progression.
NINDS, along with other NIH Institutes and Centers, is conducting a long-term study of MPS disorders to gain information that will help researchers and clinicians understand the likely or potential outcomes of MPS, as well as develop sensitive measures of disease progression and treatment. Other researchers hope to use a telephone-based surveillance system to collect information about children diagnosed with a lysosomal storage disease and more accurately follow and understand changes in development and behavior.
Scientists also hope to identify biomarkers (signs that help diagnose a disease or monitor its progression) for the mucopolysaccharidoses.
More information about research on mucopolysaccharidoses can be found using NIH RePORTER, a searchable database of current and past research projects supported by NIH and other federal agencies. RePORTER also includes links to publications and resources from these projects.
How can I or my loved one help improve care for people with mucopolysaccharidoses?
Consider participating in a clinical trial so clinicians and scientists can learn more about mucopolysaccharidoses and related disorders. Clinical research with human participants helps researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.
All types of participants are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.
For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with mucopolysaccharidoses at Clinicaltrials.gov.
Where can I find more information about mucopolysaccharidoses?
More information may be available from the following organizations and resources:
NINDS acknowledges Dr. Isha Srivastava, Dr. Meeryo C. Choe and the American Academy of Neurology for their contributions to this piece.