Mucopolysaccharidosis

Mucopolysaccharidosis is a group of rare inherited diseases that cause progressive cellular damage throughout the body, affecting appearance, physical abilities, and organ function. These conditions result from missing or malfunctioning enzymes that normally break down complex sugar molecules, leading to their harmful accumulation in cells and tissues.

Table of contents

• What is Mucopolysaccharidosis?
• Types of Mucopolysaccharidosis
• Signs and Symptoms
• Causes and Inheritance
• Diagnosis
• Treatment Options
• Impact on Families

What is Mucopolysaccharidosis?

Mucopolysaccharidoses (MPS) are a group of rare inherited metabolic diseases (conditions that affect how the body processes nutrients and chemicals). These diseases occur when the body cannot produce enough of certain special enzymes, or when these enzymes do not work properly^[1].

In healthy cells, glycosaminoglycans (also called mucopolysaccharides) are long chains of sugar molecules that help build bone, cartilage, tendons, the transparent part of the eye that covers the retina (corneas), skin, and connective tissue. They are also found in the fluid that lubricates the joints. The body normally recycles and breaks down these molecules within cells using one of 11 special enzymes^[1].

People with mucopolysaccharidosis either do not produce enough of these enzymes or produce enzymes that do not work properly. Without functioning enzymes, glycosaminoglycans cannot be broken down as needed. Over time, these molecules build up in the blood, brain and spinal cord, and connective tissues. This buildup causes permanent, progressive cellular damage that affects a person’s appearance, physical abilities, organ and system functioning, and in most cases, cognitive development^[1].

MPS conditions are classified within a larger group of disorders called lysosomal storage disorders. Lysosomes are parts of cells that break down and recycle waste materials. In these disorders, enzymes that normally break down complex molecules into smaller pieces are missing or not functioning properly, resulting in a buildup of these molecules in the body’s cells and tissues^[1].

MPS occurs worldwide in various forms though with relatively low incidence. The prevalent type varies among different continents, indicating that it may be associated with region and ethnic background^[3].

Types of Mucopolysaccharidosis

There are many different types of MPS, each caused by a deficiency of a specific enzyme. The types are numbered using Roman numerals^[2].

MPS I (Hurler, Hurler-Scheie, and Scheie Syndromes)

MPS I is the most common form of mucopolysaccharidosis. It is caused by a deficiency of the enzyme alpha-L-iduronidase, which is needed to break down the glycosaminoglycans dermatan sulfate and heparan sulfate^[4].

MPS I exists on a spectrum from severe to mild forms. The severe form is called Hurler syndrome, while the milder forms are called Hurler-Scheie syndrome (intermediate) and Scheie syndrome (mild). Healthcare providers often call the less severe forms “attenuated MPS I”^[5].

In children with severe MPS I (Hurler syndrome), symptoms usually appear within the first year of life. Without treatment, these children usually do not survive past age 10. Children with attenuated (milder) MPS I have fewer health problems, with many leading fairly normal lives into adulthood^[4].

Severe MPS I occurs in approximately 1 in 100,000 newborns, while attenuated MPS I occurs in about 1 in 500,000 newborns^[4].

MPS II (Hunter Syndrome)

MPS II is caused by a deficiency of the enzyme iduronate-2-sulfatase. This is an X-linked recessive genetic condition, which means it mostly affects boys. Symptoms usually appear at about the age of 2 to 4 years^[14].

Hunter syndrome occurs in approximately 1 in 100,000 to 150,000 male births^[14].

MPS III (Sanfilippo Syndrome)

MPS III is characterized by severe neurological problems. Children with this type experience progressive mental deterioration and behavioral problems^[12].

MPS IV (Morquio Syndrome)

Morquio syndrome causes bone growth abnormalities and symptoms throughout the body that worsen over time. There are two types: Type A is caused by deficiency of N-acetyl-galactosamine-6-sulfatase, and Type B is caused by deficiency of beta-galactosidase. About 95% of cases are type A^[17].

Morquio syndrome affects an estimated 1 in 200,000 to 300,000 people in the United States^[17].

MPS VI (Maroteaux-Lamy Syndrome)

MPS VI is another distinct form of mucopolysaccharidosis with its own characteristic features^[12].

MPS VII (Sly Syndrome)

MPS VII is one of the rarer forms of mucopolysaccharidosis. Some infants with severe MPS VII may present with hydrops fetalis (abnormal fluid accumulation in the fetus)^[3].

MPS IX

MPS IX is caused by hyaluronidase deficiency and is among the rarest forms of mucopolysaccharidosis^[2].

Signs and Symptoms

Many symptoms are shared among the different types of MPS. However, there is a wide range of symptom severity. Some 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^[1].

These features may not be apparent at birth but progress as storage of glycosaminoglycans affects bone, skeletal structure, connective tissues, and organs^[2].

Physical Symptoms

Physical symptoms generally include^[1]:

• Coarse facial features (including a flat nasal bridge, thick lips, and enlarged lips and tongue)
• Short stature with disproportionately short trunk or 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

Neurological Symptoms

Neurological complications may include damage to neurons (cells that 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^[2].

Depending on the mucopolysaccharidosis subtype, affected individuals may have normal intellect or have cognitive impairments, may experience developmental delay, or may have severe behavioral problems^[2].

Sensory Problems

Many individuals have hearing loss, either conductive (in which pressure behind the eardrum causes fluid from the lining of the middle ear to build up and eventually congeal), neurosensory (in which tiny hair cells in the inner ear are damaged), or both^[2].

The eye’s cornea often becomes cloudy from intracellular storage, and glaucoma and degeneration of the retina also may affect the patient’s vision^[2].

Other Complications

Communicating hydrocephalus (a condition in which the normal reabsorption of cerebrospinal fluid is blocked and causes increased pressure inside the head) is common in some of the mucopolysaccharidoses. A shunt can be surgically inserted into the brain to drain fluid^[2].

Causes and Inheritance

MPS is inherited, which means that parents typically pass the disease on to their children. If both parents carry a nonworking copy of the gene related to this condition, each of their children has a 25% (1 in 4) chance of developing the disease^[4].

MPS I is a genetic condition caused by disease-causing (pathogenic) changes in the IDUA gene. The IDUA gene provides the body with the instructions it needs to produce the alpha-L-iduronidase enzyme. If the body does not produce enough of this enzyme, glycosaminoglycans build up in various parts of the body and cause symptoms of disease^[8].

MPS I is inherited in an autosomal recessive manner. This means that in order to have the condition, an individual needs to have two disease-causing changes in the DNA. One change must be present in the copy of the IDUA gene that the individual inherits from their mother, and another change must be present in the copy of the IDUA gene the individual inherits from their father^[8].

Except for MPS II, mucopolysaccharidoses are genetic disorders inherited in an autosomal recessive pattern affecting both males and females. MPS II is X-linked, meaning it primarily affects males^[12].

Diagnosis

Within MPS, the wide-ranging clinical spectrum and varying degree of severity mean that diagnosis can often be delayed. It has been reported that early diagnosis and treatment can improve outcomes in MPS patients^[12].

In some states, babies are tested for MPS I as part of the newborn screening tests^[4].

Several diagnostic approaches are used to identify MPS and determine its subtype:

Urine Tests

Urine tests can detect extra mucopolysaccharides (glycosaminoglycans) in the urine, which may indicate MPS^[4].

Enzyme Assay

Enzyme assays measure the level of specific enzyme activity in the blood or other tissues. This test helps determine which enzyme is deficient and therefore which type of MPS is present^[3].

Genetic Testing

Genetic testing looks for changes (mutations) in specific genes. For example, genetic testing for changes to the alpha-L-iduronidase (IDUA) gene can confirm MPS I^[4].

Imaging Tests

X-rays of the spine and other imaging tests may be performed to look at bone abnormalities characteristic of MPS^[4].

Other Tests

Depending on symptoms, other tests may include an electrocardiogram (ECG) to check heart function^[4].

Treatment Options

There is no curative treatment available at present for most types of MPS. Management consists of supportive care and several treatment modalities. Routine assessment of multiple organ involvement is necessary to maintain the highest quality of life in these patients^[7].

Enzyme Replacement Therapy (ERT)

Enzyme replacement therapy has been a standard therapeutic option for patients with some types of MPS. ERT involves regular infusions of the missing enzyme through a vein^[7].

Laronidase (Aldurazyme) is a medication approved to treat MPS type I (Hurler and Hurler-Scheie forms). It is a form of the human enzyme alpha-L-iduronidase produced by recombinant DNA technology. It increases breakdown of glycosaminoglycans that accumulate with MPS I. Laronidase therapy has shown improvement in walking capacity and lung function^[7].

Idursulfase is a purified form of human iduronate-2-sulfatase enzyme used to treat MPS II^[7].

Elosulfase alfa is approved for patients with Morquio A syndrome (MPS IVA). Long-term use of this agent is associated with partial recovery of functional abilities in these patients^[7].

Vestronidase alfa is approved for MPS VII. Its tolerability profile is reasonable, and most adverse reactions are mild to moderate in severity^[7].

A study of enzyme replacement therapy effects on cardiovascular manifestations found that this therapy significantly reduced left ventricular hypertrophy (thickening of the heart muscle) but did not have a significant beneficial effect on valve abnormalities, pulmonary hypertension, or left atrial dilatation^[7].

Bone Marrow Transplantation

Bone marrow transplantation (BMT) has been successful in the treatment of MPS conditions, especially Hurler syndrome. Children treated with BMT generally have an increased lifespan compared with untreated children. However, the musculoskeletal condition (bone abnormalities) did not improve with BMT^[7].

Hematopoietic stem cell transplantation is also used as treatment for individuals with severe MPS I^[8].

Supportive Care

Supportive care addresses specific symptoms and complications:

Severe hearing loss is present in about 70% of patients with MPS. Routine audiologic assessment and management is extremely important to maintain the highest quality of life^[7].

Range-of-motion exercises at home are indicated to limit the progressive loss of motion that is commonly seen in these patients. Night splinting and occupational aids have also been helpful^[7].

Patients with MPS often require multiple surgical procedures for specific conditions. However, they have a high postoperative mortality because of underlying respiratory and cardiac diseases^[7].

Emerging Treatments

Newer treatments under investigation include advanced enzyme replacement therapy, gene therapy, and substrate reduction therapy^[3].

Impact on Families

Living with a rare disease is an ongoing challenge for patients and their families. MPS is a life-limiting condition where there is no curative treatment available at present. Caring for someone with MPS, a condition that is chronic, progressive and degenerative, can impact all dimensions of family life^[12].

Parents of children with MPS experience multiple challenges. They spoke of concerns about their child’s quality of life, their healthy children’s wellbeing, and for some, the impact on their own physical and psychological wellbeing. They also reflected on issues of stigmatization and isolation in their experience of living with a child with a rare disorder^[10].

Parents use terms such as “no man’s land” and “future is unknown” to describe their world. They experience a range of uncertainties as their children’s conditions are chronic, progressive, and degenerative^[12].

Support resources are available for families:

The National MPS Society provides many program offerings and coping tools for families and people with MPS, including fact sheets and booklets, advocacy and family support resources, organized fundraisers and social events, free memberships for adults with MPS, newly diagnosed patients, families and friends, and general clinical study information^[11].

Caregiver Action Network has a resource dedicated exclusively to caregivers of people living with rare diseases. Here caregivers can find tips for coping with various challenges, read personal stories and insights, and interact with other caregivers through an online forum^[11].

Experts recommend genetic counseling and testing for couples with a family history of MPS who are considering having children. Prenatal testing is available^[4].