Mucopolysaccharidoses (MPS) are rare, inherited metabolic disorders that affect how the body breaks down complex sugar molecules. These conditions are part of a larger family of lysosomal storage diseases. Individuals with MPS experience a progressive accumulation of these molecules within their cells, leading to widespread health problems that vary significantly in type and severity.
The Underlying Genetic Cause
Cells contain specialized compartments called lysosomes, often described as cellular recycling centers. Lysosomes house enzymes that break down and recycle excess cellular materials. Among the molecules processed within lysosomes are glycosaminoglycans (GAGs). GAGs are long chains of sugar carbohydrates that build bone, cartilage, tendons, corneas, skin, and connective tissue, and are found in joint lubricating fluid.
In individuals with MPS, a specific enzyme needed to break down GAGs is missing or malfunctioning. This deficiency arises from a genetic mutation, which impairs GAG chain degradation. Undegraded or partially degraded GAGs then accumulate within cell lysosomes, causing progressive damage throughout the body.
Most MPS types are inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the mutated gene, one from each parent, to develop the disorder. If both parents carry one mutated gene copy, there is a 25% chance with each pregnancy that their child will inherit two copies and be affected. MPS II (Hunter syndrome) is an exception, inherited in an X-linked recessive manner, meaning the mother alone can pass the defective gene to a son.
Classifications and Associated Symptoms
MPS disorders present with a wide range of physical and neurological symptoms, reflecting widespread GAG accumulation. Symptoms vary significantly among types and even within the same type. These features become apparent during childhood, progressing as GAG storage affects bones, skeletal structure, connective tissues, and organs.
MPS I includes Hurler, Hurler-Scheie, and Scheie syndromes. Individuals with severe Hurler syndrome show signs within the first year of life, including coarse facial features, short stature, joint stiffness, corneal clouding, enlarged liver and spleen, and progressive intellectual decline.
Those with Scheie syndrome, the mildest form, have normal intelligence or mild learning disabilities. Symptoms appear after age five, such as glaucoma, retinal degeneration, carpal tunnel syndrome, and stiff joints.
Hurler-Scheie syndrome falls between these two extremes, with symptoms appearing in early childhood and impacting physical appearance, cardiovascular, and respiratory systems.
MPS II (Hunter syndrome) affects boys almost exclusively, involving a deficiency of the iduronate-2-sulfatase (I2S) enzyme. Symptoms appear between ages two and four, including distinctive coarse facial features, stiff joints, enlarged liver and spleen, and a deep, hoarse voice. Unlike MPS I, corneal clouding is not associated with Hunter syndrome, but white pebble-like skin growths can occur. The severe form involves progressive neurological decline.
MPS III (Sanfilippo syndrome) primarily affects the central nervous system, leading to neurodegeneration. While physical features are milder than other MPS types, early signs like speech and developmental delays, behavioral problems (hyperactivity, aggression), and sleep disturbances emerge between ages one and four. As the disease progresses, children may experience worsening intellectual disability, seizures, and loss of mobility.
MPS IV (Morquio syndrome) mainly impacts the skeleton. Symptoms appear between ages one and three, including short stature, a bell-shaped chest, knock-knees, and hypermobile joints. Spinal abnormalities, such as an underdeveloped odontoid process in the neck, can lead to spinal cord compression. Corneal clouding, hearing loss, and heart valve abnormalities are common. Unlike other MPS types, intelligence is unaffected in Morquio syndrome.
The Diagnostic Process
Identifying mucopolysaccharidoses begins with a clinical evaluation based on observable physical signs and a detailed medical history. Since MPS is rare and its early symptoms can resemble other conditions, diagnosis may not be immediately suspected. Physical examination helps identify characteristic features like coarse facial features, skeletal abnormalities, joint stiffness, or organ enlargement.
Following initial clinical suspicion, specific laboratory tests support and confirm a diagnosis. Urine tests are among the first steps, detecting abnormally high levels of glycosaminoglycans (GAGs) in the urine. While a positive urine test indicates a potential MPS disorder, it requires further investigation because GAG levels can be elevated in other conditions, and false negatives can occur.
Enzyme assays are a reliable diagnostic tool performed on blood or skin fibroblast samples. These tests measure specific lysosomal enzyme activity, revealing if an enzyme required for GAG breakdown is missing or deficient. Reduced or absent enzyme activity provides strong evidence for an MPS diagnosis.
Genetic testing offers definitive confirmation by identifying specific mutations in the genes responsible for producing these enzymes. This testing uses blood, cheek swab, or saliva samples. Genetic testing also helps identify the specific MPS type, important for prognosis and guiding treatment decisions. Newborn screening programs increasingly incorporate MPS I and MPS II, allowing earlier detection by measuring enzyme activity in dried blood spots, which can lead to prompt intervention and better outcomes.
Current Management and Therapies
There is currently no cure for mucopolysaccharidoses. Existing treatments focus on managing symptoms and slowing disease progression. The two primary therapeutic approaches for some MPS types are Enzyme Replacement Therapy (ERT) and Hematopoietic Stem Cell Transplantation (HSCT).
Enzyme Replacement Therapy involves weekly intravenous infusions of a synthetic version of the missing enzyme. This therapy reduces GAG accumulation in many tissues and has shown benefits in improving respiratory function, mobility, and joint stiffness. A significant limitation of ERT is its inability to effectively cross the blood-brain barrier, meaning it does not address neurological symptoms in MPS types that affect the brain, such as severe MPS I or MPS II.
Hematopoietic Stem Cell Transplantation involves transplanting healthy donor cells, typically from bone marrow or umbilical cord blood, into the patient. These donor cells produce the missing enzyme, which is then taken up by recipient cells, helping to break down GAGs. HSCT is a standard of care for severe MPS I (Hurler syndrome) and can preserve intellectual development if performed early in life. However, HSCT carries risks, including the need for chemotherapy and the potential for graft-versus-host disease. It is not recommended for all MPS types, such as Morquio syndrome, as it has not shown to correct severe skeletal deformities.
Supportive care is a significant part of managing MPS, addressing the wide range of symptoms affecting various organ systems. This includes physical therapy to maintain joint mobility, specialized surgeries to correct skeletal abnormalities or address issues like carpal tunnel syndrome, and ongoing management of respiratory and cardiac complications. Emerging research, particularly in gene therapy, holds promise for future treatments. Gene therapy aims to introduce a functional copy of the defective gene into patient cells, offering a one-time, permanent solution by enabling the body to produce the missing enzyme itself. Clinical trials are underway for various MPS types, exploring different delivery methods, including direct injections into the central nervous system.