Mucopolysaccharidosis (MPS)

Table of Contents


  • MPS
  • MPS disorder

Understanding Mucopolysaccharidoses (MPS)

Mucopolysaccharidoses (MPSs) represent a rare group of disorders characterized by deficiencies in specific enzymes crucial for breaking down lengthy sugar chains known as glycosaminoglycans (formerly referred to as mucopolysaccharides). These glycosaminoglycans play essential roles in building various body components, including bone, cartilage, tendons, corneas, skin, and connective tissues. They also contribute to joint lubrication.

Individuals with MPS experience a deficiency in one of the 11 essential enzymes required to break down these sugar chains. Consequently, glycosaminoglycans accumulate in different bodily areas, leading to various health issues. Glycosaminoglycans are complex, long-chain carbohydrates, usually bound to proteins, forming proteoglycans. Proteoglycans are vital constituents of connective tissue ground substances, present in cell membranes, mitochondria, and nuclei.

MPS sufferers either lack or produce insufficiently functional enzymes, resulting in the permanent and progressive damage of cells, affecting appearance, physical capabilities, organ functions, and, in most cases, mental development.

In vitro fertilization (IVF) and preimplantation genetic testing (PGT) are significant advancements in the realm of reproductive medicine and genetics, particularly for individuals at risk of transmitting genetic disorders like Mucopolysaccharidosis (MPS). For couples with a known risk of passing on Mucopolysaccharidosis (MPS) to their offspring, IVF coupled with PGT offers a proactive approach. In this process, eggs are fertilized in a lab setting, and the resulting embryos are screened for the specific genetic mutations associated with Mucopolysaccharidosis (MPS). This enables the selection of embryos without the disorder for implantation, significantly reducing the likelihood of the child inheriting Mucopolysaccharidosis (MPS). Thus, IVF and PGT provide a powerful combination for family planning, particularly for those with a genetic predisposition to this condition, allowing them to minimize the risk of genetic transmission while achieving pregnancy.

Types of Mucopolysaccharidoses (MPS)

There are seven primary clinical types of MPS, each characterized by distinct symptoms. Despite these differences, individuals with MPS usually undergo a period of typical development followed by a subsequent decline in physical and/or mental functions. The MPS subdivisions are as follows:

  1. MPS I H/S (Hurler/Scheie Syndrome)
  2. MPS I H (Hurler Disease)
  3. MPS II (Hunter Syndrome)
  4. MPS III A, B, C, and D (Sanfilippo Syndrome)
  5. MPS I S (Scheie Syndrome)
  6. MPS IV A and B (Morquio Syndrome)
  7. MPS IX (Hyaluronidase Deficiency)
  8. MPS VII (Sly Syndrome)
  9. MPS VI (Maroteaux-Lamy Syndrome)

In addition, MPS IX, an exceptionally rare form linked to hyaluronidase deficiency, has been identified. MPS X, resulting from arylsulfatase K (ARSK) deficiency, has also been suggested.

MPS I is often categorized into three groups based on symptom severity: Hurler, Hurler-Scheie, and Scheie. This classification highlights a continuous spectrum of disease, with varying levels of severity. All MPS I individuals share a deficiency of alpha-L-iduronidase enzyme, essential for glycosaminoglycan breakdown.

– In severe MPS I (Hurler Syndrome), developmental delays are apparent by the end of the first year. Children typically cease development between ages 2 and 4, followed by progressive mental regression and physical skill loss. They may face limitations in language due to hearing impairment. Physical symptoms include slowed growth in the first year, short stature, skeletal abnormalities, hernias, distinct facial features, and enlarged organs. Obstructive airway disease, respiratory infections, or cardiac complications can lead to premature death, often before age 10.

– Less severe forms of MPS I may not display symptoms at birth but develop complications after the first year. Neurological symptoms may include conditions like hydrocephalus, enlarged head, and clouded corneas. Other common neurological issues include vision impairment, carpal tunnel syndrome, nerve compression, and joint mobility restrictions. Individuals with milder MPS I forms may have normal or slightly impaired intelligence, with potential psychiatric problems. Respiratory, sleep apnea, and heart problems may arise in adolescence. Some with the mildest form can live into adulthood, while others in the spectrum may survive into their late teens or early twenties.

MPS II, also known as Hunter syndrome, is caused by iduronate sulfatase enzyme deficiency, impacting the breakdown of glycosaminoglycans heparan sulfate and dermatan sulfate within cells. Although once classified into two groups based on symptom severity, MPS II is now recognized as a continuum of disease.

– It is unique in that the mother alone can pass the defective gene to a son (X-linked recessive). Typically, the disease predominantly affects young males, with rare cases reported in females.

– Severe MPS II shares neurological and physical features with severe MPS I but with milder symptoms. Symptoms typically begin between ages 2 and 4, with developmental decline noted between 18 and 36 months, followed by progressive skill loss. Other neurological symptoms may include increased intracranial pressure, joint stiffness, retinal degeneration, and progressive hearing loss. Some skin lesions may be present. Severe MPS II individuals often succumb to upper airway disease or cardiovascular complications by age 15.

– In less severe MPS II forms, diagnosis may occur in the second decade. Intellectual and social development remains unaffected. Physical characteristics are less pronounced and progress slowly. Skeletal problems may be less severe, and individuals with milder MPS II can live into their 50s or longer, although respiratory and cardiac issues may lead to premature death.

PS III, also referred to as Sanfilippo syndrome, presents severe neurological symptoms, including progressive dementia, aggressive behavior, hyperactivity, seizures, hearing loss, vision deterioration, and limited sleep duration.

– Symptoms vary among affected children, with differences in the rate of progression. Early mental and motor development may be mildly delayed.

– Children experience a significant learning decline between ages 2 and 6, followed by the loss

Prevalence of Mucopolysaccharidoses (MPS)

Mucopolysaccharidoses (MPS) comprise a group of rare genetic disorders, and their prevalence can vary among different subtypes. Estimating the exact frequency of MPS in the general population is challenging due to underdiagnosis and misdiagnosis, particularly for milder forms of the diseases. Nevertheless, prevalence figures have been determined for various MPS types:

– Overall Prevalence: The collective prevalence of all MPS forms is estimated to be approximately one in 25,000 births. However, this figure may not reflect the true frequency due to under-recognition.

– Specific MPS Type Estimates:

  – Hurler Syndrome (MPS I): Approximately one in 100,000 births.

  – Scheie Syndrome (MPS I-S): Around one in 500,000 births.

  – Hurler-Scheie Syndrome (MPS I-H/S): Estimated at one in 115,000 births.

  – Sanfilippo Syndrome (MPS III): Approximately one in 70,000 births.

  – Morquio Syndrome (MPS IV): Estimated at one in 200,000 births.

  – Sly Syndrome (MPS VII): Fewer than one in 250,000 births.

  – Hunter Syndrome (MPS II): Predominantly affects males, with an estimated incidence of one in 100,000-150,000 male births.

Worldwide Prevalence: Globally, MPS collectively affects approximately one in 16,000-30,000 births. Notably, a study in Brazil estimated MPS birth prevalence to be 4.62 per 100,000 live births, with MPS III being the most common, accounting for 80% of cases.

Age of Onset: The age at which MPS symptoms manifest can vary. While many MPS features become apparent in the first few months of life, Morquio syndrome typically presents in children aged 2-4 years. MPS IS and MPS VI may present later in childhood.

Genetic Inheritance: All MPS disorders are inherited as autosomal recessive traits, except for Hunter syndrome (MPS II), which primarily affects males.

Ethnic Variations: MPS can affect individuals from all ethnic backgrounds. However, certain populations may exhibit higher incidences, such as an elevated prevalence of MPS II among Israeli Jews and an increased occurrence of MPS IV in French Canadians.

These prevalence figures provide insights into the frequency of specific MPS subtypes but should be interpreted with consideration of potential underdiagnosis and regional variations.

Signs and Symptoms of Mucopolysaccharidoses (MPS)

Mucopolysaccharidoses (MPS) encompass a group of genetic disorders that share common clinical features but exhibit varying degrees of severity. These conditions are characterized by the accumulation of glycosaminoglycans, which progressively affect bones, skeletal structure, connective tissues, and organs. The age of onset and symptom presentation can vary widely among individuals.

Common Physical Symptoms Include:

  1. Coarse Facial Features: Individuals with MPS often display distinctive facial characteristics, including a flat nasal bridge, thickened lips, and an enlarged mouth and tongue.
  2. Short Stature: Many individuals with MPS experience short stature, often characterized by a disproportionately short trunk or torso, a condition known as dwarfism.
  3. Skeletal Irregularities: Abnormal bone size, shape, and other skeletal deformities are prevalent in MPS, contributing to physical limitations.
  4. Thickened Skin: Skin thickening is a common symptom in MPS, affecting the texture and appearance of the skin.
  5. Enlarged Organs: Some individuals may develop enlarged organs such as the liver or spleen.
  6. Hernias: Umbilical or inguinal hernias can occur in MPS patients.
  7. Carpal Tunnel Syndrome: This condition restricts hand mobility and function.
  8. Respiratory Issues: Recurring respiratory infections, obstructive airway disease, and obstructive sleep apnea are frequently observed.
  9. Cardiovascular Involvement: Heart disease is common in MPS, often leading to enlarged or diseased heart valves.
  10. Musculoskeletal Abnormalities: MPS may result in limb misalignment, such as knock knees or bowing of the legs, as well as upper cervical spine abnormalities, kyphosis, and carpal tunnel and trigger fingers.

Symptoms Vary by Age:

– 0 – 6 Months: Chronic rhinitis, recurrent otitis media or “glue ear,” umbilical or inguinal hernia, above-normal growth and head size, and gibbus of the thoracolumbar spine.

– 6 Months – 12 Years: Distinctive facial changes, hepatosplenomegaly (enlarged liver and spleen), skeletal deformities, joint stiffness, developmental delay, corneal clouding, and ongoing issues like rhinitis and otitis media.

– 12+ Years: Continued corneal clouding, joint stiffness, valvular heart disease, and cardiopulmonary complications, often resulting in easy fatigue.

Symptoms Across Different MPS Subtypes:

– Hurler Syndrome (MPS I-H): Severe developmental delays, recurrent infections, corneal clouding, spinal deformities, joint stiffness, and an enlarged liver and spleen.

– Scheie Syndrome (MPS I-S): Joint stiffness, carpal tunnel syndrome, aortic regurgitation, and corneal clouding.

– Hurler-Scheie Syndrome (MPS I-H/S): Coarse facial features, joint stiffness, short stature, corneal clouding, and hepatic/splenic abnormalities.

– Hunter Syndrome (MPS II): Progressive growth delays, facial coarsening, hearing loss, and hepatosplenomegaly.

– Sanfilippo Syndrome (MPS III): Hyperactivity, developmental regression, hearing loss, and motor function deterioration.

– Morquio Syndrome (MPS IV): Abnormal skeletal development, growth retardation, distinctive facial features, and spinal deformities.

– Maroteaux-Lamy Syndrome (MPS VI): Coarse facial features, hernias, joint contractures, and organ enlargement.

– Sly Syndrome (MPS VII): Variable symptoms, including intellectual disability, skeletal abnormalities, hernias, and more.

– Hyaluronidase Deficiency (MPS IX): Features like short stature, cysts, ear infections, cleft palate, and soft-tissue masses may be present.

These diverse MPS subtypes share core symptoms, but the specific clinical manifestations can vary widely, impacting individuals differently across their lifespan.

Genetic Disease Risk Factors

Understanding the risk factors associated with genetic diseases is crucial for assessing the likelihood of having or passing on such conditions. Several key factors can increase the chances of being affected by or transmitting a genetic disease:

  1. Family History: A significant risk factor for genetic diseases is having a family history of the condition. If there are known cases of a specific genetic disease within a family, it increases the probability that other family members may also carry or inherit the disease-causing genetic mutations.
  2. Consanguineous Relationships: Another factor that can heighten the risk is when parents are closely related by blood. Consanguineous relationships, such as marriages between first cousins, can increase the chances of inheriting autosomal recessive genetic disorders because both parents may carry the same disease gene.
  3. Ethnic or Geographical Clusters: Certain genetic diseases are more prevalent in distinct ethnic or geographically concentrated populations. Individuals from these communities may have a higher risk of carrying or transmitting specific genetic mutations due to shared ancestry and genetic heritage.
  4. Carriers without Symptoms: Some individuals may be carriers of disease-causing genetic mutations but do not exhibit any symptoms of the disease themselves. These carriers can unknowingly pass on the mutated gene to their offspring, increasing the risk of the disease appearing in subsequent generations.

It’s essential to consider these risk factors when assessing the genetic health of individuals and families. Genetic counseling and testing can help identify potential risks and provide guidance on managing and mitigating them, especially when planning for family expansion or addressing concerns related to specific genetic conditions.

Genetic Inheritance of Mucopolysaccharidoses (MPS)

Understanding the genetic inheritance of mucopolysaccharidoses (MPS) is crucial in assessing the risk and likelihood of an individual being affected by these disorders. Here’s an overview of the inheritance patterns and genetic factors associated with MPS:

  1. Autosomal Recessive Inheritance: Most MPS disorders are inherited as autosomal recessive traits. In this type of inheritance, an affected individual inherits an abnormal gene responsible for the disorder from both parents. When both copies of the gene are mutated, the person will manifest the disease’s symptoms.
  2. Carrier Status: If an individual inherits one normal gene and one gene with the mutation responsible for MPS, they become carriers of the disease. Carriers usually do not exhibit any symptoms of the disorder.
  3. Risk of Having an Affected Child: When two carriers of the defective gene have a child together, there is a 25% chance with each pregnancy that the child will inherit both mutated genes and, therefore, be affected by MPS. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. Additionally, there is a 25% chance that the child will inherit normal genes from both parents and be genetically unaffected by the specific MPS trait.
  4. Siblings and Relatives: The parents and siblings of an affected child may not show any signs of the disorder unless they are carriers themselves. Unaffected siblings and certain relatives of a child with MPS may carry one copy of the defective gene and have the potential to pass it on to their own children.
  5. Exception – MPS II (Hunter Syndrome): MPS II follows an X-linked recessive inheritance pattern. In this case, the mother carries the defective gene on one of her X chromosomes and passes it along to her son. Sons who inherit the defective gene from their mother can develop Hunter syndrome.

Diagnosing Mucopolysaccharidoses (MPS)

The diagnosis of a mucopolysaccharidosis disorder involves a comprehensive approach that includes clinical evaluation, specialized tests, and identification of specific characteristics associated with these disorders. Here are the key steps involved in diagnosing MPS:

  1. Clinical Evaluation: Healthcare professionals conduct a thorough clinical assessment, which includes observing characteristic features such as coarse facial features, skeletal abnormalities, and hepatosplenomegaly (enlarged liver and spleen).
  2. Specialized Tests: Several specialized tests are employed to aid in the diagnosis of MPS. These tests include urine analysis to detect elevated levels of mucopolysaccharides.
  3. Enzyme Assays: To confirm the diagnosis definitively, enzyme assays are essential. These assays involve testing various cells or blood samples in culture to identify enzyme deficiencies. Serum assays for lysosomal enzymes are particularly important in this regard.
  4. Prenatal Diagnosis: For families with a history of MPS or those at risk, prenatal diagnosis can be performed using amniocentesis and chorionic villus sampling (CVS). These procedures allow for the examination of amniotic fluid or placental tissue to determine if the fetus is affected by MPS.
  5. Genetic Testing: Genetic testing is conducted to identify changes in specific genes associated with MPS. For example, changes to the alpha-L-iduronidase (IDUA) gene are indicative of MPS I.
  6. Radiographic Imaging: Plain radiography is used to detect skeletal abnormalities, a phenomenon known as dysostosis multiplex, which is characteristic of MPS conditions.
  7. Additional Imaging: Computed tomography (CT) scans, magnetic resonance imaging (MRI), and echocardiography may be employed to evaluate various aspects of MPS, such as cranial abnormalities, hydrocephalus, spinal involvement, and cardiovascular issues.
  8. Electroretinography: This test assesses retinal function and may be necessary in some cases.
  9. Audiologic Assessment: An evaluation of hearing is performed to identify potential hearing loss associated with MPS.
  10. Carrier Detection: In the case of Hunter syndrome (MPS II), identifying female carriers can be achieved through hair-root analysis and fibroblast single-cell cloning. However, these tests may not be widely accessible.
  11. Genetic Counseling: Genetic counseling is recommended for families with a history of MPS. It assists parents in understanding their carrier status and risk of passing on the mutated gene to their children.

By combining these diagnostic approaches, doctors can accurately diagnose MPS and provide appropriate medical care and guidance to affected individuals and their families.

Differential Diagnosis for Morquio Syndrome

Morquio syndrome can sometimes be mistaken for other medical conditions, leading to a differential diagnosis that includes various disorders. These conditions may share certain clinical features, making it important to distinguish Morquio syndrome from them. Some of the differential diagnoses to consider are:

  1. Spondyloepiphyseal Dysplasia: This is a severe form of skeletal dysplasia, which can exhibit symptoms similar to Morquio syndrome.
  2. Legg-Calvé-Perthes Disease: This condition affects the hip joint and may present with symptoms that resemble those seen in Morquio syndrome.
  3. Sickle Cell Disease: While it primarily involves blood and hemoglobin, sickle cell disease can sometimes manifest symptoms that overlap with those of Morquio syndrome.
  4. Gaucher Disease: This rare genetic disorder can cause skeletal abnormalities and may be confused with Morquio syndrome in some cases.
  5. Multiple Epiphyseal Dysplasia: Another skeletal dysplasia disorder that shares certain clinical characteristics with Morquio syndrome.
  6. Spondylometaphyseal Dysplasia: This condition affects the spine and metaphyses of bones and may exhibit symptoms resembling those of Morquio syndrome.

Accurate diagnosis is essential for appropriate medical management and intervention. Healthcare professionals use a combination of clinical evaluation, medical history, and specialized tests to differentiate Morquio syndrome from these similar conditions.

Treatment Approaches for Mucopolysaccharidoses (MPS)

As of now, there is no cure for mucopolysaccharidoses (MPS). Medical care primarily focuses on managing systemic conditions and enhancing the patient’s overall quality of life. Dietary changes are not effective in halting the progression of the disease.

Surgery may be considered in some cases to address specific complications. Surgical procedures can help alleviate symptoms related to excessive cerebrospinal fluid in the brain, skeletal abnormalities compressing nerves, or corneal clouding affecting vision. These surgeries may include the drainage of cerebrospinal fluid, corneal transplants, removal of tonsils and adenoids to improve breathing, and the insertion of an endotracheal tube for respiratory support. In instances of hydrocephalus, the placement of a shunt to divert excess cerebrospinal fluid away from the brain can be beneficial. In certain cases, heart valve replacement may be required.

Enzyme replacement therapy is available for some MPS subtypes, such as MPS I, MPS II, MPS IVA, MPS VI, and MPS VII. Although it does not address neurological symptoms, it has demonstrated effectiveness in reducing non-neurological symptoms and alleviating pain.

Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have shown promise in treating MPS, particularly Hurler syndrome. Children who undergo BMT often experience an extended lifespan compared to those who do not receive treatment. Hematopoietic stem cell transplant (HSCT), a related procedure involving the infusion of new cells, can improve outcomes when performed at an early age. However, it does not correct bone or eye abnormalities.

Physical therapy and regular exercise play a vital role in delaying joint complications and enhancing mobility for individuals with MPS. Range-of-motion exercises are essential to prevent the progressive loss of motion frequently observed in these patients. Night splints and occupational aids can also provide valuable support.

Prognosis of Mucopolysaccharidosis (MPS)

The outlook for individuals with mucopolysaccharidosis (MPS) varies depending on the specific type of MPS they have. In general, most MPS patients have shortened life spans, and sadly, some do not survive beyond infancy. The disease significantly affects the growth and development of the musculoskeletal system, leading to issues such as joint stiffness, hyperlaxity, deformities, and a progressive loss of function.

MPS is a complex disorder that involves multiple organ systems, and the extent of organ system involvement can vary widely depending on the subtype of MPS. However, there is hope for some MPS patients.

Bone marrow transplantation has shown some positive systemic effects, including the reduction of hepatosplenomegaly (enlarged liver and spleen), relief from airway obstruction, and improved cardiopulmonary function. These improvements have contributed to an extended life span, with many patients surviving beyond their first decade of life.

While the prognosis remains challenging, ongoing research and advancements in treatments offer hope for improved outcomes and quality of life for individuals living with MPS. Regular medical care and early intervention are crucial in managing the disease and addressing its various complications.

Mucopolysaccharidosis (MPS) Complications

Individuals diagnosed with mucopolysaccharidosis (MPS) typically experience normal development during their initial stages of life. However, abnormalities become apparent in infancy or may manifest later in childhood. MPS is a complex condition that affects multiple organ systems, leading to various clinical features and complications, including:

  1. Central Nervous System Involvement: MPS can impact the central nervous system, resulting in neurological complications.
  2. Cardiovascular Diseases: Patients with MPS may develop cardiovascular issues that affect their heart and blood vessels.
  3. Pulmonary Disease: Respiratory problems and pulmonary complications can arise due to MPS.
  4. Ophthalmologic Diseases: Eye-related conditions and visual impairments are common complications associated with MPS.
  5. Hearing Impairment: Hearing difficulties and hearing loss may occur in individuals with MPS.
  6. Musculoskeletal Disease: MPS can affect the musculoskeletal system, leading to skeletal and joint abnormalities.

These complications highlight the multisystem nature of MPS, emphasizing the need for comprehensive care and management to address the diverse medical challenges individuals with MPS may face throughout their lives.

Key Questions for Your Healthcare Provider

When dealing with a diagnosis of Canavan disease for your child, it’s crucial to communicate effectively with your healthcare provider. Here are essential questions to consider and discuss with your doctor:

  1. Changes in Symptoms: Will my child’s symptoms evolve over time, and if so, what changes should we anticipate?
  2. Treatment Options: What are the most effective treatments available for my child’s condition at this stage?
  3. Treatment Side Effects: Are there potential side effects associated with these treatments, and what can be done to manage or mitigate them?
  4. Clinical Trials: Are there any ongoing or upcoming clinical trials that my child could participate in to explore new treatment options?
  5. Monitoring Progress: How do we assess and monitor my child’s progress? Are there specific symptoms or signs I should be vigilant about?
  6. Appointment Frequency: How frequently should we schedule follow-up appointments to track my child’s condition and adjust their care plan as needed?
  7. Specialist Consultation: Are there other medical specialists or healthcare professionals we should consider involving in my child’s care?
  8. Risk Assessment: If I plan to have more children, what is the likelihood that they may also be at risk for developing Canavan disease, and are there genetic counseling options available?

These questions can help you better understand your child’s condition, treatment options, and what to expect as you navigate the journey of managing Canavan disease.

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