OVERVIEW

What is mucopolysaccharidosis?

Mucopolysaccharidosis (MPS) is a disease caused by the deficiency of enzymes required for the degradation of mucopolysaccharides (also known as glycosaminoglycans), leading to the accumulation of partially degraded mucopolysaccharide fragments in lysosomes. The disease can affect the entire body, primarily manifesting as abnormalities in soft tissues, bones, visceral organs, and the central nervous system. Some cases may be treated with enzyme replacement therapy, but the prognosis is generally poor, often resulting in death due to various complications.

Is mucopolysaccharidosis common?

This disease is considered rare, with an estimated incidence of one case per 20,000 live births.

What are the types of mucopolysaccharidosis?

• Based on the deficient enzyme, mucopolysaccharidosis can be classified into MPS type I, II, III (including subtypes A, B, C, and D), IV (including subtypes A and B), VI, VII, and IX. Different subtypes exhibit distinct clinical features and ages of onset, and biochemical testing can identify the characteristic enzyme deficiency.

• Mucopolysaccharidosis can also be categorized into four groups based on primary clinical manifestations: soft tissue and skeletal storage disease, with or without encephalopathy (MPS I, II, VII); soft tissue and skeletal disease (MPS VI); predominantly skeletal disease (MPS IV A and B); and primarily central nervous system abnormalities (MPS III).

SYMPTOMS

What are the manifestations of mucopolysaccharidosis patients?

Type I mucopolysaccharidosis (MPS I, also known as Hurler disease): This is an autosomal recessive genetic disorder, likely caused by a deficiency in the lysosomal hydrolase α-L-iduronidase. This type includes three clinical subtypes: Hurler syndrome (MPS IH), Hurler-Scheie syndrome (MPS IH/S), and Scheie syndrome (MPS IS), which vary in severity, with Hurler syndrome being the most severe and the latter two milder.

• Mild cases mainly present with joint stiffness, corneal clouding, and chronic rhinitis. A few patients may have aortic valve disease, which is difficult to detect early. Early diagnosis and timely enzyme replacement therapy can reduce the likelihood of severe complications.

• Patients with Scheie syndrome typically have normal intelligence and lifespan. Those with Hurler-Scheie syndrome may exhibit facial changes and hepatosplenomegaly, but progression is slow, and intelligence is unaffected. Patients often die before the age of 20 due to heart disease or respiratory failure.

• Severe cases (Hurler type) usually manifest around 1 year of age, characterized by severe intellectual disability (mental retardation), significant skeletal abnormalities (e.g., coarse facial features, broad nasal bridge, flattened midface, craniosynostosis, hyperostosis leading to enlarged skull, kyphosis, broad hands, short fingers, contractures of knees and elbows), hepatosplenomegaly, valvular heart disease, abdominal distension, hernias (commonly umbilical and inguinal), recurrent chronic rhinitis, respiratory infections, and corneal clouding. The average age of death for Hurler syndrome patients is 5 years, with nearly all dying before age 10.

Type II mucopolysaccharidosis (MPS II, Hunter disease):

• This is an X-linked disorder, likely caused by a deficiency in iduronate-2-sulfatase.

• Hunter disease shares clinical similarities with Hurler disease but typically has a later onset (1–2 years), slower progression, no corneal clouding, milder mental decline, and uncommon hearing loss.

• Some patients may develop characteristic pearl-like papules on the scapulae, outer arms, and thighs.

• The disease may present in two clinical syndromes:

• Severe form: Intellectual impairment, death usually occurs before adolescence.

• Mild form: Relatively normal intelligence, survival into the 50s or 60s is possible.

Type III mucopolysaccharidosis (MPS III, Sanfilippo disease):

• Based on enzyme deficiency, it is divided into subtypes A, B, C, and D, all autosomal recessive, caused by heparan N-sulfatase deficiency. Each subtype leads to excessive urinary excretion of heparan sulfate.

• Onset typically occurs at 2–3 years, with progressive intellectual decline, developmental delay, and behavioral abnormalities (e.g., hyperactivity, aggression). Skeletal abnormalities may include short stature, thoracic kyphosis, and short neck. Physical changes are less severe than in Hunter or Hurler disease.

• Most patients die in their teens, though some survive into early adulthood.

Type IV mucopolysaccharidosis (MPS IV, Morquio disease):

• Includes MPS IV A (galactosamine-6-sulfatase deficiency) and IV B (β-galactosidase deficiency), with keratan sulfate detectable in urine.

• This autosomal recessive disorder often begins in early childhood, primarily affecting the skeletal system, manifesting as dwarfism and osteoporosis. Bone dysplasia can lead to deformities and compression of the spinal cord and medulla.

• Intelligence is unaffected or mildly impaired. Corneal clouding, valvular heart disease, and hepatosplenomegaly may occur.

• Severe cases show minimal height growth after age 6–7, with death typically in the 20s–30s. Mild cases may survive into their 60s.

Type VI mucopolysaccharidosis (MPS VI, Maroteaux-Lamy disease):

• Caused by arylsulfatase B deficiency, leading to excessive urinary dermatan sulfate excretion. This is an autosomal recessive disorder.

• Neurological symptoms are minimal, and intelligence is normal. The primary manifestations are severe skeletal deformities, short stature, lumbar lordosis, and coarse facial features. Hepatosplenomegaly, respiratory diseases, and heart conditions are common.

• Severe cases may develop secondary cerebrospinal damage in adulthood, such as cervical pachymeningitis, spinal cord compression, or hydrocephalus. Death usually occurs in the teens or 20s.

Type VII mucopolysaccharidosis (MPS VII, Sly disease):

• Caused by β-glucuronidase deficiency, this rare autosomal recessive disorder leads to excessive urinary excretion of dermatan sulfate and heparan sulfate.

• Patients mainly exhibit bone-related short stature, progressive thoracolumbar kyphosis, and multiple dysostoses. Hepatosplenomegaly may occur, but neurological symptoms are minimal, and intelligence is normal.

Type IX mucopolysaccharidosis (MPS IX): A very rare autosomal recessive disorder caused by hyaluronidase-1 deficiency. Only a few cases have been reported, with symptoms including severe joint involvement, swelling, pain, acetabular erosion, and short stature.

What conditions should mucopolysaccharidosis be differentiated from?

Mucopolysaccharidosis affects multiple systems and is often initially misdiagnosed as bone/joint disorders, organ diseases, or other causes of developmental delay and behavioral abnormalities in children. When multisystem involvement suggests a common etiology, differentiation from other inherited metabolic disorders is necessary, such as oligosaccharidosis, sphingolipidosis, and mucolipidosis.

CAUSES

What causes mucopolysaccharidosis?

Mucopolysaccharides are widely distributed in various human tissues and play important roles. In bones and cartilage, they are key components of the matrix and serve as ingredients in joint lubricants. The metabolic recycling of mucopolysaccharides requires a series of lysosomal enzymes working together to achieve stepwise degradation. A deficiency in any of these key enzymes can prevent complete degradation of mucopolysaccharides, leading to the accumulation of fragments in the lysosomes of cells in the brain, spinal cord, heart, other internal organs, bones, and connective tissues, impairing cellular function. The lack of mucopolysaccharides can also cause abnormalities in skeletal and central nervous system functions.
Neurological abnormalities include neuronal lipid storage and secondary complications due to skeletal and connective tissue disorders, such as skeletal deformities or obstructive hydrocephalus caused by connective tissue hyperplasia at the base of the brain, as well as cervical spinal cord compression.
The disease is currently considered a genetic disorder, mostly inherited in an autosomal recessive pattern, though X-linked inheritance (MPS type II) also occurs. Different genetic defects lead to deficiencies in specific enzymes, resulting in distinct disease subtypes.

DIAGNOSIS

How to diagnose mucopolysaccharidosis?

When children present with coarse facial features, hepatosplenomegaly, corneal clouding, and skeletal/joint abnormalities, with or without central nervous system involvement, suspicion of this disease should arise.
For suspected cases, comprehensive biochemical evaluation is required. Measuring urinary glycosaminoglycan (GAG) concentration, separating GAGs via electrophoresis or chromatography, and analyzing oligosaccharides can determine the specific type of mucopolysaccharidosis.
Genetic testing helps confirm the diagnosis.

What tests are required for patients with mucopolysaccharidosis? Why are these tests necessary?

• Urinary biochemical tests: All suspected MPS patients should undergo urinary GAG concentration measurement. Isolating GAGs helps differentiate between MPS types. Detecting mucopolysaccharide metabolites also aids in distinguishing MPS subtypes.

• Leukocyte enzyme analysis: Testing peripheral blood leukocytes for specific enzyme deficiencies helps confirm MPS diagnosis.

• Genetic mutation analysis: Genetic testing aids in definitive diagnosis and enables prenatal testing.

• Imaging studies: Radiographic examination of the skeletal system may reveal typical dysostosis multiplex features. Imaging of the head and spine helps identify spinal cord compression, hydrocephalus, etc.

What precautions should be taken for urine testing?

For urine testing, the first clean midstream urine sample of the morning should be collected, as it is relatively concentrated. Using diluted daytime urine may yield false-negative results.

TREATMENT

Which department should I visit for mucopolysaccharidosis?

Pediatrics or Neurology.

Can mucopolysaccharidosis resolve on its own?

No.

Does mucopolysaccharidosis require hospitalization?

Hospitalization is necessary for diagnosis.

How is mucopolysaccharidosis treated?

Treatment for mucopolysaccharidosis is mainly symptomatic. Etiological treatments such as plasma and leukocyte replacement therapy, bone marrow transplantation, and gene transfection are still experimental. Symptomatic treatment focuses on managing multisystem complications.
Respiratory complications and management:

• Patients with all types of MPS may develop respiratory complications, which are a major cause of mortality.

• Central apnea caused by spinal cord compression should be addressed early with spinal decompression surgery to improve function.

• Airway obstruction due to enlarged soft tissues (tongue, gums, nasopharynx) or recurrent ear/sinus infections may require tonsillectomy, adenoidectomy, nocturnal CPAP, low-flow oxygen therapy, or tracheostomy in severe cases.

• Pulmonary dysfunction from skeletal abnormalities may benefit from bronchodilators or corrective surgery.

Cardiac complications and management:

• Cardiac involvement may be primary or secondary to respiratory disease.

• Valvular dysfunction (aortic stenosis, regurgitation, pulmonary hypertension) may require high-risk surgery. Anesthesia poses challenges.

• Vascular deposits can cause myocardial ischemia, infarction, or sudden death. Limited benefit from cardiology interventions or stenting.

Skeletal complications and management:

• Most common manifestation, ranging from mild to severe spinal instability requiring fusion surgery.

• Early ERT in MPS II may improve growth. Joint pain/deformities benefit from rehabilitation and analgesia.

Neurological complications and management:

• Behavioral issues (hyperactivity/aggression) may require risperidone, olanzapine, benzodiazepines, or antidepressants.

• Anticonvulsants for seizures, melatonin/benzodiazepines for sleep disorders.

• Ventriculoperitoneal shunting may relieve hydrocephalus-induced cognitive decline.

DIET & LIFESTYLE

What should patients with mucopolysaccharidosis pay attention to in their diet?

No special precautions are required, but it is recommended to ensure adequate nutrition and vitamin intake.

What should patients with mucopolysaccharidosis pay attention to in daily life?

• Since the disease often begins in childhood, parents should closely monitor the child's intelligence, growth, development, and behavior to facilitate early detection and treatment.

• For those with behavioral abnormalities, avoid stimulating factors and prevent self-harm.

• For patients with respiratory complications, minimize infections, cold exposure, and cold air irritation. Be alert to mucus blocking the airways and consider using a ventilator at night if necessary.

• For those with some mobility, appropriate rehabilitation exercises can be encouraged, but injuries and falls should be avoided.

Does mucopolysaccharidosis require follow-up examinations? How?

Yes, regular clinical follow-ups are needed to monitor disease progression and complications.

PREVENTION

Can Mucopolysaccharidosis Be Prevented?

This disease is a genetic disorder. For families with similar conditions, prenatal diagnosis and genetic counseling are necessary during pregnancy.