Mucopolysaccharidoses

The mucopolysaccharidoses, a subset of the lysosomal storage diseases, are a group of inherited disorders characterized by absent or defective enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs). These disorders lead to the accumulation of GAGs within cells, resulting in a variety of health problems. Most patients appear healthy at birth, but physical and/or mental function deteriorates as accumulation progresses. With disease progression, multiple organ systems may be affected. The diagnosis can be made by measuring urine GAG concentrations and by performing enzyme assays to identify the enzyme deficiency. Management depends on the specific disorder, degree of accumulation, and degree of deformity.

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Overview

Definition

Mucopolysaccharidoses (MPSs) are a group of genetic metabolic diseases due to absent or defective enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs).

Etiology and classification

The MPSs are all inherited and classified on the basis of the enzyme deficiency.

  • MPS I:
    • Autosomal recessive 
    • Deficiency of alpha-L-iduronidase
  • MPS II:
    • Also known as Hunter syndrome
    • X-linked 
    • Deficiency of iduronate sulfatase
  • MPS III:
    • Also known as Sanfilippo syndrome
    • Autosomal recessive
    • Divided into 4 clinical entities on the basis of distinct enzyme deficiencies that are needed to break down heparan sulfate carbohydrate chains:
      • MPS IIIA: deficiency of heparan N-sulfatase
      • MPS IIIB: deficiency of alpha-N-acetylglucosaminidase
      • MPS IIIC: deficiency of acetyl coenzyme A (acetyl-CoA):alpha-glucosaminide acetyltransferase
      • MPS IIID: deficiency of N-acetylglucosamine 6-sulfatase
  • MPS IV:
    • Also known as Morquio syndrome
    • Autosomal recessive
    • Divided into 2 clinical entities on the basis of distinct enzyme deficiencies that are needed to break down keratan sulfate carbohydrate chains:
      • MPS IVA: deficiency of galactosamine-6-sulfate sulfatase
      • MPS IVB: deficiency of beta-galactosidase
  • MPS VI:
    • Also known as Maroteaux-Lamy syndrome
    • Autosomal recessive
    • Deficiency of N-acetylgalactosamine 4-sulfatase
  • MPS VII:
    • Also known as Sly syndrome
    • Autosomal recessive 
    • Deficiency of  enzyme beta-glucuronidase
  • MPX IX:
    • Autosomal recessive 
    • Deficiency of hyaluronidase

Epidemiology

  • Incidence: 1 in 25,000 live births 
  • Based on type:
    • Severe MPS I: 1 in 100,000 
    • Attenuated MPS I: 0.2–1 in 100,000 live births 
    • MPS II: approximately 1 in 100,000 live male births
    • MPS III (all 4 types combined): 1 in 70,000 live births
    • MPS IV: 1 in 200,000 live births
    • MPS VII: 1 in 250,000 live births
    • MPX IV: only 1 reported case

Pathophysiology

  • Lysosomes:
    • Cytoplasmic organelle cells containing degradative enzymes enclosed in a membrane
    • Degradative enzymes are targeted at specific proteins, nucleic acids, carbohydrates, or lipids.
  • Lysosomal storage diseases:
    • Deficiency of these degradative enzymes halts target processing and/or destruction of these molecules.
    • Molecular accumulation in tissues leads to disease.
  • MPSs:
    • Deficiency of lysosomal enzymes needed to metabolize GAGs
    • GAGs are long carbohydrate chains present in several tissues: 
      • Bone
      • Cartilage
      • Tendons
      • Corneas
      • Skin
      • Connective tissue
      • Solid and luminal organs
    • Glycosaminoglycans and/or metabolites accumulate in cells or connective tissues.
    • Progressive cellular damage ensues.
    • Appearance and physical, mental, organ, and system functions may be affected.

Clinical Presentation

Affected individuals are usually not affected at birth, but they experience disease progression as they age. Clinical features vary based on the MPS type.

MPS I

Divided into 3 clinical entities based on disease severity (less severe forms referred to as attenuated):

  • Hurler syndrome (most severe):
    • Developmental delay by 1 year of age
    • Arrested development between ages 2 and 4 years
    • Frequently, death by age 10 (usually from cardiopulmonary complications)
  • Hurler-Scheie syndrome (intermediate severity):
    • Symptom onset between 3 and 8 years
    • Life expectancy: late teens to early 20s
  • Scheie syndrome (least severe):
    • Symptom onset between 5 and 10 years
    • Can live into adulthood

Distinguishing clinical features (more or less pronounced depending on severity):

  • Mental/cognitive impairment
  • Language limitation
  • Hearing loss
  • Poor vision:
    • Corneal clouding
    • Retinal degeneration
  • Dysostosis multiplex:
    • Compressed spine
    • Bone/joint abnormalities
    • Joint restriction and contractures
    • Carpal tunnel syndrome
  • Distinct facial features:
    • Coarse features
    • Flat midface
    • Depressed nasal bridge
    • Bulging forehead
    • Small jaws
    • Widely spaced teeth
    • Peg-shaped teeth
    • Macroglossia
  • Organomegaly:
    • Liver
    • Spleen
    • Heart
    • Tongue
  • Obstructive airway disease:
    • Thick mucus
    • Enlarged tonsils
    • Noisy breathing
    • Frequent respiratory infections
  • Tendency to develop abdominal and inguinal hernias

MPS II

  • Attenuated cases are less severe but are not designated as distinct entities.
  • Disease progression:
    • Symptom onset between ages 2 and 4 years
    • Frequently, death by age 15 years (usually cardiopulmonary complications)
    • Patients with attenuated cases may live into their 50s.
  • Similar clinical features as for MPS I but milder presentation
  • Distinguishing characteristics:
    • Absence of corneal clouding
    • Aggressive behavioral tendencies
    • Communicating hydrocephalus
    • Chronic diarrhea
    • White lesions on limbs and trunk

MPS III

  • Disease progression:
    • Symptom onset after 1st year of life
    • Marked decline in learning between ages 2 and 6 years
    • Life expectancy variable, from late teens to early 30s
  • There are few clinical differences among the 4 clinical entities.
  • Similar clinical features as for MPS I
  • Distinguishing characteristics: severe neurologic symptoms
    • Progressive dementia
    • Aggressive behavior
    • Hyperactivity
    • Seizures
    • Deafness
    • Vision loss
    • Insomnia
    • Progressive unsteadiness on feet
    • Unable to walk by age of 10 years

MPS IV

  • Disease progression:
    • Symptom onset between ages 1 and 3 years
    • Physical growth slows and often stops around age 8 years.
    • Life expectancy to 20s or 30s, unless the severe form is present
  • Similar clinical features as for MPS I
  • Presentations are similar in both types, but appear more severe in MPS IVA.
  • Distinguishing characteristics:
    • Progressive skeletal changes, particularly in the ribs and chest
      • Bell-shaped chest
      • Flattening or curvature of the spine
      • Shortened long bones
      • Dysplasia of the hips, knees, ankles, and wrists
      • Odontoid hypoplasia (cervico-occipital malformation that can be fatal)
    • Spinal nerve and nerve root compression
    • Intelligence is normal (unless hydrocephalus is present).
Dysmorphic features in MPS

Clinical features of mucopolysaccharidosis IIIA:
Facial dysmorphism (coarse facial features, slightly depressed nasal bridge, prominent eyebrows, low-set ears, malocclusion, full cheeks, wiry and dry hair, and short neck) and skeletal symptoms (genu valga, varus feet, and stocky hands) are shown.

Image: “Dysmorphic features of our patient” by Department of Paediatrics, Medical University of Lublin, Racławickie 1, 20-059, Lublin, Poland. License: CC BY 4.0

MPS VI

  • Disease progression:
    • Normal growth and development to age 8 years
    • Development of truncal shortening, crouched stance, and joint restriction by age 10 years
    • Life expectancy variable: late teens and 20s
  • Similar clinical features as for MPS I, but commonly with normal intellectual development
  • Distinguishing characteristics:
    • Neurologic complications include: 
      • Clouded corneas
      • Deafness
      • Thickening of the dura → nerve root compression → pain 
    • Truncal shortening
    • Crouched stance (forward-curving spine)
    • Joint restriction
    • Cardiac valve disorders
    • Pulmonary hypertension
Mucopolysaccharidosis VI

Rapidly progressing MPS VI in a 16-year-old patient:
Face shows coarse facies, with frontal bossing, enlarged tongue, thick lips, abnormal dentition, and gingival hyperplasia.

Image: “Rapidly progressing 16-year old MPS VI patient” by Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, Paris, France. License: CC BY 2.0

MPS VII

  • Disease progression:
    • Rarest form; causes children to be born with hydrops fetalis:
      • Widespread fluid retention
      • Leads to infantile death
    • Most children are less severely affected:
      • Mild to moderate intellectual impairment by age 3 years
      • Life expectancy to teens or 20s
  • Similar clinical features as for MPS I
  • Distinguishing characteristics:
    • Susceptibility to pneumonia
    • Communicating hydrocephalus

MPS IX

  • Nodular soft tissue masses located around joints
  • Episodes of painful swelling of the joint masses
  • Mild facial changes
  • Short stature (as seen in other MPS disorders)
  • Normal joint movement
  • Normal intelligence

Diagnosis

Clinical history and examination:

  • Family history
  • Recognition of typical deformities in infants and young children

Laboratory analysis:

  • Urine GAG concentrations 
  • Enzyme assays to confirm the specific enzyme deficiency: 
    • Serum testing in suspected cases in infancy or early childhood
    • Prenatal diagnosis can be performed with the use of amniocentesis and chorionic villus sampling. 
  • Genetic testing

Management

There is no cure for MPS. Medical care is aimed at treating systemic conditions and at improving quality of life.

  • Genetic counseling for parents who have a family history of MPS to determine if they are carrying a causative genetic mutation
  • Physical therapy to delay joint problems and improve mobility 
  • Surgery:
    • Correction of obstructive airway disorders and sleep apnea
    • Correction of hernias
    • CSF drainage
    • Nerve/nerve root decompression
    • Corneal transplantation.  
  • Enzyme replacement therapies:
    • Currently in use for:
      • MPS I
      • MPS II
      • MPS IVA
      • MPS VI 
      • Enzyme replacement for other types is in development.
    • Therapy has proven useful in reducing:
      • Nonneurologic symptoms
      • Pain
  • Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT):
    • Limited success in treating MPSs
    • High-risk procedures usually performed only after extensive evaluation and parental counseling

Differential Diagnosis

  • Mucolipidosis: lysosomal storage disease with excessive storage of lipids. Children with mucolipidosis may share some clinical features associated with the MPSs (facial features, bony/structural abnormalities, brain abnormalities). Diagnosis is made with laboratory testing to demonstrate enzyme deficiency. Management is supportive.
  • Gaucher disease: most common lysosomal storage disorder; results from glucocerebrosidase deficiency. The 3 types have varying presentations and severity. These presentations can include hepatosplenomegaly, thrombocytopenia, easy bruising, bone fractures, and progressive neurologic deterioration. The diagnosis is made with DNA or enzyme analysis. Management depends on the type and includes enzyme replacement, splenectomy, glucosylceramide inhibitors, and bone marrow or stem cell transplantation. 
  • Tay-Sachs disease: lysosomal storage disorder resulting from hexosaminidase A deficiency. The 3 types have variable onsets. Patients may present with macular cherry-red spots, blindness, deafness, cognitive and motor deterioration, dysphagia, dysarthria, spasticity, ataxia, seizures, and psychosis. The diagnosis is made with enzyme activity testing and molecular analysis. Management is supportive.
  • Niemann-Pick disease (NPD): rare inherited, lysosomal storage disorder that is classified based on the genetic mutation. Types A and B NPD result in acid sphingomyelinase enzyme deficiency. Clinical manifestations may include failure to thrive, hepatosplenomegaly, thrombocytopenia, interstitial lung disease, cognitive and motor impairment, and macular cherry-red spots. The diagnosis can be confirmed by the measurement of sphingomyelinase activity or biomarkers, genetic testing, or biopsy. Management is supportive.

References

  1. Mucopolysaccharidoses Face Sheet. (n.d.). National Institute of Neurological Disorders and Stroke. Retrieved May 22, 2021, from https://web.archive.org/web/20160818205908/http://www.ninds.nih.gov/disorders/mucopolysaccharidoses/detail_mucopolysaccharidoses.htm
  2. Sihoun, H. (2021). Mucopolysaccharidoses: clinical features and diagnosis. Retrieved May 22, 2021, from https://www.uptodate.com/contents/mucopolysaccharidoses-clinical-features-and-diagnosis
  3. Sihoun, H. (2021). Mucopolysaccharidoses: treatment. Retrieved May 22, 2021, from https://www.uptodate.com/contents/mucopolysaccharidoses-treatment
  4. Sihoun, H. (2021). Mucopolysaccharidoses: complications. Retrieved May 22, 2021, from https://www.uptodate.com/contents/mucopolysaccharidoses-complications

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