eMedicine Specialties > Orthopedic Surgery > Pediatrics

Mucopolysaccharidosis

Author: Tarek Bittar, MD, Staff Physician, Department of Orthopedic Surgery, Martin Luther King Medical Center
Coauthor(s): Eleby R Washington III, MD, FACS, Associate Professor, Department of Surgery, Division of Orthopedics, Charles R Drew University of Medicine and Science
Contributor Information and Disclosures

Updated: Mar 4, 2008

Introduction

Background

Mucopolysaccharides consist of glycosaminoglycans attached to a link protein with a hyaluronic acid core. Lysosomal enzymes degrade these macromolecules into smaller components. Heparan sulfate, dermatan sulfate, and keratan sulfate are by-products of an incomplete degradation process. The accumulation of these compounds interferes with cell function.

Different forms of the disease were described separately throughout the 20th century. Their clinical presentations are varied depending on the type of enzyme defect and glycoprotein accumulated.

Related eMedicine topics:
Lysosomal Storage Disease
Madelung Deformity

Related Medscape topics:
Enzyme Replacement Effective in Patients With Hunter Syndrome
Enzyme Replacement Helpful in Mucopolysaccharidosis
Laronidase Prompts Improvement in Mucopolysaccharidosis

Pathophysiology

Defective activity of the lysosomal enzymes blocks the degradation process of mucopolysaccharides, leading to abnormal accumulation of heparan sulfate, dermatan sulfate, and keratan sulfate. These degradation by-products are then secreted and detected in the urine. Mucopolysaccharidosis (MPS) can be subclassified according to the type and amount of substance that accumulates, as follows: Hurler syndrome (MPS IH) (see Images 5, 7-8), Hurler-Scheie (MPS I-H/S), Scheie syndrome (MPS IS), Hunter syndrome (MPS II), Sanfilippo syndrome (MPS III), Morquio syndrome (MP IV) (see Images 1-4, 6), Maroteaux-Lamy syndrome (MPS VI), and Sly syndrome (MPS VII).^1,2,3

Frequency

International

The prevalence of all types of MPS is 1 case in 16,000-30,000 births. MPS III accounts for 80% of cases. These syndromes are found in persons of all ethnic groups, but prevalence is increased in Israeli Jews and French Canadians.

Mortality/Morbidity

These disease processes have significant effects on the growth and development of the musculoskeletal system, including joint stiffness or hyperlaxity, deformities, and progressive loss of function. Multiple other organ systems are involved. The type and extent of organ system involvement are variable depending on the subset of the disease. Most of these patients have shortened life spans and some of them die in infancy.

Race

These syndromes are found in all ethnic groups. Incidence of MPS II is increased in Israeli Jews, and incidence of MPS IV is increased in French Canadians.

Sex

All mucopolysaccharidoses are inherited as autosomal recessive disorders with the exception of Hunter syndrome (MPS II), which is inherited as sex-linked recessive condition. Thus, all patients with Hunter syndrome are males.

Age

Ages at which features of MPS present are somewhat variable. MPS features mostly present in the first few months of life. However, Morquio syndrome usually presents in children aged 2-4 years, and MPS IS and MPS VI can present late in childhood.

Clinical

History

Patients with MPS have normal development initially. Abnormalities are seen in infancy or sometimes later in childhood. Multiple clinical features are seen in the patients in whom multiple organ systems are involved.

• CNS disease: Hydrocephalus is commonly seen in these patients. It is thought to be the result of a defect in cerebrospinal fluid reabsorption. The severity of hydrocephalus correlates with the severity of mental and neurologic retardation. Cervical spine myelopathy secondary to atlantoaxial instability is also commonly seen.
• Cardiovascular disease: Symptoms of heart disease are present in many patients with MPS. Many of them have angina-type symptoms secondary to arteriosclerosis and ischemia. They also can present with valvular dysfunction, hypertension, and congestive heart failure; sudden cardiovascular collapse and death are possible.
• Pulmonary disease: Obstructive airway disease is commonly seen in patients with MPS. It is caused by a narrowed trachea and bronchial airways, thickened vocal cords, and redundant tissue in the upper airway. These characteristics can cause problems ranging from sleep apnea to severe respiratory compromise and cor pulmonale.
• Ophthalmologic disease: Corneal clouding is seen in MPS and can cause significant loss of visual acuity. Glaucoma and chronic papilledema are common complications in several of the MPS conditions. Retinal degenerations are also seen and can be diagnosed with electroretinography.
• Hearing impairment: Deafness is reported in MPS and is thought to be of combined conductive and neurosensory origin. It is attributed to recurrent middle ear infections, deformity of the ossicles, and abnormalities of the inner ear.
• Musculoskeletal disease: Short stature is seen in all MPS conditions except MPS IS. Joint stiffness is a common feature in MPS with the exception MPS IV, in which joints demonstrate hyperlaxity. Other musculoskeletal presentations include symptoms of peripheral nerve entrapment, such as carpal tunnel syndrome, and tendon entrapment, such as trigger finger.^4,5

Physical

• MPS IH (Hurler syndrome): Infants born with Hurler syndrome appear healthy at birth. Diagnosis is usually made in infants aged 6-24 months. Inguinal and umbilical hernias are commonly seen at birth. On physical examination, these patients are observed to have corneal clouding, hepatosplenomegaly, skeletal deformities (dysostosis multiplex), coarse facial features, large tongue, prominent forehead, joint stiffness, and short stature. They also have upper airway obstruction, recurrent ear infections, noisy breathing, and persistent nasal discharge. Other features include hirsutism, hearing loss, hydrocephalus, and mental retardation. Death usually occurs by age 10 years.^4,5,6
• MPS I-H/S (Hurler-Scheie syndrome): This is an intermediate form of Hurler syndrome with milder features. Onset is seen in children aged 3-8 years. These patients have normal intelligence and micrognathia, which gives them a characteristic facies. Corneal clouding, joint stiffness, and heart disease develop by the early to mid teens. Patients survive well into the third decade of life.
• MPS IS (Scheie syndrome): Onset occurs in patients older than 5 years. These patients have aortic valve disease, corneal clouding, and joint stiffness with broad short claw hands. They have normal intelligence and stature and a normal life span.
• MPS II (Hunter syndrome): Mild and severe forms exist, both of which have the same enzyme deficiency. This form of MPS is characterized by pebbly ivory skin lesions on the back, arms, and thighs. The extent of the skin lesions does not correlate with severity of the disease.^7,8
  • MPS II, severe form: Onset of disease occurs in children aged 2-4 years, with severe progressive somatic and neurologic involvement. Coarse facial features, skeletal deformities (such as claw hand), and joint stiffness are present. These patients also have retinal degeneration with clear cornea and hydrocephalus, mental retardation, and aggressive behavior. Death occurs in patients aged 10-15 years.
  • MPS II, mild form: These patients have similar features to the severe form but a much slower rate of progression. They have normal intelligence and no hydrocephalus. Hearing impairment and loss of hand function secondary to joint stiffness and deformities are common in the mild form of Hunter. These patients survive into the sixth and seventh decades of life.
• MPS III (Sanfilippo syndrome): This appears to be the most common of the MPS disorders. Four subtypes of this disease exist, based on the lysosomal enzyme deficiency (types A, B, C, and D). However, these subtypes are not distinguishable clinically. Onset of the disease usually occurs in children aged 3-6 years. These patients have severe central nervous system involvement and only minimal somatic involvement. They commonly present with hyperactivity, mental deterioration, and developmental delay. Physical findings include coarse hair, hirsutism, mild hepatosplenomegaly, and enlarged head. Occasionally, mild dysostosis multiplex and joint stiffness are seen. By age 8-10 years, these patients are profoundly retarded with severely disturbed social behavior (eg, uncontrollable hyperactivity, destructive physical aggression). These patients usually survive into the second or third decade of life.
• MPS IV (Morquio syndrome): Deficiencies of two different enzymes leading to a severe form (MPS IV A) and a mild form (MPS IV B) are recognized. Orthopedic involvement is the primary finding in these patients, with preservation of intelligence and varying degrees of skeletal involvement. Spondyloepiphyseal dysplasia is the hallmark of this disease. Physical findings include genu valgum, short stature, spinal curvature, odontoid hypoplasia, and ligamentous laxity. Atlantoaxial instability is common in Morquio syndrome and can lead to severe myelopathy, paralysis, and death. Patients with the severe form do not survive beyond the third or fourth decade of life. Patients with the mild form have much slower progression of skeletal dysplasia and a normal life span.⁹
• MPS VI (Maroteaux-Lamy syndrome): Onset occurs in patients aged 1-3 years. Mild, intermediate, and severe types have been identified, all with the same enzyme deficiency. Features are very similar to Hurler syndrome, including corneal clouding, coarse facies, joint stiffness, skeletal deformities, and heart valvular disease. Intelligence, however, is normal. These patients may survive into the third decade of life. Most die from cardiopulmonary complications.
• MPS VII (Sly syndrome): This is a very rare condition, with fewer than 20 cases identified worldwide. Mild and severe forms have been identified. The severe form of MPS VII can be detected in the neonatal period associated with hydrops fetalis and hepatosplenomegaly, with death occurring within the first few months of life. Patients with the mild form survive into adolescence. The phenotype is similar to that of Hurler syndrome. Physical findings include corneal clouding, coarse facies, macrocephaly, metatarsus adductus, prominent sternum, pelvic hypoplasia, hepatosplenomegaly, and hernias.

Causes

• Defective activity of the lysosomal enzymes blocks the degradation process of mucopolysaccharides, leading to abnormal accumulation of heparan sulfate, dermatan sulfate, and keratan sulfate.
• All mucopolysaccharidoses are inherited as autosomal recessive disorders with the exception of Hunter syndrome (MPS II), which is inherited as sex-linked recessive.

• Search for CME/CE on This Topic »

• Mucopolysaccharidosis Type IV (Pediatrics: Genetics and Metabolic Disease)
• Mucopolysaccharidosis Type II (Pediatrics: Genetics and Metabolic Disease)
• Mucopolysaccharidosis Type VI (Pediatrics: Genetics and Metabolic Disease)
• Mucopolysaccharidosis Type VII (Pediatrics: Genetics and Metabolic Disease)
• Mucopolysaccharidosis Type III (Pediatrics: Genetics and Metabolic Disease)

• Certain Genzyme Products for Rare Disorders Potentially Contaminated With Foreign Matter