Practice Essentials

Mucopolysaccharidosis (MPS) involves defective activity of the lysosomal enzymes, which blocks degradation of mucopolysaccharides and leads to abnormal accumulation of heparan sulfate, dermatan sulfate, and keratan sulfate. MPS can be subclassified as follows:

• Hurler syndrome (MPS IH)
• Hurler-Scheie syndrome (MPS I-H/S)
• Scheie syndrome (MPS IS)
• Hunter syndrome (MPS II)
• Sanfilippo syndrome (MPS III)
• Morquio syndrome (MP IV)
• Maroteaux-Lamy syndrome (MPS VI)
• Sly syndrome (MPS VII)

The image below depicts Morquio syndrome.

An 8-year-old boy with Morquio syndrome and severe kyphoscoliosis. Courtesy of Dennis P. Grogan, MD.

Signs and symptoms

Patients with MPS have normal development initially, with abnormalities appearing in infancy or later in childhood. Those with multiple organ system involvement may have the following presentations:

• CNS disease – Hydrocephalus; cervical spine myelopathy
• Cardiovascular disease – Angina; valvular dysfunction; hypertension; congestive heart failure
• Pulmonary disease – Airway obstruction, potentially leading to sleep apnea, severe respiratory compromise, or cor pulmonale
• Ophthalmologic disease – Corneal clouding; glaucoma; chronic papilledema; retinal degeneration
• Hearing impairment – Deafness
• Musculoskeletal disease – Short stature; joint stiffness; symptoms of peripheral nerve entrapment

Findings from examination may include the following:

• MPS IH – Corneal clouding, hepatosplenomegaly, skeletal deformities (dysostosis multiplex), coarse facial features, large tongue, prominent forehead, joint stiffness, and short stature; upper airway obstruction, recurrent ear infections, noisy breathing, and persistent nasal discharge; hirsutism, hearing loss, hydrocephalus, and mental retardation
• MPS I-H/S - Milder features; normal intelligence and micrognathia; corneal clouding, joint stiffness, and heart disease
• MPS IS - Aortic valve disease, corneal clouding, and joint stiffness; normal intelligence and stature
• MPS II (severe) – Pebbly ivory skin lesions on the back, arms, and thighs; coarse facial features, skeletal deformities, and joint stiffness; retinal degeneration with clear cornea and hydrocephalus, mental retardation, and aggressive behavior
• MPS II (mild form) – Similar features, but with much slower progression; normal intelligence and no hydrocephalus; hearing impairment and loss of hand function
• MPS III – The most common MPS disorder; severe central nervous system (CNS) involvement and only minimal somatic involvement; coarse hair, hirsutism, mild hepatosplenomegaly, and enlarged head; occasionally, mild dysostosis multiplex and joint stiffness; eventually, by age 8-10 years, profound retardation with severely disturbed social behavior
• MPS IV (severe) – Orthopedic involvement (eg, spondyloepiphyseal dysplasia) as the primary finding; preservation of intelligence; genu valgum, short stature, spinal curvature, odontoid hypoplasia, ligamentous laxity, and atlantoaxial instability
• MPS IV (mild) – Much slower progression of skeletal dysplasia
• MPS VI – Features very similar to MPS IH
• MPS VII – Features similar to MPS IH

See Presentation for more detail.

Diagnosis

Prenatal screening studies that may be useful include the following:

• Chorionic villus sampling
• Amniocentesis

Postnatal diagnostic studies that may be helpful include the following:

• Urinalysis, focusing on glycosaminoglycans (eg, dermatan sulfate, heparin sulfate, and keratin sulfate)
• Serum assays for lysosomal enzymes (alpha-L-iduronidase, iduronate sulfatase, heparan N -sulfatase, N -acetylglucosaminidase, alpha-glucosamine- N -acetyltransferase, N -acetyl alpha-glucosamine-6-sulfatase, N -acetylgalactosamine-6-sulfatase, N -acetylgalactosamine-6-sulfatase, B-galactosidase, N -acetylgalactosamine-4-sulfatase, and B-glucuronidase)

Imaging studies that may be warranted are as follows:

• Plain radiography (to detect dysostosis multiplex)
• Computed tomography (CT) of the cranium (to help diagnose hydrocephalus)
• Echocardiography (to monitor ventricular function and size in MPS patients with cardiovascular disease)

Other tests to be considered are as follows:

• Electroretinography
• Audiologic assessment

See Workup for more detail.

Management

Specific treatment or cure is limited for MPS. Management has been limited to supportive care and experimental treatment modalities. Medical treatment modalities include the following:

• Laronidase
• Idursulfase
• Elosulfase alfa

Surgical care for specific conditions may include the following:

• Hydrocephalus – Ventriculoperitoneal shunting
• Corneal clouding – Corneal transplantation
• Cardiovascular disease – Valve replacement
• Obstructive airway disease – Tracheostomy
• Orthopedic conditions – Carpal tunnel release; soft tissue procedures to release hip, knee, and ankle contractures; hip containment surgeries; corrective osteotomy for progressive valgus deformity at the knee; posterior spinal fusion

Multispecialty care is mandatory for these patients and should include a pediatrician (internist), a neurologist, a cardiologist, an ophthalmologist, an audiologist, an orthopedic surgeon, and a physical and occupational therapist.

See Treatment and Medication for more detail.

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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 mucopolysaccharidosis (MPS) were described separately throughout the 20th century. Their clinical presentations vary, depending on the type of enzyme defect and glycoprotein accumulated. (See Lysosomal Storage Disease and Madelung Deformity.)

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. MPS can be subclassified according to the type and amount of substance that accumulates, as follows^{[1, 2, 3]} :

• Hurler syndrome (MPS IH) (see the first three images below)
• Hurler-Scheie (MPS I-H/S)
• Scheie syndrome (MPS IS)
• Hunter syndrome (MPS II)
• Sanfilippo syndrome (MPS III)
• Morquio syndrome (MP IV) (see the fourth through eighth images below)
• Maroteaux-Lamy syndrome (MPS VI)
• Sly syndrome (MPS VII)

Hurler syndrome; lateral radiograph of thoracolumbar vertebrae illustrates vertebral plana. Courtesy of Bruce M. Rothschild, MD. Hurler syndrome; widened metaphyses and diaphyses with truncated distal portions forming a peg characterize this radiograph. Courtesy of Bruce M. Rothschild, MD. Hurler syndrome; widened metaphyses and diaphyses with truncated distal portions forming a peg characterize this radiograph. Courtesy of Bruce M. Rothschild, MD. An 8-year-old boy with Morquio syndrome and severe kyphoscoliosis. Courtesy of Dennis P. Grogan, MD. A 7-year-old girl with Morquio syndrome and typical severe genu valgum. Courtesy of Dennis P. Grogan, MD. Morquio syndrome; widened bases of phalanges with osteopenia. Courtesy of Bruce M. Rothschild, MD. Morquio syndrome; lateral radiograph of thoracolumbar vertebrae illustrates vertebral body beaking. Courtesy of Bruce M. Rothschild, MD. Morquio syndrome; anteroposterior radiograph of pelvis illustrates avascular necrosis of femoral head. Courtesy of Bruce M. Rothschild, MD.

Etiology

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 forms of MPS are inherited as autosomal recessive disorders, with the exception of Hunter syndrome (MPS II), which is inherited as sex-linked recessive.

Epidemiology

Worldwide, the prevalence of all types of MPS is 1 case in 16,000-30,000 births. MPS III accounts for 80% of cases.

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.

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.

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.

Prognosis

The prognosis varies depending on the type of MPS. Most of these patients have shortened life spans, and some of them die in infancy. 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.

Bone marrow transplantation has some positive effects systemically, such as reduction in hepatosplenomegaly, airway obstruction, and cardiopulmonary disease. These effects have resulted in improved life span, and many of these patients survive beyond the first decade of life.

Clinical Presentation