eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Mucopolysaccharidosis Type I

Author: Maryam Banikazemi, MD, Assistant Professor of Clinical Pediatrics, Department of Clinical and Molecular Genetics, Columbia University College of Physicians and Surgeons; Director of Newborn Screening Program, Director of Lysosomal Storage Disorders Program, Department of Pediatrics, Columbia University Medical Center
Contributor Information and Disclosures

Updated: Apr 14, 2009

Introduction

Background

The mucopolysaccharidoses (MPSs) are a family of metabolic disorders caused by the deficiency of lysosomal enzymes needed to degrade glycosaminoglycan (GAG).1 GAG is an important constituent of the extracellular matrix, joint fluid, and connective tissue throughout the body. Progressive accumulation of GAG within the cells of various organs ultimately compromises their function. The major sites of disease differ depending on the specific enzyme deficiency; therefore, clinical presentation and approaches to therapy are different for the various disease types.

Of the MPSs, mucopolysaccharidosis type I (MPS I) is by far the most common type. MPS I is heterogeneous, and the severity of symptoms widely varies. Historically, the range of most-to-least severe forms are as follows: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome.

Pathophysiology

Mucopolysaccharidosis type I (MPS I) is a rare, inherited lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. The disease is inherited in an autosomal recessive manner. The alpha-L-iduronidase deficiency results in an inability of the lysosome to break down GAG, namely dermatan sulfate (DS) and heparan sulfate (HS). This process is essential for normal growth and homeostasis of tissues. In this disease, GAG  progressively accumulates in the lysosomes, ultimately causing cell, tissue, and organ dysfunction by largely unknown pathophysiological mechanisms. On a biochemical level, the alpha-L-iduronidase deficiency causes an increase in the urinary excretion of dermatan sulfate (DS) and heparan sulfate (HS) in patients with MPS I.

Hurler syndrome is caused by mutation in the gene (IDUA) that encodes alpha-L-iduronidase on chromosome 4. Many different mutations have been found at this locus, including mutations that cause MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS IH/S (Hurler-Scheie syndrome), among others. MPS I and all subtypes are discussed in detail below.

Frequency

United States

Precise figures for mucopolysaccharidosis type I (MPS I) incidence are lacking, but estimated incidence is approximately 1 case per 100,000 births.

International

The birth prevalence of mucopolysaccharidosis type I (MPS I) in England and Wales from 1981-2003 was 1.07 cases per 100,000 births.²

Mortality/Morbidity

Lifespan in mucopolysaccharidosis type I (MPS I) ranges from death in early childhood in the most severe form to adulthood in the least severe variant.

Race

Mucopolysaccharidosis type I (MPS I) is inherited in an autosomal recessive manner and affects both sexes.

Clinical

History

Historically, mucopolysaccharidosis type I (MPS I) has been broadly categorized into Scheie syndrome (MPS IS), Hurler-Scheie syndrome (MPS IHS), and Hurler syndrome (MPS IH), representing clinical phenotypes ranging from least severe to most severe. These classifications are arbitrary categorizations of points on a spectrum of patient phenotypes.

Physical

Clinical manifestations of mucopolysaccharidosis type I (MPS I) show a chronic multisystemic and progressive course. The disease is highly heterogeneous, spanning a spectrum of severity. Children with Hurler syndrome appear normal at birth and develop the characteristic appearance over the first years of life. Symptoms across the types include facial dysmorphism, corneal clouding, hepatomegaly, valvular heart disease, obstructive airway disease, developmental delay, hearing loss, skeletal deformities, and joint stiffness. For patients with the more severe form of the disease, the most typical symptoms occur early in life. These patients typically have numerous progressively debilitating symptoms, including mental retardation. Their lifespan is less than 10 years. Individualswithlesssevere disease can have some of the same physical symptoms but generally retain normal intellect and stature, and may have a normal lifespan.

The most severe presentation at the other end of the disease spectrum is Hurler syndrome (MPS IH), which is outlined below. These characteristic features in children with the more severe form of MPS I can be less obvious in children with less severe forms of MPS I.

Facial dysmorphism or coarsened facial features

Coarsening of the facial features is usually the first abnormality detected. These features often first become apparent at age 3-6 months and may become progressively more evident. The head is large with bulging frontal bones. The skull is often scaphocephalic secondary to premature closure of the metopic and sagittal sutures. The nasal bridge is depressed with broad nasal tip and anteverted nostrils. The cheeks are full. The lips are enlarged, and the mouth is usually held open, particularly after age 3 years. Chronic nasal discharge is present. Eyes may be widely spaced, and eye sockets may be shallow, causing the eyes to slightly protrude.

The clinical presentation in less severe disease (MPS IS) may be limited to mild coarsening of facial features and prognathism. A large mouth with thick lips may develop. 

Corneal clouding

As a result of glycosaminoglycan (GAG) storage, progressive corneal clouding is common in MPS I and can begin as early as the first year of life. Clouding of the cornea has a ground-glass appearance and may lead to blindness. Retinal degeneration is also common in MPS I.

Visceral involvement

Progressive hepatosplenomegaly is common in MPS I. GAG storage in the liver and spleen does not lead to organ dysfunction; however, organ size may be massive. Loose stools and diarrhea are episodic problems for some patients. Inguinal and umbilical hernias are common in MPS I. They are occasionally present at birth or develop within the first several months of life and are often one of the first clinical signs noted.

Skeletal involvement

Patients with severe disease demonstrate skeletal manifestations of MPS I early in life, by about age 6 months. At that time, widening of the ribs and mild bone abnormalities (detected by radiological methods) are common, particularly within the hip and ovoid vertebrae. At the clinical level, skeletal involvement does not become obvious until age 10-14 months, when a gibbus deformity of the back, or dorsolumbar kyphosis, is observed in patients with severe disease.

Eventually, progressive skeletal dysplasia involving all bones is seen in all types of MPS. The vertebrae may become progressively flattened and beaked, often leading to spinal deformity. Typically, the pelvis is poorly formed, with small femoral heads and coxa valga. Involvement of the femoral head leads to progressive and debilitating hip deformity. Clavicles may be short, thickened, and irregular (“oar-shaped”).

Length is often normal until about age 2 years, when growth stops; by age 3 years, height is less than the third percentile, and children may not grow taller than 4 ft.

Joint stiffness

The joints may become stiffened by age 2 years, and progressive arthropathy affects all joints. The hands take on a characteristic claw deformity, resulting from both phalangeal dysostosis and synovial thickening.

Carpal tunnel syndrome, a common complication in the MPSs, probably results from a combination of excessive lysosomal storage in the connective tissue of the flexor retinaculum and a deformity secondary to the underlying skeletal dysplasia.

Cardiopulmonary

Valvular disease, specifically aortic valve disease, may be seen in these patients. Frequent upper and lower respiratory tract infections are common. Respiratory obstruction occurs secondary to enlargement of tonsils and adenoids, chronic hearing loss, and enlarged tongue. However, in mild forms, the intellectual level is normal.

Development

In severe forms of MPS I, developmental delay is often apparent by age 12-24 months, with a maximum functional age of 2-4 years, followed by progressive deterioration. Most children develop limited language because of developmental delay.

Others

The neck is short, and odontoid hypoplasia is noted. Vertebral subluxation with cord compression can occur. Body hair may be coarser than usual, and the skin may be thicker.

Causes

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal enzyme, a-L-iduronidase. This deficiency leads to accumulation of undegraded mucopolysaccharides, especially dermatan sulfate, in tissues and organs. The buildup of excess dermatan sulfate (DS) leads to the gradual development of numerous morphological abnormalities in tissues and organs. The a-L-iduronidase gene has been mapped to chromosome band 4p16.3. The metabolic defect in MPS IH has an autosomal recessive mode of inheritance.

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