Excerpt from Mucopolysaccharidosis Type III

Please click here to view the full topic text: Mucopolysaccharidosis Type III

Background

The mucopolysaccharidoses (MPSs) are a rare group of inherited lysosomal storage disorders that are caused by the deficiency or absence of specific lysosomal enzymes. The absence of these enzymes allows for the accumulation of complex carbohydrates in the body's cells and tissues and in the cellular organelles, the lysosomes. These complex carbohydrates are known as mucopolysaccharides or glycosaminoglycans (GAGs) and serve as the building blocks for connective tissues in the body. 

The MPSs comprise a group of 7 metabolic disorders, known as MPS types I-VII (MPS V is now considered a form of type I and is known as MPS IS). Each lysosomal storage disorder is associated with a defined enzymatic deficiency, although as a group, these disorders share many clinical features. Without the proper enzymatic degradation of the mucopolysaccharides, clinical symptoms, such as auditory and visual defects, cardiovascular functional impairments, hepatosplenomegaly, and dysostosis multiplex, occur due to their accumulation in organ systems. 

Severe mental retardation also occurs and is usually associated with Hurler syndrome (MPS IH), Hunter syndrome (MPS II), and Sanfilippo syndrome (MPS III). Although lysosomal storage diseases are rare individually, the estimated incidence of all types of MPS disorders combined is 1 in 20,000 live births.

MPS III, or Sanfilippo syndrome, was described in 1963 by a US-trained pediatrician named Sylvester Sanfilippo. Considered to be the most common of MPS disorders, Sanfilippo syndrome results from the deficiency or absence of 4 different enzymes that are necessary to degrade the GAG heparan sulfate. Each enzyme deficiency defines a different form of Sanfilippo syndrome, as follows: type IIIA (Sanfilippo A), type IIIB (Sanfilippo B), type IIIC (Sanfilippo C), and type IIID (Sanfilippo D). The other MPS disorders are discussed in respective articles (see Differentials).

Pathophysiology

The clinical features of Sanfilippo syndrome, including the significant impact on the CNS, result from the progressive lysosomal accumulation of the GAG heparan sulfate.

Four enzymes are involved in the different forms of Sanfilippo syndrome. Individuals with type A lack the enzyme heparan sulfate sulfatase. Individuals with type B lack the enzyme N-acetyl-alpha-D-glucosaminidase. Patients with type C lack acetyl-CoA:alpha-glucosaminide acetyltransferase. Patients with type D lack the enzyme N-acetylglucosamine-6-sulfatase. As a result of these differing enzyme deficiencies, an increase in the urinary excretion of heparan sulfate occurs.

The particular form of Sanfilippo syndrome cannot be determined based on clinical features. Precise identification of the specific form of Sanfilippo syndrome must rely on enzymatic assays (see Workup).

Frequency

International

• In 1997, Nelson reported an incidence of 1 case per 280,000 live births (0.36 cases per 100,000 live births) for Sanfilippo syndrome in Northern Ireland.¹
• In 1999, Poorthuis et al reported an incidence of 4.5 cases per 100,000 live births for all MPS disorders in the Netherlands.² MPS III accounted for 47% of all cases of MPS diagnosed and had a birth prevalence of 1.89 cases per 100,000 live births. In this study, MPS IIIA had an estimated birth prevalence of 1.16 cases per 100,000.
• A 2000 registry compiled by MPS Australia cited an incidence of 1 case per 66,000 live births for all forms of Sanfilippo syndrome. Within this combined statistic, MPS IIIA had an incidence of 1 case per 114,000 live births, and MPS IIIB had an incidence of 1 case per 211,000 live births. MPS IIIC and MPS IIID are much rarer.

Mortality/Morbidity

Sanfilippo syndrome has a progressive process with a devastating prognosis. Over time, patients develop CNS degeneration and progress to a vegetative state. Death usually occurs before age 20 years, primarily from aspiration pneumonia. Type IIIA is the most severe form; most patients with this form die during their teenage years.

Race

The MPSs are panracial.

Sex

All forms of MPS III are inherited in an autosomal recessive Mendelian pattern. The gene mutations are located in the autosomes and not in the sex chromosomes;³ therefore, Sanfilippo syndrome affects males and females equally.

Age

Children with Sanfilippo syndrome are born without clinical features of a metabolic disorder. In the toddler years, aggressive behavioral problems emerge, with marked overactivity and destructive tendencies. Mild somatic features, such as mild organomegaly, little to no corneal clouding, and orthopedic abnormalities, may be seen. Neurologic degeneration usually begins in children aged 6 years or older (sometimes even younger). Death may not occur until after puberty.

Please click here to view the full topic text: Mucopolysaccharidosis Type III