Sanfilippo Syndrome (Mucopolysaccharidosis Type III)

Updated: Oct 05, 2015
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Overview

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. Lack 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, also known as mucopolysaccharides or glycosaminoglycans (GAGs), serve as the building blocks for connective tissues in the body.

The mucopolysaccharidoses comprise a group of 8 metabolic disorders, known as mucopolysaccharidoses types I-IV, VI, VII, and IX and mucolipidosis (ML; types II and III). Mucopolysaccharidosis V is defined as a form of type I and is known as mucopolysaccharidosis 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 pathologies, hepatosplenomegaly, and dysostosis multiplex, occur due to their accumulation in organ systems.

Severe neurological impairment also occurs and is usually associated with Hurler syndrome (mucopolysaccharidosis IH), Hunter syndrome (mucopolysaccharidosis II), and Sanfilippo syndrome (mucopolysaccharidosis III). The incidence of individual types of lysosomal storage disease is rare; however, the estimated combined incidence of all types of mucopolysaccharidoses is 1 in 20,000 live births.

In 1963, mucopolysaccharidosis III, also now known as Sanfilippo syndrome, was described at the American Pediatric Society Annual Meeting by pediatrician, Sylvester Sanfilippo. Mucopolysaccharidosis III is considered the most common of these genetic disorders, occurring with an incidence of 1 in 70,000 newborns. 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 subtype of Sanfilippo syndrome, as follows: type IIIA (Sanfilippo A), type IIIB (Sanfilippo B), type IIIC (Sanfilippo C), and type IIID (Sanfilippo D). [1, 2, 3, 4] Other types of mucopolysaccharidoses are discussed in separate articles (see Differentials).

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Pathophysiology

The clinical features of Sanfilippo syndrome, including the significant CNS component (brain and spinal cord), result from the progressive lysosomal accumulation of the GAG heparan sulfate. [5]

Four enzymes are involved in the different subtypes 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 (NAG). [6] 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, there is an increase in the urinary excretion of heparan sulfate in patients with mucopolysaccharidosis type III.

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

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Epidemiology

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. [7] In 1999, Poorthuis and others reported an incidence of 4.5 cases per 100,000 live births for all mucopolysaccharidosis disorders in the Netherlands. [8] Within this incidence, mucopolysaccharidosis III accounted for 47% of all cases of mucopolysaccharidoses ,with a prevalence of 1.89 cases per 100,000 live births. In this study, mucopolysaccharidosis IIIA had an estimated birth prevalence of 1.16 cases per 100,000 newborns.

In 1999, Meikle and others cited a prevalence of mucopolysaccharidosis IIIA of 1 in 114,000 live births and the prevalence of mucopolysaccharidosis IIIB as 1 in 211,000 live births. [9] Mucopolysaccharidosis IIIC and mucopolysaccharidosis IIID were much rarer, at 1 in 1,407,000 and 1 in 1,056,000 live births, respectively. In 2000, a registry compiled by MPS Australia cited an incidence of 1 case per 66,000 live births for all subtypes of Sanfilippo syndrome. Within this combined statistic, the incidence reported for each subtype of mucopolysaccharidosis III equaled the prevalence cited earlier in 1999, by Meikle.

Mortality/Morbidity

Sanfilippo syndrome is characterized by a worsening clinical progression 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 cardiopulmonary arrest due to airway obstruction and/or pulmonary infection. Type IIIA is the most severe subtype; most patients with type IIIA die during their teenage years.

Race

The mucopolysaccharidoses are pan-racial.

Sex

All subtypes of mucopolysaccharidosis III are inherited in an autosomal recessive Mendelian pattern. The genetic mutations are located in the autosomes and not in the sex chromosomes [10] ; 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 behaviors emerge, with marked hyperactivity and destructive tendencies. Somatic features, such as mild organomegaly, little to no corneal clouding, and orthopedic abnormalities, may be present. Neurologic degeneration usually begins in children aged 6 years or older (sometimes even younger). Death may not occur until after puberty.

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