eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Mucopolysaccharidosis Type III
Updated: May 14, 2009
Introduction
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 mucopolysaccharidoses comprise a group of 7 metabolic disorders, known as mucopolysaccharidosis types I-VII (mucopolysaccharidosis V is now considered 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 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 (mucopolysaccharidosis IH), Hunter syndrome (mucopolysaccharidosis II), and Sanfilippo syndrome (mucopolysaccharidosis III). Although lysosomal storage diseases are rare individually, the estimated incidence of all types of mucopolysaccharidosis disorders combined is 1 in 20,000 live births.
Mucopolysaccharidosis III, or Sanfilippo syndrome, was described in 1963 by a US-trained pediatrician named Sylvester Sanfilippo. Considered to be the most common of mucopolysaccharidosis 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).1 The other mucopolysaccharidosis 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.2
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 (NAG).3 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.4 In 1999, Poorthuis et al reported an incidence of 4.5 cases per 100,000 live births for all mucopolysaccharidosis disorders in the Netherlands.5 Mucopolysaccharidosis III accounted for 47% of all cases of mucopolysaccharidosis diagnosed and had a birth 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.
In 1999, Meikle et al cited a prevalence of mucopolysaccharidosis IIIA of 1 in 114,000 live births; the prevalence of mucopolysaccharidosis IIIB is 1 in 211,000 live births.6 Mucopolysaccharidosis IIIC and mucopolysaccharidosis IIID were much rarer, at 1 in 1,407,000 and 1 in 1,056,000 live births, respectively. 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, the incidence reported for each form of mucopolysaccharidosis III equaled the prevalence cited by Meikle et al in 1999.
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 cardiopulmonary arrest due to airway obstruction and/or pulmonary infection. Type IIIA is the most severe form; most patients with this form die during their teenage years.
Race
The mucopolysaccharidoses are panracial.
Sex
All forms of mucopolysaccharidosis III are inherited in an autosomal recessive Mendelian pattern. The gene mutations are located in the autosomes and not in the sex chromosomes;7 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.
Clinical
History
Patients with Sanfilippo syndrome are born without symptoms and typically have normal development for the first 2 years of life. In all types of this syndrome, CNS disease predominates, with less skeletal and soft tissue involvement compared with the other mucopolysaccharidoses (MPSs). Type IIIA has the most CNS involvement. This type represents the most severe form of Sanfilippo syndrome and has an earlier and more rapid onset of symptoms than the other types.
- Onset of symptoms usually occurs at age 2-6 years in a previously healthy-appearing child. Some patients may show developmentally delays in infancy. Growth parameters are normal or accelerated prior to this age. Subsequently, growth slows at about age 3 years.
- Initial clinical signs present as a change in behavior. Patients are hyperactive and display aggressive and destructive behaviors.
- Sleep disturbances are very common.
- Mental development slows after the toddler years; then, progressive deterioration occurs in regard to gait and articulation of speech. Some patients may never speak.
- Seizures may occur but are usually well-controlled with medication.
- During the early school years, the symptoms worsen and patients show shortened attention spans and difficulties with concentration. Mental and physical disabilities prevent most children from progressing in school academics.
- By age 10 years, patients are severely limited in their activities and movement. Most children with type IIIA have severe neurological impairment by age 6 years.
- More aggressive behaviors have been reported in female patients.
- Recurrent or chronic diarrhea occurs in these patients. The etiology for this abnormal gut motility is thought to be due to lysosomal glycosaminoglycans (GAG) storage in the neurons of the myenteric plexus.
- Respiratory compromise can occur and is related to airway obstruction due to anatomical changes, excessive thick secretions and neurologic impairment. Upper respiratory tract infections and sinopulmonary disease are common.
Physical
The striking clinical features of coarse facial features and skeletal abnormalities seen in the other mucopolysaccharidosis disorders are not as apparent in those with Sanfilippo syndrome. Mild facial coarsening may be present, and the skeletal features are usually subtle. Corneal clouding, as is seen in the other mucopolysaccharidosis disorders, is not usually present. A salient clinical feature is an abundance of coarse facial and body hair.
- Head, ears, eyes, nose, and throat (HEENT)
- Mild coarse facial features
- Synophrys
- Clear corneas (Some patients may have mild corneal opacities.)
- GI: Mild hepatomegaly and splenomegaly
- Genitourinary: Inguinal hernia, umbilical hernia, or both
- Skeletal
- Dense calvaria
- Mild dysostosis multiplex (constellation of characteristic skeletal abnormalities seen in mucopolysaccharidosis disorders)
- Joint stiffness
- Neurological
- Severe progressive neurologic degeneration
- Hearing loss and speech delay in severely affected individuals
Causes
The deficiency or lack of a different particular lysosomal enzyme is responsible for each of the forms of Sanfilippo syndrome. Specifically, for type IIIA, the enzyme is heparan sulfate sulfatase; for type IIIB, the enzyme is N -acetyl-alpha-D-glucosaminidase; for type IIIC, the enzyme is acetyl-CoA:alpha-glucosaminide acetyltransferase; and for type IIID, the enzyme is N -acetylglucosamine-6-sulfatase.
- Heparan sulfate accumulates in the lysosomes of tissues and organs and leads to the diverse morphological abnormalities. Large amounts of heparan sulfate are excreted in the urine.
- The genetic etiology is as follows:
- The enzymatic defects seen in all forms of Sanfilippo syndrome are inherited as autosomal recessive disorders; this is also true of the other mucopolysaccharidosis disorders, except for mucopolysaccharidosis II (ie, Hunter syndrome), which has X-linked recessive inheritance. Because of the autosomal recessive inheritance pattern, biological parents of an affected child have a 25% risk of having another affected child with each pregnancy.
- The gene mutations for the 4 different types have been mapped on the human genome. Their chromosomal locations are as follows:
- Type IIIA - 17q25.3
- Type IIIB - 17q21
- Type IIIC - 8p11.1
- Type IIID - 12q14
More on Mucopolysaccharidosis Type III |
 Overview: Mucopolysaccharidosis Type III |
| Differential Diagnoses & Workup: Mucopolysaccharidosis Type III |
| Treatment & Medication: Mucopolysaccharidosis Type III |
| Follow-up: Mucopolysaccharidosis Type III |
| Multimedia: Mucopolysaccharidosis Type III |
| References |
| Further Reading |
| Next Page » |
References
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Kleijer WJ, Karpova EA, Geilen GC, et al. Prenatal diagnosis of Sanfilippo A syndrome: experience in 35 pregnancies at risk and the use of a new fluorogenic substrate for the heparin sulphamidase assay. Prenat Diagn. Sep 1996;16(9):829-35. [Medline].
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Kakkis E, Wraith E. Clinical features and diagnosis of the mucopolysaccharidoses. UpToDate. Available at http://www.utdol.com. Accessed November 6, 2007.
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Mucopolysaccharidosis Type III. National Organization for Rare Disorders, Inc. Available at http://www.rarediseases.org. Accessed 03/31/2009.
National Center for Biotechnology Information. Mucopolysaccharidosis Type IIIA, IIIB, IIIC, and IIID. Online Mendelian Inheritance in Man. Available at http://www.ncbi.nlm.nih.gov. Accessed April 1, 2009.
National Institutes of Health. Mucopolysaccharidosis Type III (Sanfilippo Syndrome). GeneTests. Available at http://www.geneclinics.org. Accessed 03/31/2009.
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Further Reading
The American Academy of Pediatrics have established the following relevant clinical guidelines: Hearing assessment in infants and children: recommendations beyond neonatal screening.
Keywords
mucopolysaccharidosis, MPS, MPS III, mucopolysaccharide storage disease type III, Sanfilippo syndrome, Sanfilippo disease, MPS IIIA, Sanfilippo A, MPS IIIB, Sanfilippo B, MPS IIIC, Sanfilippo C, MPS IIID, Sanfilippo D, lysosomal storage disorders, heparan sulfate, clear corneas, dysostosis multiplex, mucopolysaccharides, glycosaminoglycans, GAGs, lysosomal storage disorder, cardiovascular functional impairments, hepatosplenomegaly, dysostosis multiplex, mental retardation, Hurler syndrome, Hunter syndrome, Sanfilippo syndrome, organomegaly, diarrhea, respiratory compromise, airway obstruction, upper respiratory tract infections, synophrys, clear corneas, splenomegaly, inguinal hernia, umbilical hernia, enzyme replacement therapy, ERT, treatment, diagnosis
