Sanfilippo Syndrome · What It Is, Signs, Symptoms, Diagnosis, and More

Sanfilippo syndrome is a rare genetic disorder of metabolism characterized by low levels of the enzymes that break down heparan sulfate, a glycosaminoglycan (i.e., chains of sugar molecules called mucopolysaccharides), thereby resulting in the build-up of this molecule in various organs and tissues of the body, including the brain. Sanfilippo syndrome belongs to a family of genetic disorders called lysosomal storage disorders. More specifically, lysosomal storage disorders are divided into sphingolipidoses such as Tay-Sachs and Niemann-Pick disease and mucopolysaccharidosis (MPS), which include Hurler and Hunter syndrome. Sanfilippo syndrome is a type of MPS, known as MPS III or MPS type three. 

Sanfilippo syndrome is a genetic disorder with an autosomal recessive inheritance pattern, with the mutated gene encoding for an enzyme involved in the breakdown of glycosaminoglycans. With an autosomal recessive inheritance pattern, both parents must be carriers of the mutated gene for a child to inherit and develop the disorder. A couple who are both carriers of the disease has a 25% chance of having an affected child. 

There are four main types of Sanfilippo syndrome. MPS IIIA is the most common and severe form and is caused by a defect in the SGSH gene encoding for the enzyme heparan N-sulfatase. In MPS IIIB, there is a defect in the NAGLU gene encoding for alpha-N-acetylglucosaminidase. MPS IIIC is caused by a defect in the HGSNAT gene that encodes for alpha-Glucosaminide N-acetyltransferase. Finally, in MPS IIID, the defective gene is GNS which codes for N-acetylglucosamine 6-sulfatase.  

Signs and symptoms of Sanfilippo syndrome typically appear after the first year of life, usually between the ages of two and six. As the disease progresses, glycosaminoglycans build-up in the various body parts, causing damage to multiple organ systems, primarily the brain. The clinical presentation can vary, including childhood dementia with developmental delay, autism, speech problems, and intellectual regression. Behavioral problems are also common, including hyperactivity and irritability. Affected individuals also develop movement disorders, including a wobbly and erratic gait. Children with Sanfilippo syndrome also typically have short stature and coarse facial features with full lips and heavy eyebrows that meet above the nose, or hirsutism, which is excess hair growth. They might also present with multiple skeletal or joint abnormalities. Other signs and symptoms include recurrent sinus or respiratory infections and gastrointestinal disturbances, such as chronic diarrhea, hernias, and an enlarged liver and spleen. A child with Sanfilippo syndrome can also present with sleep disturbances, joint problems, vision impairment, and hearing loss. The average life expectancy is around 15 to 20 years of age. 

Sanfilippo syndrome is typically suspected based on a thorough medical and family history and physical examination. A urine test is usually performed and shows increased levels of heparan sulfate. Other tests can also be performed to confirm a diagnosis, including measuring enzyme activity in the blood or skin. This can help identify the individual’s specific Sanfilippo syndrome subtype (e.g., A, B, C, or D). Genetic testing can also be used to determine the presence of a particular mutation. Other exams can also be performed to diagnose organ systems affected by the disorder, including a slit lamp eye examination or imaging tests, including an X-ray of the bones to assess for joint abnormalities. 

There is currently no cure for Sanfilippo syndrome, so treatment focuses on managing symptoms and can involve a multidisciplinary team of specialists. Couples with offspring affected by Sanfilippo syndrome may also seek genetic counseling to discuss the implications of the disease in future pregnancies. Finally, ongoing research aims to develop gene therapy and enzyme replacement therapy.

Sanfilippo syndrome, also called mucopolysaccharidosis type III, is a lysosomal storage disease inherited in an autosomal recessive pattern. It is characterized by a deficiency of enzymes involved in the breakdown of the glycosaminoglycan heparan sulfate, thereby leading to its build-up in various tissues. Depending on the specific enzyme affected, there are four Sanfilippo syndrome types: A, B, C, and D. The average life expectancy is 15-20 years of age. Diagnosis starts with physical findings and the patient's medical and family history and can be confirmed with urine tests, measurement of enzyme activity, and genetic testing. Currently, there is no cure for Sanfilippo syndrome, and treatment is typically supportive, focusing on improving the quality of life.