Last Updated: September 15, 2022
Introduction to the Sanfilippo Syndromes
The Sanfilippo syndromes (mucopolysaccharidosis III; MPS III) are a group of autosomal recessive disorders that belong to a subfamily of lysosomal storage diseases that were historically referred to as the mucopolysaccharidoses (MPS). Four distinct subtypes of Sanfillipo syndrome have been described. All of these disorders are characterized by the lysosomal accumulation and excretion of un-degraded glycosaminoglycans as a consequence of deficiencies in lysosomal hydrolases.
Although the biochemical basis for each of the four types of Sanfilippo syndrome are distinct, the clinical presentations of each are quite similar. Of significance is that each of the Sanfilippo disorders is unique in that they represent MPS disorders with limited somatic disease but with severe central nervous system involvement.
Clinical symptoms usually first appear between the ages of 2 and 6 years in children who previously appeared normal. The typical manifestations begin with aggressive behavior, sleep disorders, hyperactivity, and delayed development. Severe neurological deterioration begins by age 6 in most patients. Due to the progression of dementia, Sanfilippo patients become quite withdrawn and eventually lose contact with their surrounding environments. Sanfilippo type A is the most severe form of the disease exhibiting the earliest onset, most rapid progression of symptoms, and shorter survival.
Molecular Biology of the Sanfillipo Syndrome
Type A
Sanfillipo type A disease results from deficiencies is N-sulfoglucosamine sulfohydrolase (also known as heparan N-sulfatase or heparan sulfamidase). Functional N-sulfoglucosamine sulfohydrolase exists as a homodimer. The enzyme is active on heparan sulfates.
The gene (SGSH) encoding N-sulfoglucosamine sulfohydrolase is located on chromosome 17q25.3 spanning 11 kb and is composed of 14 exons that generate three alternatively spliced mRNAs. Only one mRNA has been validated as coding for a functional enzyme. This mRNA encodes a 502 amino acid precursor protein that is processed to a 482 amino acid glycoprotein.
More than 100 mutations have been identified in the SGSH gene resulting in Sanfilippo type A disease. Most of the mutations are missense mutations with three prominent mutations being amino acid substitutions at positions 245 (histidine for arginine, R245H), 74 (cysteine for arginine, R74C), and 66 (tryptophan for serine, S66W). Another mutation with high incidence is a 1 base deletion of cytidine at nucleotide 1091 (1091delC). Studies have shown that recombinant protein is endocytosed by cells in culture demonstrating that enzyme replacement therapy may be a viable option in the treatment of Sanfilippo type A.
Type B
Sanfillipo type B disease results from mutations in the gene (NAGLU) encoding N-acetyl-α-glucosaminidase. The NAGLU gene is located on chromosome17q21.2 spanning 8.3 kb and and is composed of 7 exons that encode a 743 amino acid precursor protein that is processed to a 720 amino acid glycoprotein.
More than 80 mutations have been identified in the NAGLU gene resulting in Sanfilippo type B disease. These mutations encompass missense, nonsense, insertion, and deletion mutations with at least 1 splice site mutation characterized. Nearly 70% of all type B mutations are missense or nonsense mutations.
The vast majority of NAGLU mutations found in Sanfilippo type B patients are unique to a single individual. Only 5 mutations causing type B disease have been identified in more than one patient. These include both missense mutations: R643C (cysteine for arginine at amino acid 643), P521L (leucine for proline at amino acid 521), and R565W (tryptophan for arginine at amino acid 565), and nonsense mutations: R297X and R626X (terminations at amino acids 297 and 626, respectively).
Type C
Sanfillipo type C disease results from deficiencies in acetyl-CoA:α-glucosaminide acetyltransferase, also called heparan-α-glucosaminide N-acetyltransferase. This enzyme has also been called transmembrane protein 76 (TMEM76). The enzyme is active on heparan sulfates.
Acetyl-CoA:α-glucosaminide acetyltransferase is encoded by the HGSNAT gene. The HGSNAT gene is located on chromosome 8p11.21–p11.1 and is composed of 20 exons that generate four alternatively spliced mRNAs, each of which encode a distinct protein isoform. The originally characterized mRNA encodes a 635 amino acid precursor protein.
At least 30 different mutations have been identified in the HGSNAT gene resulting in Sanfilippo type C disease. These mutations include missense, nonsense, frameshift, and splice site mutations.
Type D
Sanfillipo type D disease results from deficiencies in N-acetylglucosamine 6-sulfatase, also referred to as glucosamine (N-acetyl)-6-sulfatase. The enzyme is active on heparan and keratan sulfates.
N-acetylglucosamine 6-sulfatase is encoded by the GNS gene. The GNS gene is located on chromosome 12q14.3 and is composed of 14 exons that encode a 552 amino acid precursor protein. At least four isoforms of the enzyme have been identified that are the result of processing of the precursor protein.