The Sanfilippo syndromes are a group of autosomal recessive disorders that belong to a family of disorders identified as lysosomal storage diseases, and historically as the mucopolysaccharidoses. 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 Due to the progression of dementia, Sanfilippo patients become quite withdrawn and eventually lose contact with their surrounding environments.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.
Type A disease results from deficiencies is heparan N-sulfatase (also called N-sulfoglucosamine sulfohydrolase). The gene (SGSH) for heparan N-sulfatase resides on chromosome 17q25.3 spanning 11 kb and comprising 12 exons encoding a 502 amino acid precursor protein that is processed to a 482 amino acid glycoprotein that is active as a homodimer. The enzyme is active on heparan sulfates. More than 30 mutations have been idetified 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 at 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 via option in the treatment of Sanfilippo type A.
Type B disease results from deficiencies in the gene encoding α-N-acetylglucosaminidase (symbol: NAGLU). The NAGLU gene is located on chromosome17q21 spanning 8.3 kp and comprising 6 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 amnio acid 643), P521L (leucine for proline at amnio acid 521), and R565W (tryptophan for arginine at amnio acid 565), and nonsense mutations: R297X and R626X (terminations at amino acids 297 and 626, respectively).
Type C disease results from deficiencies in acetyl-CoA:α-glucosaminide acetyltransferase, also called heparan-α-glucosaminide N-acetyltransferase (symbol: HGSNAT). This enzyme has also been called transmembrane protein 76 (TMEM76). The enzyme is active on heparan sulfates. The HGSNAT gene is located on chromosome 8p11.1 comprising 20 exons that encode a 635 amino acid precursor protein. At lease 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 disease results from deficiencies in N-acetylglucosamine 6-sulfatase, also referred to as glucosamine (N-acetyl)-6-sulfatase. This enzyme is encoded by the GNS gene which is located on chromosome 12q14 comprising 14 exons that encode a 552 amino acid precursor protein. The enzyme is active on heparan and keratan sulfates. At least 4 isoforms of the enzyme have been identified that are the result of processing the precursor protein.