Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations

Editor—Sanfilippo syndrome or mucopolysaccharidosis type III (MPS III) encompasses a group of four lysosomal storage disorders resulting from a failure to break down the glycosaminoglycan heparan sulphate. Each of the four subtypes, A, B, C, and D, is caused by the deficiency of a different enzyme in the degradative pathway of heparan sulphate: heparan-N-sulphatase (EC 3.10.1.1), α-N-acetylglucosaminidase (EC3.2.1.50), acetyl-CoA N-acetyl transferase (EC 2.3.1.3), and N-acetylglucosamine-6-sulphatase (EC 3.1.6.14), respectively.1 Clinical symptoms usually occur after two years of apparently normal development and include hyperactivity, aggressive behaviour, delayed development (particularly in speech), sleep disturbances, coarse hair, hirsutism, and diarrhoea. There are only relatively mild somatic manifestations. There then follows a period of progressive mental retardation with death usually between the second and third decade of life. In a small number of patients with Sanfilippo syndrome type B, there is a more slowly progressive form of the disease with later onset known as the attenuated phenotype.2-4 A late onset phenotype has also been described for Sanfilippo syndrome type A.5 Sanfilippo syndrome type A (MPS IIIA) is caused by a deficiency in the enzyme heparan-N-sulphatase (sulphamidase). The disease is autosomal recessive and the gene encoding the enzyme is situated on chromosome 17q25.3, contains eight exons, and encodes a protein of 502 amino acids.6 7 To date, 46 different mutations have been identified in Sanfilippo A patients,6 8-13 several of which have been found at high frequencies in particular populations. The R245H, R74C, 1091delC, and S66W were the most frequent mutations in the Dutch (56.7%),11 Polish (56%),8 Spanish (45.5%),13 and Italian (33%)12 populations, respectively. Several polymorphisms have been identified in the sulphamidase gene including R456H, which has a high frequency of 55% in the normal Australian population.9 In this study, mutational analysis has …