The frequency of common mutations among patients with mucopolysaccharidosis types I, II and IIIA diagnosed in Austria over the last 17 years

To the Editor: The mucopolysaccharidoses (MPS) are a clinically heterogeneous group of 11 disorders caused by the deficiency of lysosomal enzymes involved in mucopolysaccharide catabolism; with the exception of MPS II, which is X-linked, the diseases are all autosomal-recessive (1). Their phenotypes include growth retardation, dysostosis, enlargement of visceral organs, progredient psychomental retardation and reduced life span. In populations originating from northern European and Anglo-American countries, three enzyme defects comprise the majority of cases (2, 3), namely -L-iduronidase (IDUA; EC 3.2.1.76) causing MPS type I (McKusick 252800), iduronate-2-sulphatase (IDS; EC 3.1.6.13) causing MPS type II (McKusick 309900) and heparan N-sulphatase (NS; EC 3.10.1.1), causing MPS type IIIA (McKusick 252900). Several mutations have been shown to be common among European cases (4–6) and genotyping has become essential for genetic counselling and the prognosis of therapeutic risks (7). Therefore, we started to define the genotype of all cases diagnosed enzymatically in Austria between the year 1983 and 2000. We initially tested 66 cases, ethnically originating from Austria, Hungary, Slovenia, Turkey and Germany, previously diagnosed in our laboratory by enzyme analysis of skin fibroblasts for mutations shown to be common in MPS I, II and IIIA. Similar to other European countries, the majority of cases were MPS I (23), MPS II (21) and MPS IIIA (22). With the exception of two MPS I patients of an intermediate and mild phenotype, respectively, all other cases expressed the typical severe phenotypes. The following common mutations were assayed by digestion of polymerase chain reaction (PCR)derived amplicons with various restriction endonucleases: MPS I: Q70X, W402X, A327P, R89Q, IVS5-7G A, P533R; MPS II: R88H, H229R, R443X, P467L, R468Q, R468W; MPS IIIA: R74C, R245H, N389K, T360nt-1, Y40N, A44T, S66W, IVS2-2A G, P128L, R150Q, R182C, P227R, S298P, T321A, R377H, 1307del9, 1284del11, respectively. In MPS I, three of six mutations tested were found to be present on 20 of 46 alleles (43.5%), namely Q70X (30.4%), W402X (11%) and A327P (2.2%), respectively. Seven of 23 genotypes (30,4%) could be defined completely with these methods, while five genotypes showed to be heteroallelic with a so far unknown mutation. Mutations of high incidence in southern Europe (P533R) or in mild phenotypes (R89Q; IVS5-7G A) were not detected. This is similar to the findings of Scott et al. (4); although Q70X was found more frequently than W402X. In MPS II, only one (R88H) of 15 X-chromosomal alleles could be identified by restriction analysis for known mutations, which is in accordance with previous findings of genetic heterogeneity in MPS II (8–10). In the case of MPS IIIA, 20 out of 44 alleles (45.5%) accounted for a common mutation, R74C, R245H and S66W corresponding to 18.2%, 11.4% and 15.9%, respectively. The genotype was fully defined in 9 patients for MPS IIIA (41%). On four alleles (9%) from three families, the mutation N389K was found. The mutation S66W, described as common in Sardinian patients (11), was found in 15.9% of our cases, all of Austrian origin. Taken together, the frequency of common mutations in MPS I and IIIA among patients diagnosed in Austria was found to be slightly below the average distribution found in other European countries with a reversed ratio of the frequency of the main common mutations Q70X and W402X in MPS I. Moreover, S66W, a mutation common in