Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene. Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between 1 and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alleles for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles. This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype.

HGSNAT, Lysosomal storage disorder, MPS IIIC, Mutation analysis, Sanfilippo syndrome
dx.doi.org/10.1016/j.ymgme.2007.09.011, hdl.handle.net/1765/30175
Molecular Genetics and Metabolism
Erasmus MC: University Medical Center Rotterdam

Ruijter, G.J.G, Valstar, M.J, van de Kamp, J.M, van der Helm, R.M, Durand, S, van Diggelen, O.P, … Wijburg, F.A. (2008). Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Molecular Genetics and Metabolism, 93(2), 104–111. doi:10.1016/j.ymgme.2007.09.011