title: The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome).
abstract: Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is caused by mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene and the resulting defective lysosomal degradation of the glycosaminoglycan heparan sulfate. The onset and progression of the disease are highly variable. Seventy-five mutations distributed over the SGSH gene have been described. We here report on the analysis of the natural course of the disease in 54 MPS IIIA patients through the use of a detailed questionnaire and four-point scoring system and an examination of the underlying mutations. By assessing the degree of developmental regression over time a group of seven patients with a slowly progressive course of the disease were identified. In these seven patients and in 3 other mildly affected patients the missense mutation c.892T>C (p.Ser298Pro) was found on one allele. These patients showed a lower frequency and later onset of the typical symptoms of the disease. The onset of regression in speech abilities and cognitive functions were delayed by 0.7 and 0.8 years, respectively, and the onset of regression of motor functions occurred 6.1 years later than in all other MPS IIIA patients. Severe regression in speech, cognitive and motor functions were delayed by 5, 5.9, and 11.2 years, respectively. These data suggest that in MPS IIIA patients carrying the mutation p.Ser298Pro a slowly progressive phenotype can be predicted and this may have an important impact on parental counselling and therapeutic interventions.
authors.affiliation: Metabolic Center, Dept. of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ann
authors.initials: A
authors.lastname: Meyer
authors.forename: Kai
authors.initials: K
authors.lastname: Kossow
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Cordula
authors.initials: C
authors.lastname: Steglich
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Nicole
authors.initials: N
authors.lastname: Muschol
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009084:Mucopolysaccharidosis III / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D011392:Proline / Q000235:genetics*; D012694:Serine / Q000235:genetics*
chemical_list: D012694:Serine; D011392:Proline; D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase