Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands

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Abstract

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.

Introduction

Mucopolysaccharidosis III (Sanfilippo syndrome) comprises four related inborn errors of lysosomal degradation of the glycosaminoglycan heparan sulphate: MPS III types A, B, C and D. All types of MPS III are characterized by progressive mental deterioration and behavioral problems with only mild facial dysmorphisms and mild somatic disease [1]. MPS IIIC (Sanfilippo type C; MIM 252930) is caused by a deficiency of the membrane bound lysosomal enzyme acetyl-CoA:α-glucosamine N-acetyltransferase (HGSNAT; E.C. 2.3.1.3). HGSNAT catalyzes acetylation of the terminal glucosamine residues of heparan sulphate prior to its hydrolysis by α-N-acetyl glucosaminidase [2].

The initial diagnosis of all types of MPS III is based on increased concentration of heparan sulphate in the urine. Enzymatic assays in leukocytes and/or fibroblasts confirm the diagnosis and allow for discrimination between the different subtypes of the disease.

Clinically, there appear to be no significant differences between the four types of MPS III, although it has been suggested that MPS IIIA has a more severe course [3]. In general, patients have a normal development during the first year of life, after which a progressive mental deterioration leading to severe dementia becomes apparent. Behavioral problems, consisting of hyperactivity and aggressive behavior, in combination with sleeplessness, occur within the first decade. Motor problems develop generally in the second decade. It is assumed that death, often due to respiratory complications, usually supervenes before the 20th birthday, although survival into the third decade has been reported [3], [4], [5].

The birth prevalence of MPS III in the Netherlands has been estimated to be 1.89 per 100,000 live births [6]. While types A and B are the most frequent, type C comprises only 11% of MPS III with a birth prevalence of 0.21 per 100,000 live births [6]. In Australia and Portugal lower birth prevalences of 0.07 and 0.12, respectively, have been reported [7], [8]. So far, clinical information has been reported in only 30 patients [3], [9], [10], [11], [12], [13], [14], [15], [16], [17]. All these studies reported isolated case histories or small cohorts.

Recently, we and others have identified the gene encoding HGSNAT and reported molecular defects in several MPS IIIC patients [18], [19]. The HGSNAT protein is 635 amino acids in length with a predicted molecular mass of 68 kDa and containing 11 transmembrane domains [19]. Thirty-seven different mutations in 39 probands diagnosed with MPS IIIC were reported [18], [19], [20].

In this study, we report on a large cohort of 29 patients with MPS IIIC. In addition to extensive clinical description of the patients, we report on the biochemical and molecular analysis. Our study shows that the rate of deterioration of verbal and motor functions of MPS IIIC patients is slower than previously reported. Two mutations were particularly frequent in The Netherlands, suggesting a founder effect.

Section snippets

Recruitment of patients

Patients with MPS IIIC in the Netherlands were identified by studying the combined registry of the four centers in the Netherlands, located in Amsterdam, Rotterdam, Nijmegen and Groningen, where the diagnosis of MPS III is made by enzymatic studies [6]. Parents or legal representatives of patients were asked to participate in this study via physicians who had requested the initial diagnostic studies. The study was approved by the Medical Ethical Committee of the AMC, Amsterdam, and written

Patients

In the registry of the Dutch diagnostic centres, 29 patients from 21 families in whom the diagnosis MPS IIIC was previously established on the basis of both increased urinary excretion of heparan sulphate as well as a deficient HGSNAT activity in leukocytes or cultured skin fibroblasts, were registered (Table 1). Fourteen of these patients have been previously reported in the literature [3], [11].

From all 29 patients material was available for mutation analysis.

Twelve patients were deceased at

Discussion

We report the clinical, biochemical and genetic characteristics in the single largest cohort of patients with MPS IIIC. In agreement with previously published data, our results demonstrate that the clinical course is highly variable in patients with MPS IIIC. Apart from recurrent ENT infections in all patients and sleeping disturbances in some patients, most patients appear unaffected during their first year of life. Intellectual regression accompanied with a loss of speech performance precedes

Acknowledgements

We thank the patients and their families for participating in this study. We also thank P.J. Auener (Hendrik van Boeijen-Oord, Assen), J.J.T.M. van Beurden (De Lathmer, Wilp), JJP vd Kamp, M.S. van der Knaap (Department of Pediatrics and Child Neurology, VU University Medical Center, Amsterdam), T. de Koning (Department of Paediatrics, University Medical Centre Utrecht, Utrecht), W. Kleinveld (De Heygraeff, Woudenberg), J. Kleijer (Maartenswouden, Drachten), A.C. Louisse (Hooge Burch,

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