Sanfilippo type B syndrome: five patients with an R565P homozygous mutation in the α-N-acetylglucosaminidase gene from the Okinawa islands in Japan

Chinen, Yoshiaki; Tohma, Takaya; Izumikawa, Yoshinori; Uehara, Hiroyuki; Ohta, Takao

doi:10.1007/s10038-005-0258-4

Cited by 15 publications

(10 citation statements)

References 13 publications

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“…The levels of ΔDiHS-0S and ΔDiHS-NS in untreated patients with MPS IIIA or MPS IIIB were significantly raised compared with those in normal controls, as described previously using LC-MS/MS [7, 15]. The frequency of MPS IIIB is higher in a regional district in Japan, based upon the founder effect [37]. It is noteworthy that one Japanese MPS IIIB patient who received successful HSCT when under two years of age had ΔDiHS-0S and ΔDiHS-NS levels in the normal range.…”

Section: Discussionmentioning

confidence: 66%

Novel heparan sulfate assay by using automated high-throughput mass spectrometry: Application to monitoring and screening for mucopolysaccharidoses

Shimada

Kelly

LaMarr

et al. 2014

Molecular Genetics and Metabolism

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Mucopolysaccharidoses (MPS) are caused by deficiency of one of a group of specific lysosomal enzymes, resulting in excessive accumulation of glycosaminoglycans (GAGs). We previously developed GAG assay methods using liquid chromatography tandem mass spectrometry (LC-MS/MS); however, it takes 4–5 min per sample for analysis. For the large numbers of samples in a screening program, a more rapid process is desirable. The automated high-throughput mass spectrometry (HT-MS/MS) system (RapidFire) integrates a solid phase extraction robot to concentrate and desalt samples prior to direction into the MS/MS without chromatographic separation; thereby allowing each sample to be processed within ten seconds (enabling screening of more than one million samples per year). The aim of this study was to develop a higher throughput system to assay heparan sulfate (HS) using HT-MS/MS, and to compare its reproducibility, sensitivity and specificity with conventional LC-MS/MS. HS levels were measured in blood (plasma and serum) from control subjects and patients with MPS II, III, or IV and in dried blood spots (DBS) from newborn controls and patients with MPS I, II, or III. Results obtained from HT-MS/MS showed 1) that there was a strong correlation of levels of disaccharides derived from HS in blood, between those calculated using conventional LC-MS/MS and HT-MS/MS, 2) that levels of HS in blood were significantly elevated in patients with MPS II and III, but not in MPS IVA, 3) that the level of HS in patients with a severe form of MPS II was higher than that in an attenuated form, 4) that reduction of blood HS level was observed in MPS II patients treated with enzyme replacement therapy or hematopoietic stem cell transplantation, and 5) that levels of HS in newborn DBS were elevated in patients with MPS I, II or III, compared to control newborns. In conclusion, HT-MS/MS provides much higher throughput than LC-MS/MS-based methods with similar sensitivity and specificity in an HS assay, indicating that HT-MS/MS may be feasible for diagnosis, monitoring, and newborn screening of MPS.

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Section: Discussionmentioning

confidence: 66%

Novel heparan sulfate assay by using automated high-throughput mass spectrometry: Application to monitoring and screening for mucopolysaccharidoses

Shimada

Kelly

LaMarr

et al. 2014

Molecular Genetics and Metabolism

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“…The gene encoding for NAGLU is localized on chromosome 17q21.1 (Zhao et al 1996) and over 100 mutations in the NAGLU gene (HGNC: 7632) have been identified (van de Kamp et al 1976; Beesley et al 1998, 2004, 2005; Schmidtchen et al 1998; Zhao et al 1998; Bunge et al 1999; Weber et al 1999; Esposito et al 2000; Tessitore et al 2000; Emre et al 2002; Chinen et al 2005; Champion et al 2010; Valstar et al 2010a; Ouesleti et al 2011; Selmer et al 2012; Tang et al 2013). Due to this large allelic heterogeneity, establishing a genotype-phenotype correlation is difficult.…”

Section: Introductionmentioning

confidence: 99%

Residual N‐acetyl‐α‐glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB

Meijer

Welling

Valstar

et al. 2016

J of Inher Metab Disea

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BackgroundMucopolysaccharidosis type IIIB (MPS IIIB) is a rare genetic disorder in which the deficiency of the lysosomal enzyme N-acetyl-α-glucosaminidase (NAGLU) results in the accumulation of heparan sulfate (HS), leading to progressive neurocognitive deterioration. In MPS IIIB a wide spectrum of disease severity is seen. Due to a large allelic heterogeneity, establishing genotype-phenotype correlations is difficult. However, reliable prediction of the natural course of the disease is needed, in particular for the assessment of the efficacy of potential therapies.MethodsTo identify markers that correlate with disease severity, all Dutch patients diagnosed with MPS IIIB were characterised as either rapid (RP; classical, severe phenotype) or slow progressors (SP; non-classical, less severe phenotype), based on clinical data. NAGLU activity and HS levels were measured in patients’ fibroblasts after culturing at different temperatures.ResultsA small, though significant difference in NAGLU activity was measured between RP and SP patients after culturing at 37 °C (p < 0.01). Culturing at 30 °C resulted in more pronounced and significantly higher NAGLU activity levels in SP patients (p < 0.001) with a NAGLU activity of 0.58 nmol.mg-1.hr-1 calculated to be the optimal cut-off value to distinguish between the groups (sensitivity and specificity 100 %). A lower capacity of patients’ fibroblasts to increase NAGLU activity at 30 °C could significantly predict for the loss of several disease specific functions.ConclusionNAGLU activity in fibroblasts cultured at 30 °C can be used to discriminate between RP and SP MPS IIIB patients and the capacity of cells to increase NAGLU activity at lower temperatures correlates with disease symptoms.

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“…The NAGLU cDNA encodes a 720 amino acid protein that has six potential N-glycosylation sites (Weber et al 1996). Thus far, over 100 different mutations in the NAGLU gene leading to MPS IIIB have been reported (Beesley et al 1998, 2004, 2005; Bunge et al 1999; Champion et al 2010; Chinen et al 2005; Coll et al 2001; Emre et al 2002; Esposito et al 2000; Lee-Chen et al 2002; Moog et al 2007; Schmidtchen et al 1998; Tessitore et al 2000; Weber et al 1999; Yogalingam and Hopwood 2001; Zhao et al 1996, 1998). Most mutations are missense, but nonsense mutations, deletions, insertions, and splice-site mutations have also been reported.…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

Valstar

Brüggenwirth

Olmer

et al. 2010

J of Inher Metab Disea

110

108

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Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetyl-α-D-glucosaminidase (NAGLU). Information on the natural course of MPS IIIB is scarce but much needed in view of emerging therapies. To improve knowledge on the natural course, data on all 52 MPS IIIB patients ever identified by enzymatic studies in the Netherlands were gathered. Clinical data on 44 patients could be retrieved. Only a small number (n = 9; 21%) presented with a classical MPS III phenotype; all other patients showed a much more attenuated course of the disease characterized by a significantly slower regression of intellectual and motor abilities. The majority of patients lived well into adulthood. First signs of the disease, usually mild developmental delay, were observed at a median age of 4 years. Subsequently, patients showed a slowing and eventually a stagnation of development. Patients with the attenuated phenotype had a stable intellectual disability for many years. Molecular analysis was performed in 24 index patients. The missense changes p.R643C, p.S612G, p.E634K, and p.L497V were exclusively found in patients with the attenuated phenotype. MPS IIIB comprises a remarkably wide spectrum of disease severity, and an unselected cohort including all Dutch patients showed a large proportion (79%) with an attenuated phenotype. MPS IIIB must be considered in patients with a developmental delay, even in the absence of a progressive decline in intellectual abilities. A key feature, necessitating metabolic studies, is the coexistence of behavioral problems.

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Sanfilippo type B syndrome: five patients with an R565P homozygous mutation in the α-N-acetylglucosaminidase gene from the Okinawa islands in Japan

Cited by 15 publications

References 13 publications

Novel heparan sulfate assay by using automated high-throughput mass spectrometry: Application to monitoring and screening for mucopolysaccharidoses

Novel heparan sulfate assay by using automated high-throughput mass spectrometry: Application to monitoring and screening for mucopolysaccharidoses

Residual N‐acetyl‐α‐glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB

Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

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