Meijer O L M, Welling L, Valstar M J, Hoefsloot L H, Brüggenwirth H T, van der Ploeg A T, Ruijter G J G, Wagemans T, Wijburg F A, van Vlies N
Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
J Inherit Metab Dis. 2016 May;39(3):437-445. doi: 10.1007/s10545-016-9916-2. Epub 2016 Feb 23.
Mucopolysaccharidosis 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.
To 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.
A 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.
NAGLU 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.
ⅢB型黏多糖贮积症（MPS IIIB）是一种罕见的遗传性疾病，溶酶体酶N - 乙酰 - α - 氨基葡萄糖苷酶（NAGLU）缺乏导致硫酸乙酰肝素（HS）蓄积，进而引起进行性神经认知功能衰退。MPS IIIB患者的疾病严重程度差异很大。由于存在大量的等位基因异质性，建立基因型 - 表型相关性很困难。然而，需要可靠地预测疾病的自然病程，特别是用于评估潜在治疗方法的疗效。
为了确定与疾病严重程度相关的标志物，根据临床数据，将所有被诊断为MPS IIIB的荷兰患者分为快速进展型（RP；典型、严重表型）或缓慢进展型（SP；非典型、较轻表型）。在不同温度下培养患者的成纤维细胞后，测量NAGLU活性和HS水平。
在37℃培养后，RP和SP患者的NAGLU活性存在微小但显著的差异（p < 0.01）。在30℃培养时，SP患者的NAGLU活性水平更显著升高（p < 0.001），计算得出NAGLU活性为0.58 nmol·mg-1·hr-1是区分两组的最佳临界值（敏感性和特异性均为100%）。患者成纤维细胞在30℃时增加NAGLU活性的能力较低可显著预测多种疾病特异性功能的丧失。
在30℃培养的成纤维细胞中的NAGLU活性可用于区分RP和SP型MPS IIIB患者，细胞在较低温度下增加NAGLU活性的能力与疾病症状相关。
