Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients
Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients
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DOI：
10.1016/j.ymgme.2012.06.015
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发表时间：
2012-11-01
影响因子：
3.8
通讯作者：
Poorthuis, B. J. H. M.
中科院分区：
文献类型：
--
作者：
Hollak, C. E. M.;de Sonnaville, E. S. V.;Poorthuis, B. J. H. M.
尼曼-皮克病(NPD)是一种由酸性鞘磷脂酶(ASM)缺乏引起的神经内脏溶酶体储存障碍，可分为Niemann-Pick病A型[NPD-A型]，伴进行性神经系统疾病并在儿童早期死亡；或Niemann-Pick病B型[NPD-BETA]，临床表现较为多样。重组鞘磷脂酶的酶替代疗法(ERT)目前被研究为治疗NPD-B患者的潜在方法。这项研究的目的是描述荷兰和比利时ASM缺乏患者的临床特征，重点是NPD-B患者的自然病程。荷兰和比利时部分地区收集了ASM缺乏患者的前瞻性和回顾性数据。对可随访的NPD-B患者每隔6~12个月进行肺功能、6分钟步行试验(6MWT)、影像(QCSI测量骨髓浸润、MRI和CT肺扫描测量器官体积)和生化指标的评估。25例ASM缺乏症患者中男性13例，女性12例，中位年龄13岁，范围159岁。在研究进行时，已有9名患者死亡，包括4名1岁、1岁、2岁、3岁的NPD-A患者和5名5岁、6岁、43岁、56岁和60岁的NPDB患者。在NPD-B患者中，常见的p.Arg608del突变的纯合性和复合杂合性的发生率分别为43%和19%。在NPD-B患者中，大多数患者出现血小板减少，而贫血和白细胞减少较少(分别为33%和6%)。大多数患者的高密度脂蛋白胆固醇都降低了。几名患者的肺部疾病很严重。随访11年，发现血小板计数逐渐减少。对6例NPD-B患者的详细调查显示，4例患者随访6年，病情参数显著稳定，肺功能和6MWT有所下降。骨髓脂肪组分减少，表明存在储存巨噬细胞。肺部受累与内脏肿大、细胞减少或骨髓受累的程度无关。总之，在NPD-B患者中，肺部疾病是最令人衰弱的特征。在消瘦的患者中，疾病表现大多稳定。骨髓浸润是该病的一个不太突出的特征。(C)2012 Elsevier Inc.保留所有权利。
Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-beta], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients.Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers.Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13 years, range 159 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2,3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement.In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease. (C) 2012 Elsevier Inc. All rights reserved.