Dr von Haunersches Kinderspital, University of Munich, Munich, Germany.
Clin Genet. 2010 Feb;77(2):119-30. doi: 10.1111/j.1399-0004.2009.01325.x. Epub 2009 Dec 10.
Niemann-Pick diseases are hereditary neurovisceral lysosomal lipid storage disorders, of which the rare type C2 almost uniformly presents with respiratory distress in early infancy. In the patient presented here, the NPC2 exon 4 frameshift mutation c.408_409delAA caused reduced NPC2 protein levels in serum and lung lavage fluid and the synthesis of an aberrant, larger sized protein of around 28 kDa. Protein expression was strongly reduced also in alveolar macrophages. The infant developed failure to thrive and tachypnea. Lung lavage, computer tomography, and histology showed typical signs of pulmonary alveolar proteinosis with an abnormal intraalveolar accumulation of surfactant as well as macrophages. An NPC2-hypomorph animal model also showed pulmonary alveolar proteinosis and accumulation of macrophages in the lung, liver, and spleen long before the mice died. Due to the elevation of cholesterol, the surfactant had an abnormal composition and function. Despite the removal of large amounts of surfactant from the lungs by therapeutic lung lavages, this treatment was only temporarily successful and the infant died of respiratory failure. Our data indicate that respiratory distress in NPC2 disease is associated with a loss of normal NPC2 protein expression in alveolar macrophages and the accumulation of functionally inactive surfactant rich in cholesterol.
尼曼-匹克病是遗传性神经内脏溶酶体脂质贮积症，其中罕见的 C2 型几乎普遍在婴儿早期出现呼吸窘迫。在本病例中，NPC2 外显子 4 框移突变 c.408_409delAA 导致血清和肺灌洗液中 NPC2 蛋白水平降低，以及合成异常的、约 28 kDa 大小的较大蛋白。肺泡巨噬细胞中的蛋白表达也明显减少。患儿出现生长不良和呼吸急促。肺灌洗、计算机断层扫描和组织学显示出典型的肺泡蛋白沉积症的征象，肺泡内有异常的表面活性剂和巨噬细胞积聚。NPC2 低功能动物模型也显示出肺肺泡蛋白沉积症和肺、肝和脾中的巨噬细胞积聚，远在小鼠死亡之前就已经出现。由于胆固醇升高，表面活性剂的组成和功能异常。尽管通过治疗性肺灌洗从肺部清除了大量的表面活性剂，但这种治疗只是暂时成功的，患儿最终死于呼吸衰竭。我们的数据表明，NPC2 病的呼吸窘迫与肺泡巨噬细胞中正常 NPC2 蛋白表达的丧失以及富含胆固醇的功能失调的表面活性剂的积累有关。
