Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.

细胞中脂质稳态的紊乱会引发人类疾病。潜在机制的阐明和有效疗法的开发代表了生物医学研究的巨大挑战。典型案例是两种罕见的、常染色体隐性遗传且最终致命的溶酶体疾病，历史上将其命名为“尼曼-匹克病”，以纪念医生，他们的开创性观察导致了他们的发现。酸性鞘磷脂酶缺乏症 (ASMD) 和尼曼匹克 C 型疾病 (NPCD) 是由鞘磷脂磷酸二酯酶 1 ( SMPD1 ) 和NPC 细胞内胆固醇转运蛋白 1 ( NPC1 ) 或NPC 细胞内胆固醇转运蛋白 2 ( NPC2 ) 的特定变异引起的) 分别扰乱两个关键膜成分鞘磷脂和胆固醇体内平衡的基因。患有这些疾病的严重形式的患者会出现内脏和神经系统症状，并死于过早死亡。本概要追溯了尼曼-匹克病的曲折发现，强调了在遗传罪魁祸首和细胞机制方面的重要进展，并揭示了改进诊断和探索新治疗方法的努力。