The Niemann-Pick type diseases-A synopsis of inborn errors in sphingolipid and cholesterol metabolism

Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mecha-nisms 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 sphingo-myelinase 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 intra-cellular 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.

Automated summary

Disturbances of lipid homeostasis in cells lead to human diseases, and understanding the mechanisms and developing efficient therapies are major challenges in biomedical research. Acid sphingo-myelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are rare genetic diseases caused by specific gene variants that disrupt the homeostasis of sphingomyelin and cholesterol, respectively. This article traces the discovery of these diseases, highlights advances in genetic culprits and cellular mechanisms, and reveals efforts to improve diagnosis and explore new therapies.