Niemann-Pick Disease

Author: Amelia Garofalo
Date: 19/07/2011


Types A and B NPD (Niemann-Pick Disease) are caused by recessive mutations in gene encoding ASM.
Type A NPD is the infantile form of ASM deficiency, characterized by a rapidly progressive neurodegenerative course that leads to death by age 2–3. In contrast, Type B NPD is the later-onset form in which patients exhibit little or no neurological symptoms, but may have severe and progressive visceral organ abnormalities, including hepatosplenomegaly, pulmonary insufficiency and cardiovascular disease. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)

The most consistent laboratory finding is a highly atherogenic lipid profile (i.e. high triglycerides
and LDL-cholesterol; low HDL-cholesterol), and a history of coronary artery disease may be found (Lee et al 2003;McGovernetal 2004). Other clinical findings may include bleeding, headaches, fatigue, gastrointestinal pain and dysfunction, joint pain, and bone fractures. (The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann–Pick disease. E. H. Schuchman. J Inherit Metab Dis)

The different clinical presentations of Types A and B NPD are likely due to small differences in the amount of residual, functional ASM activity. The first patient with NPD (Type A) was described in 1914 by the German pediatrician, Albert Niemann, and by the 1930s the primary lipid accumulating in these individuals was identified as sphingomyelin. It is now known that secondary to sphingomyelin storage, other lipids, including cholesterol and gangliosides, also accumulate in these patients, leading to many cellular abnormalities. ASM is also important in membrane formation and function suggests that defective function of the enzyme at the cell surface also could contribute to the pathophysiology of NPD as well.

Because of the low incidence of the disease and therefore of the few human cases to study, ASMKO mice were created to further understand the biology of this disease.
Brain, lung, heart, gonads, and skin are the organs most affected by the disease and on which we have more information about the effects of the disease. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)


Brain tissues and cultured cerebellar granule neurons from ASMKO mice, had increased gangliosides, mainly GM2 and GM3. Gangliosides have diverse and important functions in the brain, and changes in these lipids were not intuitively expected as a result of ASM deficiency. It was also observed a reduction in fluidity of specific membrane areas due to the accumulation of sphingolipids, and provided some of the first direct evidence that ASM deficiency alters the lipid composition of the plasma membrane.
Another feature of the ASMKO mice is that following activation of the ATP receptor P2X7, microparticle shedding and IL-1beta release from microglia was markedly reduced as compared to normal mice. This finding, which has been shown to occur also in PNS, is important in case of inflammation followed damage to a peripheral nerve. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)


By its nature, infection requires a close interaction of pathogens with membranes of the target cell. It has been demonstrated the importance of ASM in this process, in fact ASM inhibition prevented the entry of Neisseria gonorrhoeae into epithelial and phagocytic cells. Interestingly, subsequent studies with Listeria monocytogenes showed that ASMKO mice are 100-fold more sensitive to infection with this bacterium than wild-type mice, presumably because the ASM-deficient macrophages were unable to kill the bacteria and restrict their growth. These latter data suggested a novel function of ASM in infectious biology that directly relates to its role in controlling the fusion of intracellular phagosomes with lysosomes, a process that is inherently dependent on the interaction of vesicle membranes. The involvement of ASM has been shown in infection of other bacteria as well, including Staphylococcus aureus, Salmonella Typhimurium, Escherichia Coli, Mycobacterium and Pseudomonas Aeruginosa. Studies with this latter pathogen have important implications for patients with systemic infections, ventilator-associated pneumonia, and cystic fibrosis. Infection of lung epithelial cells with P. Aeuroginosa normally leads to a rapid activation of ASM that correlates with translocation of the enzyme to the extracellular leaflet of the cell membrane and the site of bacterial infection. The activity of ASM at this site leads to the formation of ceramide-enriched rafts, which are critical for the internalization of P. Aeurginosa into the cells, the induction of cell death, and the gradual release of inflammatory cytokines. Ceramide-enriched membrane domains may regulate internalization of P. Aeurginosa by clustering of the CFTR protein, as it has been shown that internalization of the pathogen can be prevented by disruption of these membrane structures. Compromised host response in ASMKOmice further corroborated the importance of ASM in effective phagocytosis and eradication of pathogens via membrane modulation. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)

Pseudomonas aeruginosa induces surface translocation and clustering of the acid sphingomyelinase at the bacterial infection site.
(Physiological and pathophysiological aspects of ceramide. Pin Lan Li. Am J Physiol Regul Integr Comp Physiol).

Electron microscopy demonstrating similarities between ASMKO mouse and human NPD lungs. Both mouse (A, C, and E) and human (B, D, and F) lungs show type I alveolar cells with cytoplasmic inclusions (A and B), macrophages with lamellar inclusions (C and D), and endothelial cells with large amounts of storage material (E and F). Lungs from mice also show cytoplasmic inclusions within ciliated cells of the bronchi and trachea (A, inset).
(Analysis of the Lung Pathology and Alveolar Macrophage Function in the Acid Sphingomyelinase–Deficient Mouse Model of Niemann-Pick Diseas. Edward H Schuchman. Lab Invest)


It has been known that Types A and B NPD patients have abnormal plasma lipid profiles, characterized by increased levels of LDL-cholesterol and triglycerides, and markedly reduced HDL-cholesterol. However, the precise role of ASM in lipoprotein assembly and metabolism is unclear, as is its role in normal cardiac function. Secreted form of ASM (S-SMase) was present in atherosclerotic lesions and bound to specific components of the subendothelial extracellular matrix. S-SMase could hydrolyze sphingomyelin present in LDL at physiological pH, stimulating subendothelial retention and aggregation. The atherosclerosis relates to remodeling of the lipoproteins in a way that results in a propensity towards interactions with the subendothelial cell membrane. Inhibition of this LDL-membrane interaction could have important implications in the treatment of atherosclerosis. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)


Fertilization, like infection, is inherently dependent on complex membrane interactions, and sperm are known to secrete large amounts of hydrolytic enzymes, including ASM, presumably to reorganize the membrane of the oocyte and facilitate fertilization. Sperm from ASM-KO mice showed elevated levels of sphingomyelin and cholesterol that resulted in morphologic abnormalities such as kinks and bends at the midpiece-principle piece junction, leading to reduced motility.
Flow cytometric analysis revealed that spermatozoa from ASMKO mice had disrupted acrosomal membranes and did not undergo proper capacitation, as assessed by nitric oxide release and bilayer translocation of phosphatidylserine. In addition, these sperm exhibited compromised plasma membranes and mitochondrial membrane depolarization. Notably, spermatozoa from the ASMKO mice regained normal morphology upon incubation in mild detergent, demonstrating that these defects were a direct consequence of membrane lipid accumulation.
More recently, ASM also was found to be an important component of normal oocyte maturation and survival by modulating ceramide signaling, although the direct effect of this enzyme on the oocyte membrane has not been elucidated. There also have been sporadic reports in the NPD literature of reduced fertility among female NPD patients, although the mechanism remains unknown. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)

In the right panel: Nomarski micrographs showing morphological abnormalities in caudal spermatozoa of ASMKO–/– and ASMKO+/– mice at 6 months of age. Spermatozoon tail retroflexion: <90° (arrow 1), 90° (arrow 2), and 180° (arrow 3). Note the presence of both straight and bent sperm in the ASMKO+/– micrograph. In the left panel: Membrane disruption in electron micrographs of ASMKO–/– and ASMKO+/– caudal spermatozoa at 6 months of age. Arrows indicate premature acrosome reaction or plasma membrane disruption. Note two populations of sperm in ASMKO+/– individuals resembling normal and mutant sperm.
(Sperm Abnormalities in Heterozygous Acid Sphingomyelinase Knockout Mice Reveal a Novel Approach for the Prevention of Genetic Diseases. Edward H. Schuchman. American Journal of Pathology)


Ceramide plays a critical function in epidermal barrier homeostasis by constituting an integral component of the extracellular lipid bilayer at the stratum corneum. However, despite the well documented role of ceramide in this process, the precise function of ASM in the generation of epidermal ceramide has not been studied in great detail. It has been showed that a subset of NPD patients with severe ASM deficiency demonstrated abnormal permeability barrier homeostasis, presumably due to an abnormally low ceramide content. (Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. Edward H. Schuchman. Elsevier)


During the past two decades substantial advances have been made in our understanding of ASM-deficient NPD, leading to improved methods to diagnose and potentially treat this debilitating disorder. Many mutations causing the disease have been identified and this led to the first genotype–phenotype correlations and the potential of DNA-based screening in certain populations. The development of a mouse model have provided new and important insights into the pathogenesis of ASM deficiency, and revealed the novel role of this enzyme in ceramide-mediated signal transduction. The mouse models have also permitted the evaluation of various therapeutic approaches, including Enzyme Replacement Therapy (ERT), gene therapy, and stem cell transplantation, furthermore several new approaches are under evaluation.

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