Niemann: Pick's Disease
Niemann Pick disease consists of a group of genetic disorders in which the common feature is a varying degree of sphingomyelin storage in certain tissues of the body. According to the current classification based on the enzymatic defect underlying these disorders, two main groups are distinguished. The first group, which comprises type A, which is characterized by a severe deficiency in acid sphingomyelinase activity, includes infantile neuronopathic form; and type B, an adult chronic form without neurologic symptoms. In the second heterogeneous group called type C, neuro-visceral involvement is massive and lipid metabolism is affected.
The sphingomyelin that accumulates in the lysosomes of the Niemann-Pick disease cells is thought to arise from the degradation of cells and their organelles since it is a major component of all mammalian cell membranes, the myelin sheath and the erythrocyte stroma. In Niemann-Pick type C, the main lipid accumulated in patients cells is not sphingomyelin but cholesterol, however, there is a close relationship between sphingomyelin metabolism and cholesterol metabolism.
Sphingomyelinase is an acidic lysosomal hydrolase that catalyses the cleavage of sphingomyelin to phosphoryl choline and ceramide. In patients with Pick’s disease its activity is deficient in all lysosome containing tissues. Patients with type A, the infantile form have 0.7% of the normal sphingomyelinase activity with median values in the range of 0-1% , while in patients with adult onset neuronopathic or non-neuronopathic disease the activity range is 0-19% of the normal, with median values in several tissues from 2-8% . This enzyme defect explains the massive deposition of sphingomyelin in tissues of the reticuloendothelial systems. Patients with group A variant store sphingomyelin and other lipids in the brain in elevated amounts consistent with the neuropathic features, while patients with group B form do not appear to store sphingomyelin in nervous tissue. The reason for this significant difference in neurological involvement is not clear, but it may be consistent with the level of residual sphingomyelinase activity. Fibroblasts from normal individuals and patients with Niemann- Picks disease types A and B, synthesize the sphingomyelinase polypeptide having the same molecular mass 110 Kilo Daltons (KDa) and in the same degree of abundance, during further processing the 110 KDa polypeptide is processed to a lower molecular weight 84 KDa. Deficiency of sphingomyelinase is due to intragenic defects. Experiments done so far, suggest that specific defects could be small inframe deletions or additions or point mutations. The differences in clinical course of types A and B suggest that mutations are different. Sphingomyelinase follows the same intracellular targeting and post-translational processes as the majority of the lysosomal hydrolases. However, unlike any other enzyme there are two differently sized...