Niemann-Pick disease types C and D.

Patients grouped into categories termed type C Niemann-Pick disease and the Nova Scotia isolate called type D Niemann-Pick disease are characterized by mild to moderate hepatosplenomegaly, sea-blue histiocytes in the bone marrow, supranuclear gaze paresis in the vertical plane, slowly progressing ataxia, and mental deterioration. These signs are caused by abnormal intracellular cholesterol homeostasis. Cholesterol that enters cells from the circulation through the LDL receptor is not processed in a timely, normal manner by cells in parenchymal organs and the CNS. It therefore accumulates in toxic quantities as unesterified cholesterol causing cellular and tissue damage. Knowledge of the primary, consistent disturbance in cholesterol disposition has led to the development of tests to diagnose patients, identify heterozygotes, and assure the prenatal detection of these disorders. Therapeutic strategies include reduction of dietary cholesterol, apheresis techniques designed to reduce LDL cholesterol available to cells, and reduction of formation of LDL and increase of synthesis of HDL to lower cellular uptake of cholesterol and enhance egress of this lipid from intracellular storage sites. The development of procedures that block cholesterol formation but do not up-regulate LDL receptors on plasma cell membranes is considered to be highly important for the therapy of types C and D Niemann-Pick disease.