A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C.

BACKGROUND Niemann-Pick disease, type C (NPC), is a lipid storage disease that may present at any age from fetal life to the seventh decade. Its protean manifestations include hepatic and pulmonary failure, as well as a range of progressive neuropsychiatric phenotypes. Late onset disease has been increasingly recognized as the biochemical diagnosis of NPC has been more widely applied. REVIEW SUMMARY The phenotypes, biochemical, and molecular bases of NPC are reviewed. Indistinguishable phenotypes are produced by mutations in two distinct genes, designated NPC 1 and NPC 2, that play key roles in the intracellular trafficking of lipids. The diagnosis of NPC is challenging as the characteristic vertical supranuclear gaze palsy is difficult to recognize, organomegaly is often absent, and standard biochemical screening studies are usually normal. Definitive diagnosis requires demonstration of the trafficking defect in cultured fibroblasts, supplemented in selected cases by genotyping. Animal studies have shown that inhibition of glycosphingolipid synthesis may delay the onset of disease and prolong survival; a human trial of this approach is underway. CONCLUSIONS NPC is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipid storage diseases. NPC should be considered in the differential diagnosis of progressive neurodegenerative disorders at any age. The astute clinician can provide great comfort to families afflicted by NPC by making an accurate diagnosis, notwithstanding the absence of definitive treatment.