The Niemann-Pick diseases

Two distinct metabolic disorders are included under the eponym “Niemann-Pick disease (NPD).” The first is due to the deficient activity of the lysosomal enzyme acid sphingomyelinase (ASM). Patients with this disorder [also referred to as ASM-deficient (ASMD) NPD] are broadly classified as having types A, A/B, and B NPD depending on their degree of neurologic involvement. Type A NPD patients, also known as the infantile neurovisceral form, exhibit hepatosplenomegaly in infancy and profound central nervous system (CNS) involvement. They rarely survive beyond 2-3 years of age. Type B patients, also known as the chronic visceral form, have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and many may survive into adulthood. Patients with phenotypes intermediate between types A and B NPD (type A/B), known as the chronic neurovisceral form, also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second NPD category have been historically designated as having types C and D NPD. These individuals generally have less hepatosplenomegaly than those with ASMD, but the CNS is profoundly affected. Impaired intracellular trafficking of cholesterol causes types C and D NPD, and two distinct gene defects have been found (NPC1 and NPC2 genes, encoding the NPC1 and NPC2/HE1 proteins, respectively). All type D patients originate from a common Nova Scotian ancestry. Enzyme replacement therapy (Xenpozyme) is available throughout the world for the treatment of the nonneurological features of ASMD, while one approved substrate reduction therapy (Zavesca) in available for type C NPD in the EU and some other countries.