Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age. Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly. Hepatosplenomegaly is usually the first physical sign. Hypotonia and pulmonary infections are common. These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.
The less severe form of Niemann-Pick disease, type B, has a later onset and slower course. Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood. Mutations in the same gene are involved, however.
Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized. The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.
Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration. Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.
