Clinical Information

Niemann-Pick disease types A, B, and C are a group of autosomal recessive lysosomal storage disorders affecting metabolism of specific lipids within cells.

Niemann-Pick types A and B (NPA and NPB, OMIM 257200 and 607616) are caused by a deficiency of sphingomyelinase resulting in extensive storage of sphingomyelin and cholesterol in the liver, spleen, lungs, and, to a lesser degree, brain. Classification of NPA or NPB is based on the age of onset as well as the severity of symptoms. NPA disease is more severe and characterized by early onset with feeding problems, dystrophy, persistent jaundice, cherry red maculae, development of hepatosplenomegaly, neurological deterioration, deafness, and blindness. Individuals with NPA typically die by age 3. NPB disease is limited to visceral symptoms with survival into adulthood. Some patients have been described with intermediary phenotypes. Characteristic of the disease are large lipid-laden foam cells on bone marrow biopsy.

The combined prevalence of NPA and NPB is estimated to be 1 in 250,000. NPA and NPB are inherited in an autosomal recessive manner and are caused by mutations in the SMPD1 gene. Although there is a higher frequency of type A among the Ashkenazi Jewish population, both types are pan-ethnic.

Individuals with NPD types A and B typically have elevation of the oxysterol lyso-sphingomyelin (LSM); cholestane-3 beta, 5 alpha, 6 beta-triol (COT), and/or 7-ketocholesterol (7-KC) may also be elevated.

Molecular genetic testing for NPA and NPB disease is also available (see NPABZ / Niemann-Pick Disease, Types A and B, Full Gene Analysis).

Niemann-Pick disease type C (NPC, OMIM 257220) is caused by a defect in cellular cholesterol trafficking that results in the accumulation of unesterified cholesterol in late endosomes/lysosomes. Age of onset is variable and ranges from the perinatal period to adulthood, and clinical presentation is also highly variable. Most individuals are diagnosed during childhood with symptoms including ataxia, vertical supranuclear gaze palsy, dystonia, progressive speech deterioration, and seizures resulting in death by the second or third decade of life. Infants may present with or without hepatosplenomegaly and respiratory failure. Those without liver and pulmonary disease may present with hypotonia and developmental delay. Adult-onset NPC is associated with a slower progression and is characterized by psychiatric illness, ataxia, dystonia, and speech difficulties.

The incidence of NPC is approximately 1 in 120,000-150,000 live births. NPC is an autosomal recessive condition and is caused by mutations in either the NPC1 or NPC2 genes. Individuals with NPC exhibit elevated levels of oxysterol cholestane-3 beta, 5 alpha, 6 beta-triol (COT); 7-ketocholesterol (7-KC) may also be elevated. For molecular confirmation, genetic testing for NPC disease can be performed (see NPCZ / Niemann-Pick Type C Disease, Full Gene Analysis).