Clinical Information

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

NPA and NPB, also known as acid sphingomyelinase deficiency, result in extensive storage of sphingomyelin and cholesterol in the liver, spleen, lungs, and may also affect the brain. NPA disease is more severe than NPB, and it is characterized by early onset with feeding problems, dystrophy, persistent jaundice, development of hepatosplenomegaly, neurological deterioration, deafness, and blindness leading to death by 3 years of age. NPB disease is limited to visceral symptoms, such as hepatosplenomegaly, with survival into adulthood. Some patients have been described with intermediary clinical phenotypes. Large, lipid-laden foam cells are characteristic of the disease. Approximately 50% of patient with this condition have cherry-red spots in the macula.

The combined prevalence of NPA and NPB is estimated to be 1 in 250,000 individuals. NPA and NPB are inherited in an autosomal recessive manner and are caused by biallelic disease-causing variants in the SMPD1 gene. Although there is a higher frequency of type A among the Ashkenazi Jewish population, both types are panethnic. Individuals with NPA and NPB typically have elevations of lyso-sphingomyelin (LSM) and LSM 509 combined with potential elevations in cholestane-3 beta, 5 alpha, 6 beta-triol (COT) or 7-ketocholesterol (7-KC). Molecular genetic testing for NPA and NPB disease is also available (see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify gene list ID: IEMCP-W6S9XD).

NPC is caused by a defect in cellular cholesterol trafficking that results in the progressive accumulation of unesterified cholesterol in late endosomes/lysosomes.(2) NPC is considered a lipid storage disorder with variable age of onset, from the neonatal period to adulthood, and highly variable clinical presentation. Most individuals are diagnosed during childhood with symptoms that include ataxia, vertical supranuclear gaze palsy, dystonia, progressive speech deterioration, and seizures. 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 to 150,000 live births. NPC is an autosomal recessive condition and is caused by variants in either the NPC1 or NPC2 genes. Most individuals with NPC exhibit elevated levels of oxysterol COT in dried blood spots, however, testing in plasma (OXNP / Oxysterols, Plasma) is more sensitive, particularly in patients with an atypical presentation. Elevations may also be seen in LSM 509 and 7-KC. The diagnosis of NPC can be confirmed by demonstration of impaired cholesterol esterification and positive filipin staining in cultured fibroblasts (NIEM / Niemann-Pick Type C Detection, Fibroblasts) or by molecular genetic analysis of the NPC1 and NPC2 genes (see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify gene list ID: IEMCP-H683JG).