Niemann-Pick disease (NP) is a group of autosomal recessive lysosomal storage disorders of hereditary acid sphingomyelinase deficiency. Lipid storage, including sphingomyelin and cholesterol, is impaired in all subcategories in NP. This results in systemic symptoms (hepatosplenomegaly) and, depending, symptoms of central nervous system dysfunction. There are 4 types of NP, typically organized into 2 subgroups:

• Type A and B
• Type C (C1 and C2)

NP type A (NP-A) and NP type B (NP-B) are rare diseases with an estimated combined prevalence of about 1:250 000 live births. NP-A and NP-B are attributed to mutations in the sphingomyelin phosphodiesterase-1 gene (SMPD1) on chromosome 11p15 leading to deficiencies in acid sphingomyelinase. Hepatosplenomegaly is a characteristic finding in both NP-A and NP-B, often starting in early infancy.

The neuropathic type, NP-A, results in rapid neurologic deterioration and interstitial lung disease from sphingomyelin storage in pulmonary macrophages. It is often fatal by age 2 years. NP-A is most common in Ashkenazi Jews who carry the SMPD1 allele mutation, with an incidence of about 1:100. Macular cherry-red spots are present in all patients with NP-A, although they may be visible at variable ages.

The non-neuropathic NP-B is a less severe phenotype that has equal prevalence across all populations. It is characterized by hepatosplenomegaly, a cherry-red spot of the retina, and later onset with milder neurologic symptoms. Due to its varied severity and age of presentation, NP-B has a widely variable phenotype. Other signs and symptoms include hypersplenism and resulting thrombocytopenia, liver dysfunction, interstitial lung disease, atherogenic lipid profile, and osteopenia with short stature. Neurologic symptoms are rare, mild, and often not progressive in NP-B. Life expectancy is longer, and most of these patients live into adulthood. Late complications are often attributed to progression of lung disease, of liver fibrosis into cirrhosis, and hypersplenism. NP-B is due to an SMPD1 gene mutation with some preservation of gene and enzyme activity (unlike NP-A where there is a complete acid sphingomyelinase deficiency).

The second subgroup of NP disease describes type C (NP-C). NP-C is a rare disease with an estimated prevalence in Europe of 1:100 000. Similar to NP-B, NP-C has variable phenotypes and can present in infancy or adulthood. Systemic symptoms such as ascites, hepatomegaly, and interstitial lung disease will precede neurologic symptoms. Common central nervous system manifestations of NP-C include dementia, seizures, dystonia, dysphagia, dysarthria, ataxia, and vertical supranuclear gaze palsy. Phenotypic variability and delayed age of onset can result in delays in diagnosis. NP-C is attributed to 2 different gene mutations, NPC1 on chromosome 18q11-q12 and NPC2 on chromosome 14q24.3. NPC1 is the predominant gene mutation in NP-C. It is present in 95% of patients with NP-C.