What is Niemann-Pick Disease?

A lysosomal storage disease leading to cell death and tissue and organ damage

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Niemann-Pick disease is an inherited lysosomal storage disease that affects many different tissues and organs. The symptoms, severity, age of disease onset and expected lifespan vary between individuals.

What are the Symptoms of Niemann-Pick Disease?

Niemann-Pick disease affects many body systems and is divided into four main types based on the genetic cause and the signs and symptoms of the disease. This Jewish disease panel tests for the mutations associated with Niemann-Pick type A and Niemann-Pick type B. While both types A and B are pan-ethnic, more cases of type A are reported among individuals of Ashkenazi Jewish descent.

The first symptoms of Niemann-Pick type A usually occur by the age of three months when babies develop an enlarged liver and spleen (hepatosplenomegaly) and fail to gain weight and grow at expected rates. Aside from these complications, affected infants continue to develop at the normal rate until one year of age. However, health deterioration rapidly occurs from one year onward. They suffer from a progressive loss of mental abilities and movement (psychomotor regression), swollen lymph nodes, a cherry-red spot eye abnormality, difficulty feeding, poor muscle tone, and widespread lung disease that causes recurrent lung infections, resulting in respiratory failure. Niemann-Pick type A is a severe, neurodegenerative disease and affected children generally do not survive past the age of three years.

Niemann-Pick type B patients show little or no involvement of the central nervous systems, therefore do not experience the typical neurodegeneration seen in Niemann-Pick type A patients. Symptoms usually appear in mid-childhood and are less severe than Niemann-Pick type A. These patients have hepatosplenomegaly, recurrent lung infections, thrombocytopenia (low platelet count), slower growth (resulting in a short stature) and slower mineralization of bone (leading to osteoporosis or osteopenia in adulthood). Some patients have poor coordination, mental retardation and other psychiatric disorders. Only about one third of affected individuals will show the cherry-red spot eye abnormality and most individuals survive into adulthood.

The remaining two subtypes (Niemann-Pick type C1 and C2) are not as common in people of Jewish heritage and are not tested for in this Jewish disease panel. Types C1 and C2 are biochemically, genetically and clinically distinct from types A and B. Patients may show a wide range of symptoms, including hepatosplenomegaly and progressive neurological disease. If disease symptoms first appear in infants or young children, the disease progression tends to be rapid and fatal within the first few years. However, if symptoms do not appear until adolescence or adulthood, the disease progression is generally slower and affected individuals may often have a near-normal life expectancy.

What Causes Niemann-Pick Disease?

Niemann-Pick disease type A and type B are caused by mutations in the SMPD1 gene. SMPD1 encodes an enzyme called acid sphingomyelinase (ASM), an enzyme found in the lysosomes, which are compartments within the cell that break down and recycle different types of molecules. ASM converts fat (lipids) called sphingomyelin into another type of lipid called ceramide. Mutations in SMPD1 lead to lower levels of ASM, causing fat to accumulate in cells. This accumulation of fat results in cell death, impairing the function of tissues and organs, including the brain, lungs, spleen and liver.

Mutations that cause type A often result in the complete loss of ASM activity, whereas mutations causing type B usually still retain some enzyme activity. The Jewish disease panel tests for four mutations in SMPD1 commonly known as R496L, L302P, fsp330 and delta608. The delta608 mutation causes Niemann-Pick disease type B and the three other mutations, (R496L, fsp330 and L302P), account for over 90% of the Niemann-Pick type A cases seen in Ashkenazi Jewish individuals. These four mutations may also be referred to by the DNA nucleotide change or protein amino acid change based on HGVS nomenclature, as shown in the table below.

Common Name DNA Nucleotide Change Protein Amino Acid Change (HGVS Nomenclature)


c.1493G>T p.Arg498Leu




c.911T>C p.Leu304Pro




c.996delC p.Phe333SerfsTer52




c.1828_1830del p.Arg610del


How is Niemann-Pick Disease Diagnosed?

Diagnosis of Niemann-Pick disease types A and B involves a blood or bone marrow test to measure ASM activity levels in white blood cells, and molecular genetic testing to identify mutations in SMPD1.

People with Niemann-Pick type A have little or no ASM activity (less than 1% enzyme compared to normal individuals) while people with type B will have about 10% of the normal levels. However, this test alone is not sufficient to distinguish between type A and type B forms of the disease, because there are intermediate variants. This test is also not able to identify carriers (with only one defective copy of SMPD1), since they will have normal ASM levels.

Molecular genetic testing of the SMPD1 gene allows carrier identification, as well as distinguishing between types A and B. Three mutations in SMPD1 (L302P, R496L and fsp330) account for more than 90% of the Niemann-Pick type A cases in Ashkenazi Jews. The delta608 mutation is the most common cause of Niemann-Pick type B. Targeted analysis for these mutations can be used to identify the majority of Jewish cases of Niemann-Pick disease type A and type B. In the absence of these four mutations, sequence analysis of SMPD1 can be performed to identify other mutations that have been linked to Niemann-Pick disease type A and B.

How is Niemann-Pick Disease Treated?

There is no cure for Niemann-Pick disease and currently there are no treatment options available for Niemann-Pick disease type A. Supportive treatment to manage the symptoms associated with type A requires a care team that involves a cardiologist, liver and spleen specialist, nutritionist, a pulmonologist, a physical therapist and a gastroenterologist. Physical and occupational therapy is provided to maximize function. Feeding difficulties may require nasogastric tube feeding or surgical placement of a feeding tube, and sometimes sedatives may be required to provide adequate sleep.

For Niemann-Pick disease type B, stem cell transplantations have been successful in some cases. Infants and children with type B disease require frequent meals to promote growth because many patient experience early satiety due to splenomegaly (abnormal enlargement of the spleen and the liver). Adult patients with elevated cholesterol levels should be treated to bring cholesterol levels to normal, and liver function should be closely monitored if statins are required to lower cholesterol levels. Supplementary oxygen may be used for patients with lung disease, and blood transfusions may be necessary to treat episodes of bleeding secondary to hypersplenism and thrombocytopenia. Patients with splenomegaly should avoid contact sports due to the high risk of spleen rupture. Enzyme replacement therapy, providing recombinant acid sphingomyelinase, is being explored as a treatment option for Niemann-Pick disease type B.

Niemann-Pick disease type B patients should be evaluated at least yearly for growth and weight gain, neurological function, liver enzyme analysis, platelet and cholesterol levels, pulmonary function testing, and skeletal and nutritional assessment.

Recommended Links:
Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.

Ishii H, Takahashi T, Toyono M et al. (2006) Acid sphingomyelinase deficiency: Cardiac dysfunction and characteristic findings of the coronary arteries . J Inh Metab Dis. 29(1): 232-234.

Jones I, He X, Katouzian F, Darroch PI, Schuchman EH. (2008) Characterization of Common SMPD1 Mutations Causing Types A & B Niemann-Pick Disease and Generation of Mutation-Specific Mouse Models. Mol Genet Metabol. 95(3): 152-162.

Wasserstein MP, Schuchman EH. (2006) [Updated 2015 Jun 18]. Acid Sphingomyelinase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.