Niemann-Pick disease is a condition that affects many body systems. It has a wide range of symptoms that vary in severity. Niemann-Pick disease is divided into four main types: type A, type B, type C1, and type C2. These types are classified on the basis of genetic cause and the signs and symptoms of the condition.

Infants with Niemann-Pick disease type A usually develop an enlarged liver and spleen (hepatosplenomegaly) by age 3 months and fail to gain weight and grow at the expected rate (failure to thrive). The affected children develop normally until around age 1 year when they experience a progressive loss of mental abilities and movement (psychomotor regression). Children with Niemann-Pick disease type A also develop widespread lung damage (interstitial lung disease) that can cause recurrent lung infections and eventually lead to respiratory failure. All affected children have an eye abnormality called a cherry-red spot, which can be identified with an eye examination. Children with Niemann-Pick disease type A generally do not survive past early childhood.

Niemann-Pick disease type B usually presents in mid-childhood. The signs and symptoms of this type are similar to type A, but not as severe. People with Niemann-Pick disease type B often have hepatosplenomegaly, recurrent lung infections, and a low number of platelets in the blood (thrombocytopenia). They also have short stature and slowed mineralization of bone (delayed bone age). About one-third of affected individuals have the cherry-red spot eye abnormality or neurological impairment. People with Niemann-Pick disease type B usually survive into adulthood.

The signs and symptoms of Niemann-Pick disease types C1 and C2 are very similar; these types differ only in their genetic cause. Niemann-Pick disease types C1 and C2 usually become apparent in childhood, although signs and symptoms can develop at any time. People with these types usually develop difficulty coordinating movements (ataxia), an inability to move the eyes vertically (vertical supranuclear gaze palsy), poor muscle tone (dystonia), severe liver disease, and interstitial lung disease. Individuals with Niemann-Pick disease types C1 and C2 have problems with speech and swallowing that worsen over time, eventually interfering with feeding. Affected individuals often experience progressive decline in intellectual function and about one-third have seizures. People with these types may survive into adulthood.

Niemann-Pick disease types A and B is caused by mutations in the SMPD1 gene. This gene provides instructions for producing an enzyme called acid sphingomyelinase. This enzyme is found in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Acid sphingomyelinase is responsible for the conversion of a fat (lipid) called sphingomyelin into another type of lipid called ceramide. Mutations in SMPD1 lead to a shortage of acid sphingomyelinase, which results in reduced break down of sphingomyelin, causing this fat to accumulate in cells. This fat buildup causes cells to malfunction and eventually die. Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A and B.

Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease type C. The proteins produced from these genes are involved in the movement of lipids within cells. Mutations in these genes lead to a shortage of functional protein, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells. Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired. The accumulation of lipids as well as the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease types C1 and C2.

Normal Function

The SMPD1 gene provides instructions for making an enzyme called acid sphingomyelinase. This enzyme is found in lysosomes, which are small compartments in the cell that digest and recycle molecules. Acid sphingomyelinase is responsible for the conversion of a fat (lipid) called sphingomyelin into another type of lipid called ceramide. Sphingomyelin also binds (attaches) to a fat called cholesterol and helps to form other lipids that play roles in various cell processes. The formations of these lipids is critical for the normal structure and function of cells and tissues.

Health Conditions Related to Genetic Changes

Niemann-Pick disease

At least 175 mutations in the SMPD1 gene have been found to cause Niemann-Pick disease types A and B. These types of Niemann-Pick disease are characterized by a buildup of fat within cells that leads to lung disease and enlargement of the liver and spleen (hepatosplenomegaly). Type A is more severe and is characterized by severe neurological impairment in early childhood.

SMPD1 gene mutations that cause complete loss of enzyme function tend to cause Niemann-Pick disease type A. In the Ashkenazi (eastern and central European) Jewish population, three mutations are responsible for about 90 percent of all Niemann-Pick disease type A cases. Mutations that lead to the production of an enzyme that retains some activity often cause Niemann-Pick disease type B. A reduction in enzyme activity within cells allows sphingomyelin to accumulate in cells. The accumulation of this lipid causes cells to malfunction and eventually die. Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A and B.

Other Names for This Gene

• acid sphingomyelinase
• ASM
• ASM_HUMAN
• sphingomyelin phosphodiesterase 1, acid lysosomal
• sphingomyelin phosphodiesterase 1, acid lysosomal (acid sphingomyelinase)

Genomic Location

Normal Function

The NPC1 gene provides instructions for making a protein that is located within the membrane of compartments in the cell called lysosomes and endosomes, which digest and recycle materials. While the exact function of this protein is unclear, it plays a role in the movement of cholesterol and other types of fats (lipids) within cells and across cell membranes.

Health Conditions Related to Genetic Changes

Niemann-Pick disease

More than 380 mutations in the NPC1 gene have been found to cause Niemann-Pick disease type C1. This type of Niemann-Pick disease is characterized by a buildup of fat within cells that leads to movement problems, neurological impairment, lung and liver disease, and speech and feeding problems. Many of the NPC1 gene mutations result in a change in a single protein building block (amino acid) in the NPC1 protein. These mutations usually cause a shortage of functional protein, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells. Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired. The accumulation of lipids and the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease type C1.

Other Names for This Gene

• Niemann-Pick disease, type C1
• NPC

Genomic Location

Normal Function

The NPC2 gene provides instructions for making a protein that is located inside lysosomes, which are compartments in the cell that digest and recycle materials. The NPC2 protein attaches (binds) to cholesterol. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods. Research suggests that the NPC2 protein plays an important role in moving cholesterol and certain other fats (lipids) out of the lysosomes to other parts of the cell.

Health Conditions Related to Genetic Changes

Niemann-Pick disease

More than 20 mutations in the NPC2 gene have been found to cause Niemann-Pick disease type C2. This type of Niemann-Pick disease is characterized by a buildup of fat within cells that leads to movement problems, neurological impairment, lung and liver disease, and speech and feeding problems. The NPC2 gene mutations that cause Niemann-Pick disease type C2 reduce or eliminate NPC2 protein activity, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells. Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired. The accumulation of lipids and the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease type C2.

Other Names for This Gene

• epididymal secretory protein
• HE1
• MGC1333
• Niemann-Pick disease, type C2
• NP-C2
• NPC2_HUMAN

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick disease types A and B, occurs when the body cannot break down a compound called sphingomyelin properly.

Signs of ASMD may appear anywhere from early infancy (infantile neurovisceral ASMD, type A) to mid-childhood or even adulthood (chronic visceral ASMD, type B). Some patients have symptoms in the nervous system and other organs that starts after infancy (chronic neurovisceral ASMD).

Early signs of the condition may include the following:

• Brain issues
• Large liver and spleen (hepatosplenomegaly)
• Failure to gain weight and grow (failure to thrive)
• Feeding problems
• Loss of developmental skills (developmental delay)
• Lung disease and lung infections
• Unusual eye findings (cherry-red spot)
• Vison and hearing loss

Newborn screening can only identify ASMD (Niemann-Pick types A and B). Newborn screening for ASMD requires collecting a small amount of blood from your baby’s heel. Screening measures how much ASM enzyme is in your baby’s blood. This enzyme is responsible for breaking down sphingomyelin. Babies with a low level of this enzyme might have ASMD.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for ASMD is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies and infants with this condition can have serious health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. Treatment manages the health problems caused by this condition by reducing symptoms.

Treatments may include the following:

• Bone marrow transplant or enzyme replacement therapy (for type B)
• Medications to help cholesterol levels (statins)
• Physical and occupational therapy

Children who receive early and ongoing treatment for ASMD may live longer and have better growth. There is not yet effective treatment for brain issues by ASMD in the infantile neurovisceral and chronic neurovisceral forms of the disease. It is important to talk to your health care provider about how to best care for your baby. Health care providers will develop a plan that is tailored to the needs of each child.

Niemann-Pick disease types A and B is estimated to affect 1 in 250,000 individuals. Niemann-Pick disease type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in the general population. The incidence within the Ashkenazi population is approximately 1 in 40,000 individuals.

Combined, Niemann-Pick disease types C1 and C2 are estimated to affect 1 in 150,000 individuals; however, type C1 is by far the more common type, accounting for 95 percent of cases. The disease occurs more frequently in people of French-Acadian descent in Nova Scotia. In Nova Scotia, a population of affected French-Acadians were previously designated as having Niemann-Pick disease type D, however, it was shown that these individuals have mutations in the gene associated with Niemann-Pick disease type C1.