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Niemann-Pick disease (NPD) is a group of diseases passed down through families (inherited) in which fatty substances called lipids collect in the cells of the spleen, liver, and brain.
There are 3 common forms of the disease: • Type A • Type B • Type C Each type involves different organs. It may or may not involve the nervous system and breathing. Each one can cause different symptoms and may occur at different times throughout life.

Frequency

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.

Genetic Changes

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.

Inheritance Pattern

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.

Other Names for This Condition

• lipid histiocytosis

• neuronal cholesterol lipidosis

• neuronal lipidosis

• sphingomyelin lipidosis sphingomyelinase

Other health conditions may cause similar symptoms. The early stages of the disease may only cause a few symptoms. You may never have all symptoms.

Type A usually begins in the first few months of life. Symptoms may include:

Abdominal (belly area) swelling within 3 - 6 months

Cherry red spot in the eye

Feeding difficulties

Loss of early motor skills (gets worse over time)

Causes

NPD types A and B occur when cells in the body DO NOT have an enzyme called acid sphingomyelinase (ASM). This substance helps break down (metabolize) a fatty substance called sphingomyelin, which is found in every cell in the body. If ASM is missing or does not work properly, sphingomyelin builds up inside cells. This kills your cells and makes it hard for organs to work properly. Type A occurs in all races and ethnicities. It is more common in the Ashkenazi (Eastern European) Jewish population. Type C occurs when the body cannot properly break down cholesterol and other fats (lipids). This leads to too much cholesterol in the liver and spleen and too much of other lipids in the brain. Type C is most common among Puerto Ricans of Spanish descent. Type C1 is a variant of type C. It involves a defect that interferes with how cholesterol moves between brain cells. This type has only been seen in French Canadian people in Yarmouth County, Nova Scotia.

Diagnosis

Diagnosis of Niemann-Pick disease begins with a thorough physical exam, which can show an early warning sign such as an enlarged liver or spleen. Your doctor will also take a detailed medical history and discuss symptoms and family health history. Niemann-Pick disease is rare, and its symptoms can be confused with other diseases. Diagnostic techniques depend on the type of Niemann-Pick disease. • Type A or B. Using a blood or skin sample (biopsy), experts measure how much sphingomyelinase is in white blood cells to confirm the diagnosis. • Type C. Experts take a small sample of skin to test for Niemann-Pick to assess how the cells move and store cholesterol. Other tests also may be done, such as: • Magnetic resonance imaging (MRI). An MRI of the brain may show loss of brain cells. But in the early stages of Niemann-Pick, an MRI may be normal because symptoms typically occur before the loss of brain cells. • Eye exam. An eye exam can show signs that may be an indication of Niemann-Pick disease, such as eye movement difficulties. • Genetic testing. DNA testing of a blood sample may show the specific abnormal genes that cause Niemann-Pick types A, B and C. DNA tests can show who the carriers are for all types of Niemann-Pick disease if the mutations have been described in the first person identified in a family (the index case). • Prenatal testing. Ultrasound can detect the enlarged liver and spleen that's caused by type C. And amniocentesis or chorionic villus sampling may be used to confirm a diagnosis of Niemann-Pick.

Treatment

No specific treatment is known for type A, but symptoms are treated. In adult patients with type B, physicians try to keep cholesterol levels down to normal levels. If statins are used, they monitor liver function. If the spleen is enlarged and platelet levels low, acute episodes of bleeding may require transfusions of blood products. If they have symptoms of interstitial lung disease, they may need oxygen. Anecdotally, organ transplant has been attempted with limited success. Future prospects include enzyme replacement and gene therapy. Bone marrow transplant has been tried for type B. In January 2009, Actelion announced the drug miglustat (Zavesca) had been approved in the European Union for the treatment of progressive neurological manifestations in adult patients and pediatric patients with NPC. The drug is available to patients in the United States on an experimental basis. In March 2010, the FDA requested additional preclinical and clinical information regarding Zavesca from Actelion before making a final decision on approving the drug in the United States for NPC.