Sphingomyelinase deficiency (type A Niemann-Pick disease)

Alternative names

Niemann-Pick disease is caused by specific genetic mutations. The four forms of Niemann-Pick Disease are all characterized by an accumulation of sphingomyelin and cholesterol in cells, particularly in the cells of major organs, such as the liver and the spleen. The three most commonly recognized forms of the disease are types A, B, and C.

Causes, incidence, and risk factors

All forms of Niemann-Pick are genetic diseases inherited in an autosomal recessive manner.

Types A and B Niemann-Pick are both caused by deficiency of a specific enzyme, acid sphingomyelinase (ASM). If ASM is absent or not functioning properly, sphingomyelin cannot be broken down (metabolized) properly and accumulates within the cells, eventually causing cell death and the malfunction of major organ systems.

Type C Niemann-Pick is very different. Patients with type C are not able to break down cholesterol and other lipids (fats) properly. Consequently, excessive amounts of cholesterol accumulate in the liver and spleen and excessive amounts of other lipids accumulate in the brain. This defect in metabolism occasionally leads to reduced ASM activity in some cells.

Type C Niemann-Pick disease has been reported in all ethnic groups but it is most prevalent among Puerto Ricans of Spanish descent.

Type D Niemann-Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now thought to be a variant of type C. Geneological research indicates that Joseph Muise (c. 1679 - 1729) and Marie Amirault (1684 - c. 1735) are common ancestors to all people with type D. This couple is the most likely origin for the type D variant.

Based on tissue and chemical changes similar to type C, but with very late adult onset, a type E Niemann-Pick has also been suggested.

Pick’s disease is sometimes confused with Niemann-Pick but it is a different disease.


Type A Niemann-Pick begins in the first few months of life. Symptoms may include:

  • Feeding difficulties  
  • A large abdomen within 3 to 6 months  
  • Progressive loss of early motor skills  
  • Cherry red spot in the eye

Type B is biochemically similar to type A, but the symptoms are more variable. Abdominal enlargement may be detected in early childhood, but there is almost no neurological involvement, such as loss of motor skills. Some patients may develop repeated respiratory infections.

Type C Niemann-Pick usually affects children of school age, but the disease may strike at any time from early infancy to adulthood. Symptoms may include:

  • Jaundice at (or shortly after) birth  
  • An Enlarged spleen and/or liver  
  • Difficulty with upward and downward eye movements (Vertical Supranuclear Gaze Palsy)  
  • Unsteadiness of gait, clumsiness, problems in walking (ataxia)  
  • Difficulty in posturing of limbs (dystonia)  
  • Slurred, irregular speech (dysarthria)  
  • Learning difficulties and progressive intellectual decline (Dementia)  
  • Sudden loss of muscle tone which may lead to falls (cataplexy)  
  • Tremors accompanying movement and, in some cases, seizures

Symptoms of all forms of Niemann-Pick are variable - no single symptom should be used to include or exclude Niemann-Pick as a diagnosis. A person in the early stages of the disease may exhibit only a few of the symptoms. Even in the later stages of the disease, not all symptoms may be present.

In addition, symptoms are progressive but the rate of progression is different from person to person. Finally, the symptoms of Niemann-Pick are also found in other, more common, diseases. These factors make it difficult to diagnose Niemann-Pick without appropriate testing.

Signs and tests

Type A and B Niemann-Pick are diagnosed by measuring the ASM (acid sphingomyelinase) activity in white blood cells. The test can be performed after taking a small blood sample. This test can identify those with the disease, but not those who may be carriers.

It is, however, possible to diagnose types A and B carriers by DNA testing because the gene containing the blueprint for ASM has been cloned and many of its mutations identified.

Type C Niemann-Pick is initially diagnosed by taking a skin biopsy, growing the cells in the laboratory, and then studying their ability to transport and store cholesterol. It is important that tests for both transport and storage be performed. Genetic testing is feasible following the discovery of two genes that cause Niemann-Pick type C disease.

Additional tests might include:

  • Slit-lamp eye exam  
  • Liver biopsy or bone marrow aspiration looking for foamy histiocytes that have a mulberry appearance (a particular type of cell with a characteristic appearance)  
  • Liver biopsy (usually not necessary)  
  • Sphingomyelinase assays


For Types A and B Niemann-Pick, the ASM gene has been isolated and extensively studied. DNA testing and prenatal diagnosis is currently available.

Research into treatments for types A and B has progressed rapidly since the early 1990s. Mount Sinai School of Medicine is conducting research on bone marrow transplantation, enzyme replacement therapy, and gene therapy. All of these therapies have had some success against type B Niemann-Pick in a laboratory environment. Unfortunately, none of the potential therapies has been effective against type A.

No specific treatment is available for type C Niemann-Pick. A healthy, low-cholesterol diet is recommended, although research into low-cholesterol diets and cholesterol-lowering drugs does not indicate that these halt the progress of the disease or change cholesterol metabolism at the cellular level. Additionally, many type C symptoms, such as cataplexy and seizures, can be controlled or tempered by drugs.

The National Niemann-Pick Disease Foundation website has more in-depth reporting on the research into potential treatments.

Support Groups
The National Niemann-Pick Disease Foundation, 877-287-3672

Expectations (prognosis)

Although types A and B are both caused by the same enzymatic deficiency, the clinical prognosis for these two groups of patients is very different.

Type A Niemann-Pick is a severe neurologic disease, which generally leads to death by 2 to 3 years of age. In contrast, patients with type B generally have little or no neurologic involvement and may survive into late childhood or adulthood.

The underlying reason for this dramatic difference in the two forms of the disease is not really understood, and, at present, it is not possible to accurately predict the severity of the disease by enzyme testing.

A child showing signs of type C before 1 year of age may not live to school age. Children showing symptoms after entering school may live into their mid to late teens, with few surviving into their 20s.


  • Damage to the brain with varying degrees of mental retardation and delayed development of physical skills  
  • Blindness  
  • Deafness  
  • Progressive deterioration in conditon (this is a fatal disorder)

Calling your health care provider

Call for an appointment with your health care provider and genetic counselor if you have a family history of this disorder and you plan to have children. Consider calling your health care provider if your child has feeding problems, does not seem to be developing properly, or is not gaining weight properly.


All types of Niemann-Pick are autosomal recessive. This means that both parents are carriers - they each carry one copy of the abnormal gene without having any signs of the disease themselves.

When both parents are carriers, there is a 25% chance that their child will have the disease and a 50% chance that a child will be a carrier.

Carrier detection testing for all families is not yet reliable. The mutations for types A and B have been extensively studied, particularly among the Ashkenazi Jewish population, and DNA tests for these forms of Niemann-Pick are available.

Mutations have been identified in the DNA of many patients with type C Niemann-Pick disease - carrier detection may be possible. Diagnosis in the fetus is available in a limited number of centers. Carrier detection is possible for other families only after their specific mutation is identified.

Johns Hopkins patient information

Last revised: December 3, 2012
by Levon Ter-Markosyan, D.M.D.

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